- Email: [email protected]
Lipid storage myopathies: Current treatments and future directions
Accepted Manuscript Lipid storage myopathies: Current treatments and future directions
Emily R. Vasiljevski, Matthew A. Summers, David G. Little, Aaron Schindeler PII: DOI: Reference:
S0163-7827(18)30017-1 doi:10.1016/j.plipres.2018.08.001 JPLR 968
To appear in:
Progress in Lipid Research
Received date: Revised date: Accepted date:
4 April 2018 20 June 2018 6 August 2018
Please cite this article as: Emily R. Vasiljevski, Matthew A. Summers, David G. Little, Aaron Schindeler , Lipid storage myopathies: Current treatments and future directions. Jplr (2018), doi:10.1016/j.plipres.2018.08.001
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ACCEPTED MANUSCRIPT Lipid storage myopathies: Current treatments and future directions Emily R Vasiljevski
1,2
, Matthew A Summers
3,4
, David G Little
1. Orthopaedic Research & Biotechnology,
1,2
, Aaron Schindeler
1,2*
The Children’s Hospital at Westmead,
Westmead, NSW, Australia. 2. Discipline of Paediatrics & Child Heath, Faculty of Medicine, University of Sydney,
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Camperdown, NSW, Australia
3. Bone Biology Division, The Garvan Institute of Medical Research, Darlinghurst, NSW
4.
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Sydney, Australia
St Vincent’s Clinical School, University of New South Wales, Faculty of Medicine,
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Sydney, Australia.
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* Corresponding author
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Mailing address:
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Orthopaedic Research & Biotechnology, Research Building The Children's Hospital at Westmead
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Locked Bag 4001
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Westmead, NSW 2145, Australia Phone: +61-2-98451451
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Fax: +61-2-98453078
Email: [email protected]
Conflicts of interest Authors have no conflicts of interest to declare.
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ACCEPTED MANUSCRIPT
ABSTRACT Lipid storage myopathies (LSMs) are a heterogeneous group of genetic disorders that present with abnormal lipid storage in multiple body organs, typically muscle. Patients can clinically present with cardiomyopathy, skeletal muscle weakness, myalgia, and extreme fatigue. An early
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diagnosis is crucial, as some LSMs can be managed by simple nutraceutical supplementation.
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For example, high dosage L-carnitine is an effective intervention for patients with Primary
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Carnitine Deficiency (PCD). This review discusses the clinical features and management practices of PCD as well as Neutral Lipid Storage Disease (NLSD) and Multiple Acyl-CoA
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Dehydrogenase Deficiency (MADD). We provide a detailed summary of current clinical management strategies, highlighting issues of high-risk contraindicated treatments with case
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study examples not previously reviewed. Additionally, we outline current preclinical studies providing disease mechanistic insight. Lastly, we propose that a number of other conditions involving lipid metabolic dysfunction that are not classified as LSMs may share common
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features. These include Neurofibromatosis Type 1 (NF1) and autoimmune myopathies, including
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Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM).
Keywords: Lipid, metabolism, myopathy, diet
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ACCEPTED MANUSCRIPT
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Abbreviations: ABHD5, α/β-Hydrolase Domain-5; AC, adenylate cyclase; anti-ACVR2B, mouse monoclonal activin receptor type IIB; ATGL, adipose triglyceride lipase; BEZ, bezafibrate; CACT, carnitine translocase; CD36, cluster of differentiation 36; CGI-58,
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comparative gene identification-58; CoA, coenzyme A; CoQ10, co-enzyme Q10; CPT I,
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carnitine palmitoyltransferase I; CPT II, carnitine palmitoyltransferase II; DM, dermatomyositis;
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EM, electron microscopy;ETF, electron transfer flavoprotein; ETFDH, electron transfer flavoprotein dehydrogenase; ETF-QO, electron transfer flavoprotein -ubiquinone
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oxidoreductase; FABP4, fatty acid binding protein-4; FACS, fatty acyl-CoA synthetase; FADH2 , flavin adenine dinucleotide; FAT, fatty acid translocase; FATP, fatty acid transport protein; GC-
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MS/MS, gas chromatography - tandem mass spectrometry; HDL-C, high-density lipoproteincholesterol; HSL, hormone sensitive lipase; IBM, inclusion body myositis; IMCL,
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intramyocellular lipid; TCA, tricarboxylic acid; jvs, juvenile visceral steatosis; LSM, lipid storage myopathy; MADD, multiple acyl-CoA dehydrogenase deficiency; MCFA, medium chain
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fatty acids; MCT, medium chain triglycerides; MGL, monoglyceride lipase; MS/MS, tandem mass spectrometry; NADH, nicotinamide adenine dinucleotide; NaHB, sodium-D-L-3-
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hydroxybutyrate; NEFA, non-esterified fatty acid; NF1, neurofibromatosis type 1; NLSD-I, neutral lipid storage disease with ichthyosis; NLSD-M, neutral lipid storage disease with
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myopathy; OCTN2, organic cation/carnitine transporter 2; PCD, primary carnitine deficiency; PKA, protein kinase A; PM, polymyositis; PNPLA2, Patatin-like Phospholipase Domain
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Containing 2; PPAR, peroxisome proliferator-activated receptors; SLC22A5, Solute Carrier Family 22 Member 5; UDCA, ursodeoxycholic acid VHE, valproate hyperammonaemic encephalopathy; VLDL-C, very low-density lipoprotein-cholesterol; ↑, high/elevated; ↓, low/reduced.
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1.
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INTRODUCTION
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Lipid storage myopathies (LSMs) are a group of genetic disorders characterized by excessive and pathological lipid accumulation, chiefly within muscle fibers [1]. There are four classic LSMs with a defined genetic cause: Neutral Lipid Storage Disease with Myopathy (NLSD-M),
and
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Neutral Lipid Storage Disease with Ichthyosis (NLSD-I), Primary Carnitine Deficiency (PCD) Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) [2]. These conditions are
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associated with dysfunction in intracellular triacylglycerol catabolism, mitochondrial fatty acid oxidation, or transport of carnitine, acyl-carnitines, and/or long chain fatty acids [1]. Lipid
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dysmetabolism can cause a range of clinical features, but most commonly encompass a
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progressive myopathy with muscle weakness, myalgia, and fatigue [1]. Triacylglycerols are a broad category of non-polar lipid molecules made up of three fatty acids
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bound to a glycerol backbone. They are the predominant metabolic substrate utilized at rest, during routine activities, and for low to moderate-intensity exercise (30-65% maximal oxygen
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consumption). While most body triacylglycerol (>80%) is derived from sources of dietary fat, endogenous triacylglycerol synthesis occurs primarily in the adipocytes and liver; this is fueled
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by excess available glucose and/or precursors of hepatic gluconeogenesis [3]. In healthy individuals triacylglycerol is primarily stored in subcutaneous and visceral adipose tissue [4]. While minimal, skeletal muscle also contains triacylglycerol stores that can provide energy for muscle activity [5]. These are primarily stored in adipocytes situated between muscle fibers, but can also be present in small, lipid droplets within muscle fibers termed intramyocellular lipid (IMCL) inclusions [5]. Resting tissue IMCL levels can vary in response to environment and energy demand; indeed while increased muscle IMCL is a hallmark of metabolic disease, in elite endurance trained athletes IMCL stores are dramatically elevated as a response to chronic training (termed fat adaptation) [6].
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2.
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OVERVIEW OF FATTY ACID METABOLISM
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In order to contextualize the pathways dysregulated in lipid storage myopathy patients, it is important to define the normal mechanism for the breakdown of fats. In this section we provide a brief overview of the key pathways and enzymatic steps in fatty acid metabolism relevant to lipid
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storage diseases. For an in depth and complete review of metabolic biochemistry we recommend reviews by Zechner, et al, 2012 [7], Longo, et al, 2016 [8], Houten, et al, 2016 [9], and Letts and
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Sazanov, 2017 [10].
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Briefly, triacylglycerol stored in cells are hydrolyzed sequentially into glycerol and fatty acids via lipolytic pathways. Next, the fatty acids are transported across the mitochondrial membrane
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and then broken down by beta-oxidation to generate acetyl-CoA. Finally, within the mitochondria, acetyl-CoA molecules are used to fuel classical aerobic respiration pathways of
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the TCA cycle and the electron transport chain. Many of the key regulatory enzymes and factors
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2.1
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governing these processes are linked to lipid storage myopathies.
Intracellular lipolysis The enzyme adipose triglyceride lipase (ATGL) catalyzes the initial and often rate-limiting step of intracellular lipolysis [11]. This involves the conversion of a triacylglycerol molecule to diacylglycerol, which releases a fatty acid [11]. ATGL is predominately expressed in adipose tissue and to a lesser extent in non-adipose tissue including liver, heart and skeletal muscle [7]. It has been speculated that other neutral lipases may play a role in the initiation of lipolysis in nonadipose tissues [7].
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ACCEPTED MANUSCRIPT Diacylglycerols
are
subsequently
hydrolyzed
by
hormone
sensitive
lipase
(HSL),
to
monoacylglycerols, which are finally hydrolyzed by monoglyceride lipase (MGL) to liberate the final fatty acid [7]. HSL can also hydrolyse triacylglycerols and monoacylglycerols, but with lesser specificity [7]. Lipolysis occurs largely in response to energy demand, and is initiated by the release of
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hormones such as glucagon, epinephrine, and norepinephrine [7, 12]. In adipose tissue, these
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trigger the activation of adenylate cyclase (AC) and subsequently Protein Kinase A (PKA) [12]. PKA phosphorylates Perilipin-1 causing CGI-58 to dissociate from Perilipin 1 and induce ATGL
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activity [12] (Figure 1 A). In non-adipose tissue ATGL and its co-activator CGI-58 are recruited, and directly bind to Perilipin-5 to induce the hydrolysis of triacylglycerol to
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diacylglycerol [13, 14] (Figure 1 B).
2.2
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Fatty acid transport
After fatty acids are released into circulation, they are transported in the blood bound to serum
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albumin, a protein with high-affinity fatty acid binding sites [15]. When the fatty acid-albumin complex reaches the target cell, it is thought that the fatty acid then dissociates to begin the
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cellular uptake process [15, 16]. Several membrane-associated fatty acid binding transport proteins, in particular members of the Fatty Acid Transport Protein (FATP) family, promote the
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uptake of fatty acids into various cell types [17]. FATP rapidly translocate to the plasma membrane in response to insulin, and facilitate fatty acid transport across cellular membranes
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[17]. Additionally, Fatty Acid Translocase (FAT)/CD36 is another key fatty acid transporter at the plasma membrane, which modulates long-chain fatty acid oxidation during times of rapid energy demand [18].
2.3 Carnitine Shuttling of Fatty Acyl-Coenzyme A’s Once transport proteins take up the non-esterified fatty acids (NEFAs), the NEFAs are coupled with Coenzyme A (CoA) to form short-chain (
ACCEPTED MANUSCRIPT C24), or very Long-chain acyl-CoA (>C24), depending on the length of the fatty acid carbon chain [17]. This is catalyzed by a family of intracellular enzymes with different chain-length specificities, known as the Fatty Acyl-CoA Synthetase’s (FACS). This conjugation prevents NEFAs from re-entering the circulation and facilitates their transport across the mitochondrial membrane [17] (Figure 2).
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While short and medium-chain acyl-CoA can passively diffuse across the mitochondrial
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membrane, long-chain and very long-chain acyl-CoA require active transport via the Carnitine Shuttle system [8]. Carnitine Palmitoyltransferase I (CPT I) is a key enzymatic regulator of
acyl-CoAs.
Carnitine
Translocase
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carnitine bioactivity and catalyzes the binding of free carnitine and long chain/very long chain (CACT) then shuttles acylcarnitine across the inner
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mitochondrial membrane. Inside the mitochondrial matrix, the acylcarnitine is separated back into a long chain acyl-CoA and free carnitine by Carnitine Palmitoyltransferase II (CPT II)
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(Figure 2) [8].
The action of CPT I requires sufficient endogenous carnitine to be present [19]. Carnitine can be
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synthesized from lysine and methionine by kidney and liver cells, but this is insufficient and humans require carnitine intake from dietary sources [19]. Free carnitine (unbound to fatty acid
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CoA molecules) is circulated in the blood and is actively transported into tissues by tissuespecific plasma membrane carnitine transporters [20]. These include Organic Cation/Carnitine
2.4
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Beta-Oxidation
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Transporter 2 (OCTN2) (Figure 2) [20].
Beta-oxidation describes the enzymatic removal of carbon molecules from a fatty acid chain, beginning at the beta-carbon. This is catalyzed by a family of acyl-CoA dehydrogenases, which include short-, medium-, long-, and very long- chain acyl-CoA dehydrogenase [9, 21]. There are four enzymatic steps within a cycle, and each cycle liberates a 2-carbon acetyl-CoA molecule. The acetyl-CoA molecules can subsequently be metabolized via the tricarboxylic acid (TCA) cycle (also known as the Krebs or Citric acid cycle). The reduced intermediates, including
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ACCEPTED MANUSCRIPT Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FADH2 ), feed electrons from the 2-carbon acetyl-CoA to the electron transport chain [9] (Figure 3).
2.5 The Electron Transport Chain and Oxidative Phosphorylation
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The mitochondrial electron transport chain is a series of protein complexes that transfer electrons from electron donors, to electron acceptor molecules via a series of biochemical redox reactions
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[10]. Electrons are transferred to ubiquinone through electron acceptors including Electron Transfer Flavoprotein (ETF) and Electron Transfer Flavoprotein - Ubiquinone Oxidoreductase
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(ETF-QO) [22]. The respiratory chain and oxidative phosphorylation are not specific to lipid precursors, as acetyl-CoA is also a product of glucose and amino acid metabolism [23] (Figure
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3).
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LIPID STORAGE MYOPATHIES
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Individuals with LSMs do not produce or produce inadequate amounts of crucial enzymes in the pathways just described. This results in intracellular lipid accumulation, which is associated with
quality of life.
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muscle weakness, myalgia and fatigue; these can have a profound impact on an individual’s
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Today, many lipid storage myopathies are effectively managed, but they are often reliant on an early and accurate diagnosis and can otherwise be lethal. A subset of lipid storage myopathies is still lacking in effective management strategies, and requires further extensive research.
3.1 Neutral lipid storage disease Neutral lipid storage diseases (NLSD) are rare (prevalence unknown with ~50 cases reported in the literature) autosomal recessive disorders of lipolysis. They are clinically heterogeneous;
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ACCEPTED MANUSCRIPT however classically present with myopathy (NLSD-M, OMIM: #610717) and/or ichthyosis (NLSD-I, OMIM: #275630), which is dry, thickened, scaly skin. NLSD is often diagnosed by the presence of lipid inclusions within leukocytes, which is assessed from a peripheral blood smear. These lipid inclusions were first described by Jordans in 1953, and are now commonly
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known as Jordans’ anomaly [24].
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Neutral Lipid Storage Disease with Myopathy (NLSD-M)
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3.1.1
NLSD-M is caused by mutations in the Patatin-like Phospholipase Domain Containing 2
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(PNPLA2) gene [25]. PNPLA2 encodes for Adipose Triglyceride Lipase (ATGL), the enzyme responsible for the first, often rate-limiting step of triacylglycerol hydrolysis. NLSD-M patients
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thus accumulate intracellular triacylglycerol depositions in most tissues, including the liver, and skeletal and cardiac muscle. Multiple mutations in PNPLA2 have been reported, and there is a
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suggestion that disease severity can correlate with specific mutations. For example, nonsense mutations in the C-terminal region often result in a less severe phenotype [26].
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NLSD-M patients present clinically with little to no obesity despite the underlying lipolytic deficiency [25]. They are affected in adulthood, and most commonly present with muscle
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weakness, exercise intolerance, myalgia and/or cardiomyopathy (Table 1). There is great variability in cardiac versus skeletal muscle involvement and severity. For example, the
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cardiomyopathy can be lethal or require a heart transplant to survive, while others exhibit a milder phenotype [27, 28]. Extrinsic factors such as diet and lifestyle are likely to influence
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disease severity and progression, however sex and other genetic factors may also be involved. Additional to Jordans’ anomaly, lipid storage in muscle and mutations in the PNPLA2 gene are also frequently used in diagnosis of NLSD-M (Table 1). There is no curative treatment for NLSD-M, and currently only dietary changes are recommended.
Dietary regimes focused on supplying sufficient carbohydrate for energy
production are the most encouraged (Table 1). This is likely due to one study reporting improvements in maximal oxygen uptake in patients following intravenous glucose delivery [29].
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ACCEPTED MANUSCRIPT A murine model of Pnpla2 deficiency has been developed [30]. Corresponding to the clinical phenotype, Pnpla2 deficient mice are not overly obese and are protected against weight gain on a high-fat diet whilst remaining insulin-sensitive [30-32]. Subsequent studies suggested that this was due to these mice having significantly less adipose tissue [33]. Pnpla2 deficient mouse hearts showed decreased mRNA expression of PPAR𝛼 and PPAR𝛿 target genes including multiple acyl-CoA dehydrogenases, and CPT and essential co-activators [34]. By lipolysis-
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independent PPAR activation using an agonist of PPAR-𝛼 (WY14643), mitochondrial defects
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and lethal cardiomyopathy could be reversed, and prevented premature death suggesting that
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treatment targeting this pathway could be beneficial in a clinical setting [34]. In contrast, a clinical study of triacylglycerol deposits in NLSD-M patients cardiac muscle showed an up
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regulation of PPAR expression [35]. Downstream gene expression of CD36 and Fatty Acid Binding Protein-4 (FABP4) was also markedly increased. It is still unclear whether these
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divergent results should be attributed to species differences [35]. Bezafibrate, a PPAR-𝛼 activator, has been tried in two NLSD-M patients because it is able to induce FATP and FACS
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expression in adipose tissue, subsequently promoting cellular NEFA uptake [36]. Although there was negligible overall clinical benefit, these patients showed a reduction in triacylglycerol
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accumulations in muscle and improved oxidative metabolism [35, 37, 38]. Additional long-term treatment studies are required to determine the therapeutic potential of Bezafibrate.
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Beta-blockers have also been tried in a clinical setting due to a partial rescue of patient myoblasts and fibroblasts reported in the literature [27]. However this was unsuccessful [35, 37]. Enzyme
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replacement therapy could be a potential treatment option, which has been under explored. Successful enzyme therapy has been observed in Fabry disease and Pompe disease [39], and may
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be applicable here.
3.1.2 Neutral Lipid Storage Disease with Ichthyosis (NLSD-I) NLSD-I, also known as Chanarin-Dorfman syndrome, is caused by mutations in the Comparative Gene Identification-58 (CGI-58) also annotated as α/β-Hydrolase Domain-5 (ABHD5) gene [25]. The CGI-58/ABHD5 protein interacts with factors associated with the surface of lipid droplets, including the perilipins, and co-activates ATGL [40, 41]. Some mutant 11
ACCEPTED MANUSCRIPT versions of CGI-58 have been shown to lose the ability to interact with perilipin; they are not recruited to lipid droplets and thus fail to activate ATGL [40, 41]. Patients with NLSD-I show a markedly different clinical phenotype and can be affected earlier in life compared to those with NLSD-M, despite CGI-58 and ATGL functioning in the same biochemical pathway [42]. NLSD-I can feature global developmental delay (including motor
feature
of the
condition
is
ichthyosis,
specifically
non-bullous
congenital
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characteristic
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function and IQ), hepatomegaly and intestinal disease, but not cardiomyopathy. However the
ichthyosiform erythroderma (Table 2). The underlying mechanism is believed to be the
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excessive incorporation of nonpolar lipids into the lamellar membrane. This is followed by the formation of a non-lamellar phase within the stratum corneum interstices (outer skin layer),
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which impairs barrier function [43]. Ichthyosis is not observed in patients with NLSD-M. This suggests an ATGL-independent function of CGI-58 in the skin, and potentially other organs.
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Seasonal fluctuation of ichthyosis have also been observed, leading to speculation that temperature elevation may affect ATGL activity or other lipolytic pathways [44, 45]. Both skin
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and liver biopsies frequently aid in the diagnosis of NLSD-I, as well as genetic sequencing of CGI-58/ABHD5 (Table 2).
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Similar to NLSD-M, there is no curative treatment for NLSD-I. Topical application of ureacontaining emollients, and dietary intervention are the mainstays for clinical treatment (Table 2).
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One of the original case reports for NLSD-I describes treatment with a gluten-free diet, which was reported to ameliorate gastrointestinal symptoms and slightly improve muscle strength [46].
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The patient was initially prescribed prednisone (25-30mg daily/ 1 year), vitamin D (5000 U daily/ 1 year), nystatin, and tetracycline however these had no effect [46]. Despite the beneficial
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response to a gluten-free diet, there have been no other reports involving this type of dietary intervention. A
combination
of high
carbohydrate,
low
fat
diet
supplemented
with medium-chain
triacylglycerols has shown to be a beneficial therapeutic dietary strategy (Table 2). There are several other recent case reports in the literature that outline other dietary interventions, including low fat [47, 48], LCFA-restricted [49] and protein-restricted carbohydrate-rich diets [50], however have no clinical report to treatment effects, and therefore have been excluded from Table 2. This suggests these dietary interventions may have had little therapeutic benefit.
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ACCEPTED MANUSCRIPT It is commonly advised throughout the literature that retinoids including acitretin should be avoided in cases where a NLSD-I patient has disturbed liver function. However, there are three recent reports where patients with impaired liver function have been prescribed acitretin [51-53]. In all cases, the individuals showed improvements in liver function, suggesting a review of clinical retinoid usage could be justified. Although retinoids may not be appropriate for all patients with impaired liver function, they could provide a viable treatment option provided they
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are used with caution and there is careful monitoring.
NLSD-I can be misdiagnosed as Sjogren-Larsson Syndrome, which also presents with ichthyosis
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[54]. Some clinical studies have shown in these patients the severity of itching is reduced with zileuton treatment [55]. This could be beneficial for NLSD-I patients but has yet to be
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investigated.
A Cgi58-/- knockout mouse model was generated in order to investigate the role of Cgi58 in
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triacylglycerol catabolism [56]. The study found Cgi58-/- mice failed to thrive and died within 16 hours after birth, in contrast to heterozygous Cgi58+/- mice, which were comparable to wildtype
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littermates. Cgi58-/- mice featured marked triacylglycerol levels in carcasses, hypoglycemia, hepatic steatosis, and lamellar ichthyosis associated with loss of skin permeability barrier
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function. Glucose injections, increased humidity and Vaseline® application failed to rectify the defects or extend the lifespan [56]. A more recent study in Cgi58-/- mice showed that the lethal
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skin barrier defect could be rescued by promoting Cgi-58 expression in the suprabasal epidermal
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3.2
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layers, a prerequisite for a functional skin permeability barrier [57].
Primary Carnitine Deficiency Primary Carnitine Deficiency (PCD, OMIM: #212140) is an autosomal recessive disorder caused by mutations in the Solute Carrier Family 22 Member 5 (SLC22A5) gene. The SLC22A5 gene encodes for the Organic Cation/Carnitine Transporter 2 (OCTN2) protein. It is responsible for the majority of cellular carnitine uptake, and does so in a sodium-dependent manner. The majority of PCD patient mutations in SLC22A5 have been shown to reduce transporter activity, and transporter activity has been shown to correlate with disease severity [58, 59].
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ACCEPTED MANUSCRIPT The incidence of PCD varies with a frequency of 1:3000-1:120,000 worldwide. It typically presents from early infancy or childhood, and chiefly manifests with liver, skeletal and cardiac muscle
involvement.
Patients
can
experience
episodes
of
hypoketotic
hypoglycemia,
hyperammonemia, hepatomegaly, and hepatic encephalopathy. Additionally, skeletal muscle weakness, impaired motor function, prominent fatigue and cardiomyopathy are also commonly reported (Table 3). Low levels of free and total carnitine indicated by routine biochemistry, or
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tandem mass spectrometry (MS/MS) suggests carnitine deficiency. In Australia, newborns are
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routinely screened for PCD by dried blood spot testing. Additionally, screening for mutations in
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the SLC22A5 gene can confirm a diagnosis (Table 3).
The cardiac and skeletal muscle function of PCD patients is rescued by pharmacological doses of
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carnitine (Table 3). Carnitine supplementation restores carnitine plasma levels, however muscle tissue carnitine concentration reaches only 5-10% of normal [60]. This is due to the persistent
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impairment of the OCTN2 carnitine membrane transporter that limits carnitine uptake in muscle to passive diffusion [61]. Nonetheless, the increases in muscle carnitine are sufficient to regain
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normal physiological function [60, 61]. Additionally, carnitine may act via antioxidant activity [62]. In skeletal muscle, reactive oxygen and nitrogen species are normally synthesised at low
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levels during force production. However, when reactive species accumulation overtakes tissue antioxidant capacity, then oxidative stress activates pathophysiologic signalling leading to
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reduced muscle strength capacity and fatigue [62].
L-carnitine has been shown to protect key
enzymes of the antioxidant defense system from further peroxidative damage [63].
carnitine
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Multiple long-term follow-up studies have been reported to ascertain the efficacy of lifetime supplementation
[64,
65]
showing
it’s
safe
and
effective.
Notably
many
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underdeveloped countries lack newborn genetic screening, which can result in preventable mortalities of young children with PCD [66]. This highlights the importance of both newborn screening and early intervention before irreversible organ damage occurs [67]. Individuals who are heterozygous for SLC22A5 gene are reported to have mildly reduced plasma carnitine levels, and they can progressively develop benign cardiac hypertrophy. It is estimated these asymptomatic PCD individuals may encompass up to 1% of the population. It is unclear whether SLC22A5 heterozygosity leads to an increased risk of cardiomyopathy [68-71].
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ACCEPTED MANUSCRIPT The addition of sodium pivalate to the drinking water of rodents to induce a PCD phenotype is a well-established pre-clinical model. Pivalic acid and carnitine form a pivaloylcarnitine ester; this is excreted to induce carnitine deficiency [72]. This model has proven useful for studying the cardiac manifestations of carnitine deficiency syndromes, including asymptomatic PCD [72]. In the pivalic acid-treated rat model, -adrenergic stimulation of the myocardium resulted in a 50% mortality rate. This was rescued by carnitine supplementation [73]. The heterozygous juvenile
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visceral steatosis (jvs/+) mouse is an alternative genetic rodent model of asymptomatic PCD [74]. The jvs/+ mice are prone to cardiomyopathy and heart failure when challenged by
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surgically induced pressure overload on the heart [75]. These models justify further clinical research into the cardiac risks associated with asymptomatic PCD, and whether these individuals
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may benefit from prophylactic carnitine treatment.
3.2.1
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HIGH RISK: Pivalic acid containing antibiotics are contraindicated for PCD patients The death of five adults with PCD has recently been attributed to the consumption of antibiotics
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containing pivalic acid, a chemical that depletes carnitine by esterification [76]. These cases were reported in the Faroe Islands, an archipelago in the North Atlantic Ocean with the highest
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reported frequency of PCD worldwide (1:3000). Additionally, a recent case report associated pivalic acid containing antibiotics with an extremely severe hospital course for another patient
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[77]. Pivalic acid is commonly used to increase oral bioavailability of antibiotics, including pivampicillin and pivmecillinam. Current studies are estimating the prior mortality associated
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with pivalic acid in PCD patients, as well as determining the risk associated with these drugs in asymptomatic heterozygous individuals. As PCD is not widely recognized as a contraindication for prescription of antibiotics containing pivalic acid, this may continue to cause preventable deaths [76]. The following is a list of available pivalic acid containing antibiotics that should be avoided in suspected or diagnosed PCD individuals: Cefditoren pivoxil, cefcapene pivoxil, cefteram pivoxil, pivmecillinam and pivampicillin.
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ACCEPTED MANUSCRIPT 3.3 Multiple Acyl-Coenzyme A Dehydrogenase Deficiency (MADD) Multiple Acyl-Coenzyme A Dehydrogenase Deficiency (MADD, OMIM: #231680), also known as Glutaric Acidemia Type II, is an autosomal recessive genetic disorder caused predominately by mutations in the Electron Transfer Flavoprotein (ETFA, ETFB) or Electron
Electron Transfer Flavoprotein-Ubiquinone
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of Electron Transfer Flavoprotein (ETF) and
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Transfer Flavoprotein Dehydrogenase (ETFDH) genes. These genes encode the α and β subunits
Oxidoreductase (ETF-QO) respectively. Disruption of ETF and ETF-QO function impairs the
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transfer of electrons received from acyl-CoA dehydrogenases, compromising the β-oxidation of fatty acids [78].
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MADD has a clinically heterogeneous phenotype, but is classically characterized based on age at presentation. There are two types of neonatal-onset MADD, with (type I) or without (type II)
hepatomegaly,
non-ketotic
hypoglycemia,
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congenital anomalies. Neonatal-onset MADD is severe and often lethal, and can feature metabolic
acidosis,
hypotonia,
and
sometimes
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cardiomyopathy [79, 80]. Adult-onset MADD predominantly features muscle-related symptoms, including weakness, fatigue, and myalgia (Table 4). Excessive lipid build-up has been observed
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in muscle biopsies of patients with both neonatal and adult onset types [81, 82], which aids in diagnosis. Elevated urine organic acids, including glutaric acid, and acyl carnitines are also
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characteristic diagnostics. Finally, most cases report mutations in the three “classical” MADD genes (ETFA, ETFB and ETFDH), which confirm diagnosis. If a mutation cannot be identified
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then other genes associated with riboflavin transport, for example SLC52A1, SLC52A2 and SLC52A3, or FAD transport or synthesis, including SLC25A32 and FLAD1 can be investigated
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[83] (Table 4). MADD is associated with a genotype-phenotype correlation, with ETFA and ETFB mutations linked to early onset disease and ETFDH mutations late onset [80, 84, 85]. Most adult-onset patients are responsive to riboflavin supplementation (riboflavin responsive (RR)–MADD), which ameliorates symptoms. Carnitine, CoQ10, and vitamin B12 are also recommended to enhance clinical outcomes (Table 4). However, neonatal-onset MADD (mutations in ETFA and ETFB) is often lethal and cannot be treated [79]. There has been one treatment-outcome case report within the last 8 years detailing a patient with neonatal-onset MADD (confirmed mutation in the ETFA gene). The patient underwent sodium-D-L-3-
16
ACCEPTED MANUSCRIPT hydroxybutyrate (NaHB) therapy, which improved clinical outcome (Table 4). NaHB therapy could be further investigated for treatment of neonatal-onset MADD. MADD has predominately been modeled in vitro using patient fibroblasts and genetically modified mammalian cell lines. Recently, bezafibrate, a fibrate drug commonly used to lower human serum lipid levels, has been tried [86] following promising findings of its application in
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other metabolic diseases [87-89]. Fibrates are known to induce FATP and FACS expression in
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adipose tissue, which promotes cellular NEFA uptake through PPAR activation [36]. In vitro, bezafibrate significantly reduced the levels of palmitoylcarnitine (C16) and octanoylcarnitine
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(C8), suggesting a possible improvement of 𝛽-oxidation capacity [86], which could be translatable. However, there has been one clinical report of bezafibrate treatment within the last 8
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years, and it was only found beneficial when supplemented with riboflavin [90]. Aside from in vitro studies, Zebra fish (Danio rerio) have been found to be a good in vivo model
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of MADD. They feature mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased glycolytic flux and hyperplastic neural progenitor cells [91, 92]. In an
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etfa-null Zebrafish model, increased Mechanistic Target of Rapamycin Complex 1 (mTORC1)
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signalling was treated with rapamycin, and this partially reversed the MADD- phenotype [92]. In an etfdh-null Zebrafish model, it was shown that the PPARγ-ERK pathway was up regulated, and
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a PPARγ agonist partially rescued the model [91]. However, the clinical relevance of these
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studies is yet to be ascertained.
3.3.1
MADD
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HIGH RISK: MADD patients are frequently misdiagnosed with polymyositis. patients
are
often
mistakenly
diagnosed
with polymyositis,
and
treated
with
glucocorticoids. Mistreatment with glucocorticoids was compared with riboflavin in a cohort of 45 patients with late-onset MADD. 18 were initially administered glucocorticoids (1mg/kg/day), and the remaining 27 patients took riboflavin (90-120mg/day) and coenzyme Q10 (60mg/day) for at least one month. Muscle strength was only improved in the riboflavin group [93]. Moreover, glucocorticoids have the potential to increase lipid levels and lipid accumulation,
17
ACCEPTED MANUSCRIPT which would be particularly harmful in these patients. Potential adverse events include metabolic disorder, Cushing syndrome, and gastrointestinal ulcers [94].
3.3.2
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HIGH RISK: MADD patients are particularly sensitive to dietary changes
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Care also needs to be taken when advising MADD deficiency patients on dietary changes. A 2014 case study reported a 33-year old woman who presented with a history of progressive weakness
[78].
The patient was taking citalopram (20mg/day) and
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proximal muscle
hydrocodone/ibuprofen (7.5mg/200mg for pain, however still required hospital admission).
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Gabapentin (300mg 3 times daily) and hydrocodone/ibuprofen were further prescribed. Serum carnitine level was low, and carnitine supplements were given four times a day (1mg).
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Symptoms persisted. A cocktail of carnitine (4mg/twice daily), coenzyme Q10 (150mg twice daily) and riboflavin (100mg twice daily) was then given. However treatment failed to reverse
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symptoms, and respiratory function declined resulting in death. Notably, prior to death the patient revealed deliberate restriction of carbohydrate intake as a means of weight loss [78],
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potentially exacerbating metabolic decline.
These studies highlight the shortfalls that can still occur in the clinical care of MADD deficiency,
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4.
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due to either misdiagnosis or neglecting an appropriate clinical interrogation of dietary practices.
METABOLIC INVOLVEMENT IN CLASSICALLY NON-METABOLIC SYNDROMES In a clinical and genetic analysis study of LSMs only 24% of cases were attributed to mutations in the ‘classic’ LSM genes, including PNPLA2, CGI-58 or ABHD5, SLC22A5, ETF-A, ETF-B and ETF-DH [2]. Thus, we speculate that some LSMs may be associated with genes not previously associated
with metabolic disorders, including Neurofibromatosis type 1 and
autoimmune myopathies.
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4.1 Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 1 (NF1) is a complex, multi-system autosomal dominant genetic disorder affecting ~1:3000 individuals. Individuals with NF1 present with a spectrum of
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characteristic clinical and sub-clinical features including a high tumor burden, skin pigment
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abnormalities, osseous dysplasias, and cognitive abnormalities. While there are many anecdotal
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reports of reduced muscle strength, high fatigability, and decreased motor function in NF1, these have historically been attributed to neuromuscular causes [95]. However, several recent seminal studies have highlighted the prevalence and impact of muscle weakness in well-described
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paediatric cohorts [96] and revealed a biological mechanism using genetic mouse models [97,
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98].
Most notably, murine Nf1 knockout muscle [97] and human NF1 muscle biopsies [99] exhibit
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substantively elevated levels of intramyocellular lipid. A 2018 study has revealed that this is associated with an increase in long-chain fatty acids in a murine model and that the muscle lipid
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phenotype could be rescued by a reduced long-chain fatty acid diet and L-carnitine supplementation [99]. These data suggest that NF1 shares many features of a LSM both in terms
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of muscle function and histology, and may be potentially treated using a targeted metabolic
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4.2
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intervention.
Autoimmune myopathies Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM) are a rare and heterogeneous group of autoimmune myopathies with a combined prevalence of 15-32 cases per 100,000 [100]. These diseases are characterised by muscle weakness and fatigue [101-103]. An abnormal immune response has been implicated by the infiltrations of inflammatory cells in histopathology of muscle biopsies. High levels of serum triacylglycerol, non- high-density lipoprotein-cholesterol (non HDL-C), and very low-density lipoprotein-cholesterol (VLDL-C) are common to PM/DM patients [102, 19
ACCEPTED MANUSCRIPT 103]. Intramyocellular lipid droplets have been observed in PM patient muscle tissue [104]. Similarly, accumulations of free (non-esterified) cholesterol are found in the muscle fibers of patients with IBM [101]. Potential mechanisms for muscle dysfunction and fatigue include impaired fatty acid metabolism and reduced energy bioavailability and/or lipotoxicity. In a clinical setting patients respond poorly to immune therapy [105], despite being the
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traditional approach to autoimmune myopathies treatment. For example, the phase IIb/III multi-
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center international study for Bimagrumab, an anti-ACVR2B monoclonal antibody to improve muscle performance failed to achieve its primary outcome goals [106]. Therefore, a need to
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develop another targeted therapy for autoimmune myopathies is necessary. Triheptanoin oil is a medium odd-chain fatty acid-enriched oil that has been speculated to improve muscle and
is
currently
registered
for
phase
I
US
performance
trial
for
treatment
of IBM
[ACTRN12614000082606]. Statins are potent cholesterol-lowering drugs, which may benefit
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patients with PM/DM/IBM [107]. While they may affect lipid droplet formation, statins have also been associated with muscle pain, weakness and fatigue [108]. It is unknown whether statins
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have a positive or negative affect on muscle in the context of PM/DM/IBM [107]. There are cases of PM/DM, which have been triggered by prior exposure to statin use, and these were
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associated with a more aggressive clinical course [109].
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5. CONCLUSION
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Lipid Storage Myopathies (LSMs) represent a diverse class of metabolic disorders that result in lipid accumulation and impaired muscle function. The underlying causes of disease have been linked to genes associated with triacylglycerol lipolysis, fatty acid transport, and beta-oxidation. Based on the different and often highly effective treatments available for LSM, early and correct diagnosis is imperative. Conditions such as MADD deficiency are associated with a higher than acceptable rate of misdiagnosis, which can result in delays to treatment and high morbidity. For PCD, understanding the risks associated with pivalic acid-containing antibiotics is critical to reduce mortality in this patient population. Finally, conditions such as NF1 and PM/DM/IBM have not been historically classified as LSMs, but exhibit many features common to LSMs. Thus
20
ACCEPTED MANUSCRIPT there may be justification to reevaluate the current classification systems to accommodate these related conditions.
6.
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ACKNOWLEDGEMENT
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We thank Ms Fiona Tea for her assistance with graphical design of the Figures during
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manuscript revision.
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Figure 1: Intracellular lipolysis. A) In adipose tissue, Protein Kinase A (PKA) signaling phosphorylates Perilipin -1, which causes CGI-58 to dissociate from Perilipin-1 and bind to Adipose Triglyceride Lipase (ATGL). ATGL catalyses the initial, rate-limiting step of lipolysis by converting a triglyceride to a diglyceride by releasing a bound fatty acid. Subsequently, diglycerides are hydrolysed by Hormone Sensitive Lipase (HSL) releasing a second fatty acid, and Monoglyceride Lipase (MGL) hydrolyses monoglycerides to liberate the last fatty a cid from the glycerol back bone. B) In non-adipose tissue lipid droplets, ATGL and CGI-58 are recruited by Perilipin-5 to form a complex, and this triggers the sequential hydrolysis of triglycerides to liberate all three fatty acids from the glycerol backbone. The release of free fatty acids into circulation is tightly regulated, and once released into the vasculature the free fatty
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acids are bound to albumin and transported as a complex to target tissue.
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Figure 2: Cellular uptake and the Carnitine Shuttling System. Once the free fatty acid-albumin bound complex reaches the target cell, the free fatty acid is transported across the cellular membrane by a Fatty Acid Transport Proteins (FATP). During times of rapid oxidative demand Fatty Acid Translocase (FAT/CD36) is also involved. Once inside the cytoplasm, it is then processed into a fatty acid acyl CoA molecule by Fatty Acyl-Coenzyme A Synthetase (FACS). The OCTN2 transporter is responsible for cellular uptake of carnitine. Carnitine is used by Carnitine Palmitoyltransferase 1 (CPT I) to synthesize an acylcarnitine molecule, which is shuttled across the inner mitochondrial membrane by Carnitine Translocase (CACT). Finally, acyl carnitine is converted back into carnitine, and a fatty acid acyl-CoA molecule by Carnitine Palmitoyltransferase 2 (CPT II) for beta-oxidation within the mitochondrial matrix.
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Figure 3: Beta oxidation and the Electron Transport Chain. Beta oxidation is the catabolic process by which a fatty acyl-CoA molecule is broken down within the mitochondrial matrix to produce 1) an acetyl CoA molecule that feeds into the Krebs cycle and 2) NADH and FADH 2 which act as reducing agents and transfer electrons across the Electron Transport Chain (ETC) complexes. The initial rate-limiting step of beta oxidation is catalyzed by a class of enzymes, knowns as the Acyl-CoA Dehydrogenases. These enzymes transfer electrons to the electron acceptors Electron Transfer Flavoprotein (ETF) and Electron Trans fer Flavoprotein-Ubiquinone Oxioreductase (ETF-UO). They then transfer the electrons to complex 1, Ubiquinone, of the electron transport chain (ETC). The ETC involves a series of 5 protein complexes, transferring electrons through a series of redox reactions to the ATPSynthase (complex 5) resulting in the phosphorylation of ADP into ATP.
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Table 4: Treatment-outcome case reports of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) patients since 2011
Author/yea r
Patien t
Clinical presentation
Diagnostic testing
Treatment
Transient MADD
Mosegaard, et al 2017 [131]
Newborn, Female
- Lethargy, hypotonia, hyperammonemia, metabolic lactic acidosis and encephalopathy.
- Urine: excretion of lactate, ketones, dicarboxylic acids and traces of glutaric acid
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IP
T
Lipid Storage myopath y
- Riboflavin (200mg/day, 2 divided doses), fat and protein restricted diet, avoidance of fasting, carnitine substitution
Hyperammonemi a and metabolic lactic acidosis did not recur (30 month follow-up).
- Riboflavin (100mg/day slowly lowered to 20mg/day).
- Muscle weakness had completely resolved (22 years follow-up)
40 years of age, Female
- Diffuse myalgia, muscle stiffness, exercise intolerance and progressive weakness.
MADD
Creanza, et al, 2017 [133]
18 years of age, Female
- Preganant
- Riboflavin was discontinued and normal psychometric development pursued.
- PCR analysis: heterozygous intronic c.1134 + 11G>A variation in SLC52A1 - Muscle biopsy: atrophic fibres and lipid storage
- Gene screening: no mutations in ETFA, ETFB or ETFDH.
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Vattemi, et al, 2017 [132]
PT
ED
M
AN
- Newborn screening: ↑ acyl carnitines (C6-C18)
MADD
Clinical outcomes
- Urine organic acids: typical dicarboxylic aciduria.
- Gene analysis: compound heterozygosity in ETFDH c.1074G>C
- ↑ carbohydrate, ↓ fat, six meal diet, and riboflavin (100mg/day), pyridoxine (300mg/day), Lcarnitine (up to 4g/day during third trimester) and protein supplements (up to 30g/day during
- T reatment withdrawal resulted in muscular symptoms, resolved upon riboflavin reintroduction. - Pregnancy progressed and patient gave birth without complications
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Pooja, et al, 2017 [134]
24 years of age, Male
- MS/MS: ↑ medium and long chain acyl carnitines
- Exertion-induced weakness and fatigue
- During delivery and postoperative period carnitine (3g/day) and an isotonic solution (with 10% dextrose) was administered. - Riboflavin (100mg/day), CoQ10 (60mg/day) and carnitine (500mg/day)
IP
MADD
second trimester) throughout pregnancy
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and c.1073G>A in exon 9.
- Dramatic improvement in exercise tolerance (6 month follow up).
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- Urine: ↑ 2-hydroxy glutaric acid, 2hydroxy adipic acid and palmitic acid
6 adults (17-40 years of age, 1 Female and 5 Males)
- Exertional myalgia, and muscle weakness
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Vengalil, et al, 2017 [135]
Fu et al. 2016 [136]
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MADD
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ED
MADD
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- Muscle biopsy: lipid storage
MADD
Behin, et al, 2016 [82]
23 years of age, 68 years of age and 15 years of age, Male
13 Adults (21-55 years of age, 8 Female and 5
- Muscle weakness and exercise intolerance
- Exercise intolerance, myalgia and muscle weakness
- MS/MS: ↑ acylcarnitines and carnitine
- Muscle biopsy: lipid storage
- Initially received a course of oral steroids (for polymyositis) - Riboflavin, CoQ10 and carnitine and restriction of fat intake.
- Gene analysis: 3 compound heterozygous variants of EFTDH including c.892C>T, c.453delA and c.449_453delTAACA ,
- Prednisolone (60 mg per day) (for polymyositis)
- Muscle biopsy: lipid storage
- All treated with L-carnitine, 11 with riboflavin, 4 with CoQ10, 1 with MCT ’s, all on adapted diet
- Proton pump inhibitors (for irritable bowel syndrome)
- No definitive benefits of oral steroids. - All patients reported alleviation of symptoms:fatigue , muscle weakness, dysphagia, myalgia and dropped head syndrome (follow-up period not stated). - Ongoing myalgia and weakness with prednisolone (8 year follow up). - Symptom free with riboflavin (6 month follow up)
- Riboflavin (6090mg/day) and CoQ10 (60mg/day) - Followed up for up to 27 years there was a good response, 11/13 continued to display minor
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6 Adults (33-54 years of age, 1 Female and 5 Male)
- Proximal limb weakness and sensory neuropathy, particularly distal limb numbness
- Muscle biopsy: myofibre size variability and lipid storage
- Riboflavin (60mg/day), carnitine (2g/day) and CoQ10 (100mg/day), vitamin B12 (500ug/day)
- Strength returned (two weeks follow-up)
- Riboflavin (60mg/day), after 3 weeks dropped down to riboflavin (30mg/day), CoQ10 (100mg/day) and vitamin B12 (500ug/day)
- Spine and dropped head completely resolved 93 week follow-up)
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Wang, et al, 2016 [137]
and limited fat intake
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MADD
- Gene analysis: ETFDH mutations including c.250G>A, c.571G>A, c.622G>C, c.877C>G, c.1732C>T, c.79C>T, c.406-2A>G, C.1366C>T, c.877C>G, c.245C>T and c.769T>C.
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Male)
- 2/6 patients reported none to mild alleviation of sensory disturbances (18 month follow-up).
46 years of age, Male
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Peng, et al, 2015 [138]
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MADD
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- Urine: ↑ 2hydroxyglutaric acid, 2hydroxyadipic acid, 3-hydroxypropanoic acid and ethylmalonic acid.
symptoms of exercise intolerance
- Bent spine, dropped head and numbness
- Next gen. seq.: c.242T>C, c.770A>G, c.1227A>C, c.65A>G, c.920C>G and c.1450T>C in ETFDH - Urine: ↑ glutarate, 2-hydroxyglutaric acid, 3hydroxyglutaric acid, glyceric acid and 2-hydroxyadipic acid. - Serum: ↑ acylcarnitines
- Muscle strength improved and mild alleviation of numbness after persistent administration (6 month follow-up)
- Muscle biopsy: lipid storage
- Gene screening: c.770A>G in exon 7, and c.920C>G in
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ACCEPTED MANUSCRIPT exon 8 of EFTDH. 9 years of age, Female
- Muscle weakness, intermittent vomiting and hepatosplenomegal y
- Muscle biopsy: lipid storage
- Riboflavin (100mg/day) and L-carnitine (50mg/kg/day), ↑ calorie ↓ fat diet
- MS/MS: ↑ ethylmalonate, glutarate, 2hydroxyglutaric acid, adipic acid and suberic acid.
- Muscle strength restored (1 month follow-up) - Liver and spleen size normalised (3 month follow-up)
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Zhuo, et al, 2015 [139]
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MADD
24 years of age, Male
- General fatigue, weakness, muscle pain, intermittent nausea and vomiting
- Muscle biopsy: myofibre size variability and lipid storage
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Wen, et al, 2015 [140]
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MADD
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- Gene seq.: compound heterozygous mutations c.389A>T in exon 3 and c.736G>A in exon 7 of EFTDH
CE Ersoy, et al, 2015 [141]
19 years of age, Female
- L-carnitine (2g/day) and Riboflavin (30mg)
- Progressive muscle weakness, dyspnea and hepatomegaly
- MS/MS: and organic acid analysis: ↑ acyl carnitines
- Muscle weakness and exercise intolerance persisted with prednisone (40 day follow-up)
-Muscle weakness mildly improved with carnitine (24 day follow-up)
- Seq. analysis: compound heterozygous mutations c.1211T>C in exon 10 and c. 1450T>C in exon 11 of ETFDH.
AC MADD
- Serum: ↑ acyl carnitines
- Prednisone therapy (60mg/day) (for polymyostitis)
- Exercise intolerance and muscle weakness dramatically improved, and eventually all symptoms resolved (2 year follow-up). - Carnitine (1g), riboflavin (100mg) and CoQ10 (100mg), hemodialysis and physiotherapy
Progressive recovery with the ability to walk and swallow dramatically improving (4
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2.5 years of age, Male
- Progressive muscle weakness, severe metabolic decompensation, hypoglycemia and diffuse leukodystrophy.
- Serum: acylcarnitines and urinary organic acids suggestive of MADD
- Racemic mixture of NaHB (3-4% of daily caloric need)
25 years of age, Female
- Erythematous rash, rhabdomyolysis, and progressive quadriparesis becoming bedbound
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Rosenbohm, et al, 2014 [143]
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PT
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MADD
AN
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- Gene analysis: homozygous mutation c.1106G>C in exon 9 of EFTDH.
- A fat and protein restricted diet and carnitine, riboflavin (100mg/day) and ubiquinone (510mg/kgBW/day) .
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MADD
Shioya, et al, 2014 [90]
31 years of age, Male
- MS/MS: ↑ some long chain acylcarnitines, adipic, suberic, sebacic, 2hydroxyglutaric and ethylmalonic acid
- Motor function improved, mood and behaviour normalized and vocabulary increased. There was some indigestion and dehydration (1 month of NaHB treatment)
- Catch up of development continuing (3 year follow-up) - Riboflavin (200mg/day), CoQ10 (15mg/kg/day), a diet with ↓ fat (10-15%), ↑ carb, and medium protein levels (10%)
- Almost complete recovery, 10kg of weight was regained and strength improved (9 month follow-up)
- L-carnitine, and riboflavin (105mg/day) or BEZ (8.2mg/kg/day).
- When riboflavin was added to the L-carnitine and BEZ, symptoms completely resolved (21 month followup).
- Gene sequencing: homozygous c.1544G>T mutation in ETFDH.
AC MADD
- Muscle biopsy: lipid storage
- Patient did not respond to riboflavin
- Muscle weakness and limb fatigability
- Muscle biopsy: lipid storage
- Serum: ↑ acyl carnitines - Urine: ↑ 2-OHglutarate, ethylmalonate, 3-
- Riboflavin was added to L-
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ACCEPTED MANUSCRIPT carnitine and BEZ treatment.
OH-propionate
- Muscle weakness, exercise intolerance, myalgia and recurrent vomiting after fatty meals
- Muscle biopsy: lipid storage
- Mutation screening of ETFA, ETFB and ETFDH: 13 heterozygous changes in ETFDH of each patient, including c.3G>C, c.389A>T, c.524G>A, c.715G>A, c.770A>G, c.821G>A, c.1084G>A, c.1211T>C, c.1227A>C, c.1395T>G, c.1399G>A, c.l773_1774delAT, c.1828G>A, c.295C>T, c.303T>A, c.518T>G, c.1586A>G and c.1810G>T
AN M ED CE
PT MADD
Van Rijt, et al, 2014 [84]
AC
MADD
Wen, et al, 2013 [145]
Newborn, Female
34 Adults (6-50 years of age, 18
- L-carnitine (2g/day), riboflavin (60mg/day), CoQ10 (90mg/day).
IP
13 adults (26-57 years of age, 4 Females and 9 Males)
CR
Zhu, et al, 2014 [144]
US
MADD
T
- Gene analysis: compound heterozygous missense mutations (890G>T/W297L and 950C>G/P317R) in ETFDH.
- Hypoglycemia, developmental delay, severe tachyarrhythmias and progressive cardiomyopathy.
- Gene analysis: homozygosity for a mutation in ETFA (specific mutation not stated).
- All adults showed proximal muscle weakness and
- Muscle biopsy: lipid storage
- Muscle weakness, myalgia and exercise intolerance were completely resolved (1 month follow-up)
- Less responsive patients (3) were administered a higher dose of riboflavin (120mg/day) and prednisone (30mg/day)
- Frequent feedings, restriction of fat, riboflavin, CoQ10. - NaHB was added (increased from 450mg/kg/day to 900mg/kg/day and finally 2600mg/kg/day). - CoQ10 (60mg/day), and after two weeks
- Following the highest dosage of NaHB clinical improvement observed (followup not stated)
- Partial recovery of muscle weakness with
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exercise intolerance
riboflavin therapy
55 years of age, Male
- Osphyalgia, muscle weaknesss, difficulty walking, fatigue, swallowing and speaking anorexia and intermittent nausea
- Muscle biopsy: lipid storage
US
Zhao, et al, 2012 [146]
- Riboflavin (100mg/day) and ↓ protein/fat and ↑ carb diet
- Symptoms subsided and exercise intolerance improved within a few weeks (6 year follow-up)
- Intravenous carnitine (660mg 3 times daily), riboflavin (100mg), intravenous 10% dextrose and ondansetron, commercial oral rehydration
- Recurrent vomiting associated with fatigue resolved by treatment. Gastrienteritis improved with oral rehydration solution. Gave birth to a child by
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PT
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M
AN
MADD
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Gene analysis: ETFDH gene mutations at c.1227A>C, c.242T>C, c.770A>G, c.380T>G, c.122T>C, c.1436G>C, c.1295T>A, c.389A>T, c.250G>A, c.256C>T and c.251C>T.
T
- Serum and urine: changes consistent with MADD.
CoQ10 (2 week follow-up), and on the addition of riboflavin muscle strength almost returned too normal (2 month follow-up).
Trakadis, et al, 2012 [147]
24 years of age, Female
- MS/MS: ↑ acyl carnitines
- Gene analysis: compound heterozygous mutations including c.1522C>A and c.1583_1584insA in ETFDH.
AC MADD
- Urine: abnormal excretion of glutarate, methylmalonic acid and 2hydroxyglutaric acids
- Pregnant haha this is not a disease.
Was she doing a standard preg test or something?
- At diagnosis blood acyl-carnitine and urinary organic acid profiles were consistent with MADD.
- PCR and
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- Muscle biopsy: lipid storage
- Riboflavin (100mg/daily) and ↓ fatty acid, ↓ protein and ↑ carbs diet
- Able to walk normally with no significant weakness (1 year follow-up)
- Carnitine (1gr/day) and after one month additional riboflavin (100mg/day) and ubiquinone (50mg/day) treatment
- Modest improvement of limb weakness with carnitine (1 month follow-up)
- Riboflavin (100mg/day), Lcarnitine (50mg/kg/day) and ↓ fat diet
- Muscle weakness and fatigue gradually improved (3 week follow-up)
T
- Waddling and stepping gait, reduced reflexes and muscle weakness
- Intravenous carnitine (During delivery -1000mg every 8 hours, after delivery – 1320mg and reduced back to pre-delivery levels)
IP
20 years of age, Male
CR
Cotelli, et al, 2012 [148]
solution during pregnancy.
- ESI-MS/MS: ↑ long and medium-chain carnitine esters
C-section. Remained stable with no hypoglycemia or acidosis during or after delivery.
US
MADD
bidirectional DNA seq.: homozygous c. 1601C>T mutation in exon 12 of ETFDH.
Rosa, et al, 2012 [149]
7 months of age, Male
- Developmental delay and muscle weakness
AC MADD
Izumu, et al, 2011 [150]
56 years of age, Male
- PCR analysis: No identified mutations - MS/MS: ↑ short, medium and long chain acylcarnitines
- Urine: ↑ ethylmalonic, glutaric, OHcaproic, adipic, suberic and sebacic acids
CE
PT
MADD
ED
M
AN
- Urine: ↑ hydroxyglutaric and ethyl-malonic acid
- Fatigability, muscle weakness, myalgia, weight loss and dysarthria.
- Muscle biopsy: lipid storage
- Serum: ↑ free carnitine and acylcarnitine - Urine: ↑ glutarate
- Improved motor function, and effect of therapy on intellectual disability (6 month follow-up)
- No relapse of rhabdomyolysis and returned to
44
ACCEPTED MANUSCRIPT normal daily activity (6 month follow-up)
Kaminsky, et al, 2011 [151]
55 years of age, Female
- Severe myalgia, muscle weakness,
- Muscle biopsy: lipid storage
CR
MADD
IP
- Gene analysis: compound heterozygous missense ETDH mutation c.1211T>C in exon 10 and c. 1786G>A in exon 13.
T
and 2-OH-glutarate
Able to walk normally and myalgia resolved (6 month followup)
-PCR analysis: heterozygous c.877C>G in ETFDH
ED
M
AN
US
- MS/MS: ↑ short, medium and longchain acylcarnitine
- Riboflavin (30mg/day), Lcarnitine (50mg/kg/day) and a ↓ fat, ↓ protein, ↑ carb diet
PT
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary
CE
Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”, “Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
AC
Storage Disease with Myopathy”. To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including unconfirmed diagnoses, or non-intervention observational studies were not included. Only Englishwritten articles published within the last seven years were assessed (2011-2017 inclusive).
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ACCEPTED MANUSCRIPT Table 2: Treatment-outcome case reports of Neutral Lipid Storage Disease with Ichthyosis (NLSD-I) patients since 2011. Confirmation diagnostic testing
Arora, et al, 2017 [53]
8 years of age, Male
- Generalised scaling, erythema, distended abdomen, hepatomegaly, reduced tone and muscle weakness
- Skin biopsy: Hyperkeratosis, lipid storage.
Verma, et al, 2017 [113]
17 years of age, Male
- Nephritis, proteinuria and ichthyosiform erythroderma
- T opical emollients and acitretin (10mg/day)
IP
- Parents were unwilling for genetic analysis.
Treatment
T
Clinical presentatio n
- 4-mm punch biopsy: Acanthotic dermatitis. -Liver biopsy: macrocellular hepatosteatosis and Jordans anomaly.
AN
NLSD-I
Patient (age and gender )
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NLSD-I
Author and year
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Lipid Storage myopath y
29 months of age, Female
Developmentally delayed in all spheres, generalized scaling of the whole body, abdominal distension, central hypotonia and hepatomegaly - On and off fever, progressive abdominal distension, hepatomegaly and generalised erythroderma
- Peripheral blood smear: Jordans anomaly
- Motor development delay, slight hypotonia, and generalised ichthyosiform squamae and excoriations
- Peripheral blood smear: Jordans anomaly
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Gupta, et al, 2016 [114]
Waheed, et al, 2016 [115]
1 year of age, Male
Huigen, et al, 2015 [54]
18 months of age, Female and Age not clear, Male
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NLSD-I
CE
PT
NLSD-I
NLSD-I
- Significant pruritic ichthyosis and
- Liver biopsy: distorted globular architecture and ballooning - Gene analysis: homozygous nonsense mutation c.297>C in exon 3 of ABHD5.
- Blood smear: Jordans anomaly - Liver biopsy: Moderate to severe steatosis, ballooning and pericellular fibrosis
- Gene analysis: homozygous mutations c.47+1G>A in intron 1 (patient 1), c.594insC in exon 4 (patient 2) of ABHD5
- Scaling and erythema reduced - Liver enzymes have normalised - Muscle weakness is static
- Prednisolone (tapering dose of 0.5mg/kg-1 ) and diuretics -Petroleum jelly, and a ↓ fat diet with, moderatecarbs
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- Bidirectional Sanger seq.: homozygous missense mutation c.752>C. of ABHD5.
Reporte d clinical outcome s
- ↓ fat, ↓ protein, ↑ MCT ’s and ↑ carb diet - UDCA, vitamin E and local emollients
- Advised a ↓ fat, ↓ protein, ↑ MCT’s and ↑ carb diet and emollients
- Diverse emollients and MCT diet
- Kidney functioning normally. - Proteinuria persisted. Erythroderma severity unchanged (1 year followup) - Repeat lipid profile showed almost similar levels (6 month follow-up)
Improvement in clinical condition was reported (no specific detail; 3 month follow-up). - Motor and cognitive development normalized (2 year followup). - At seven years of age hepatomegaly vanished. It
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Newborn, Female
- Congenital ichthyosis, and hepatomegaly (from 2 years of age).
- Peripheral blood smear: Jordans anomaly - Liver biopsy: Severe macro and micro-vesicular steatosis
- Liver biopsy: diffuse micro and macro-vesicular steatosis
- Peripheral blood smear: Jordans anomaly
- Progressive upper abdominal distension, generalised ichthyosis and hepatomegaly.
- Peripheral blood smear: Jordans anomaly
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18 months of age, Male
- Aquaphor® ointment applied from birth
- Liver biopsy: macrovesicular steatosis, cirrhosis and steatohepatitis - Skin biopsy: Hyperkeratosis
- Hydrocortisone topical from 2 years old - ↓ fat diet with MCT ’s and UDCA and vitamin E initiated at 4 years and 9 old. - Oral acitretin (10mg biweekly) and a diet with ↑ MCT ’s and ↓ LCFAs.
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Srinivasarag havan, et al, 2013 [51]
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- Gene analysis: 3955bp homozygous deletion associated with a 26bp insertion (NG_007090.3: g.43728907_43732862del3955ins 26) in ABHD5. NLSD-I
- ↓ fat diet and topical emollients/treatme nt
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Missaglia, et al, 2014 [117]
29 years of age, Female
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NLSD-I
Kazemi, et al, 2015 [116]
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NLSD-I
erythrodermia, mild diffuse bilateral cataract and hepatomegaly - Generalised skin scaling, mild erythema, brown hyperpigmentatio n and hyperkeratosis
Israeli, et al, 2012 [52]
2 years of age, female
- Generalised skin scaling, mildly distended abdomen and hepatomegaly.
- Peripheral blood smear: Jordans anomaly - Skin biopsy: Compact orthokeratosis, irregular acanthosis and papillomatosis. - Direct seq. analysis: homozygous transition located within an intron 6 (c.960 + 5G>A) of ABHD5
- Moderate amounts of carb, and MCT ’s, and oral acitretin (0.5mg/kg/day)
- Skin lesions were significantly reduced, and liver function tests improved, e.g. aspartate transaminase decreased (2 month follow-up) - Dramatic improvement s of the skin condition and liver function tests were observed (2 month follow-up)
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CE
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NLSD-I
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- Genetics: homozygous c.5063C>G in ABHD5.
was reported the diet was ineffective and discontinued. T ransaminase s levels continually fluctuating (follow-up period and outcomes not detailed). Improvement s of liver size and skin condition following dietary treatment, UDCA and vitamin E (1 year followup).
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”, “Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid Storage Disease with Myopathy”. To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including
47
ACCEPTED MANUSCRIPT unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
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written articles published within the last seven years were assessed (2011-2017 inclusive).
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Table 1: Treatment-outcome case reports of Neutral Lipid Storage Disease with Myopathy (NLSD-M) patients since 2011
Clinical
Diagnostic testing
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Patient
Clinical outcomes
Treatment
IP
Author/year
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PT
ED
M
AN
US
CR
Presentation
AC
Lipid Storage myopathy
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26 years of age, Male
- Syncope, shortness of breath, muscle weakness, severe dilated biventricular cardiomyopathy.
- Muscle weakness, walking difficulties, left ventricular dilation, ↓ left ventricular systolic function
- Muscle biopsy: lipid storage - Sanger seq.: homozygous missense mutation c.497A>G in PNPLA2.
- Muscle biopsy: lipid storage - Gene analysis: homozygous deletion of seven nucleotides in exon 7 (c.41_47_delGCTGCGG) of PNPLA2
- Beta-blocker, ACE inhibitor, Eplerenone, warfarin and a defibrillator was implanted
- Enalapril (5mg bid) and ivabradine (7.5mg/di)
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Pasanisi, et al, 2016 [110]
22 years of age, Male
Pennisi, et al, 2015 [111]
72 years of age, Female
- Exercise intolerance, myalgia and muscle weakness.
- Peripheral blood smear: Jordans anomaly. - Muscle biopsy: mild non-specific myopathic changes - Gene analysis: c.497A>G in exon 5 and c.1442C>T in exon 10 of PNPLA2.
- Salbutamol (4mg, two divided doses), dexamethasone, (25mg/day), and phenofibrate (160mg/day)
Kaneko, et al, 2014 [112]
59 years of age, Male
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CE
NLSD-M
PT
ED
M
AN
NLSD-M
US
CR
NLSD-M
Muggenthaler, et al, 2016 [37]
IP
NLSD-M
NLSD-M
NLSD-M
Perrin, et al, 2013 [26]
Van De Weijer, et al, 2013 [38]
17 years of age, Male
37 and 39 years of age, Female
- Muscle weakness, cardiomegaly with dilation of the left ventricle and decreased ejection fraction.
- Fatigue, increased difficulties in running and walking, and myalgia after prolonged exercise.
- Progressive muscle weakness, diffuse hypokinesia of the left and right ventricles of the heart with ↓ ejection
- Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly - Gene analysis: Homozygous c.576delC PNPLA2 mutation.
- Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly. - Gene analysis: homozygous mutation c. 865C>T in exon 7 of PNPLA2 - Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly
- Beta-blockers, ACE inhibitors and diuretics, -Intensive care and cardiovascular treatment
- Initial improvements in shortness of breath - Condition deteoriated and patient required cardiac implantation (follow-up not stated). - Ejection fraction ↑ - Improved exercise capacity (oxygen consumption increased from 48 to 57% of the predicted value) (18 month follow-up) - Salbutamol was not tolerated and dexamethasone was stopped after no clinical improvement (2 month followup)
- ↓ myalgia and fatigue with phenofibrate treatment (follow-up not stated). - Over 10 years cardiac function deteoriated. Patient was discharged and received medication in outpatient settings.
- Oral Carnitine (1g/daily)
- No significant clinical improvement was observed and treatment ceased (6 month follow-up).
- Implantable cardioverter defibrillator in patient one and BEZ treatement
- No improvements in grip strength or cardiac
50
ACCEPTED MANUSCRIPT fraction.
in both patients (Bezalip, Actavis, 400mg/daily).
function (7 month followup)
- Some improvement in leg strength.
- The only notable difference was cardiac and muscle fat content.
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- Mild myopathy and reduced exercise intolerance (heterozygote carrier).
- Gene seq. analysis: deletion causing a frame shift at amino acid position 270 in PNPLA2 of both patients. Additionally patient one has a missense mutation 548C>T .
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and
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ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”,
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“Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
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Storage Disease with Myopathy”.
To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including
PT
unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
AC
CE
written articles published within the last seven years were assessed (2011-2017 inclusive).
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ACCEPTED MANUSCRIPT
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CE
PT
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AN
US
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Table 3: Treatment-outcome case reports of Primary Carnitine Deficiency (PCD) patients since 2011
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ACCEPTED MANUSCRIPT
Patient
PCD
Ravindranath, et al, 2017 [118]
8 months of age, Male
Clinical presentation
Diagnostic testing
Treatment
- Recurrent vomiting, lethargy, jaundice, enlarged liver, nonketotic hypoglycemia and hyperammonemia
- MS/MS: ↓ free & total carnitine & medium-chain dicarboxylic aciduria.
- Intravenous dextrose, sodium benzoate,& uncooked cornstarch in water
Clinical outcomes - No episodes of hypoglycemia ammonia levels & liver function normalized (4 month follow-up).
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Author/year
CR
IP
Lipid storage myopathy
3 years of age, Female
- Progressive fatigue, shortness of breath, pallor of skin and conjunctivae and left ventricular hypertrophy.
ED PCD
Jun, et al, 2016 [77]
PT
Ganigara, et al, 2017 [119]
8 years of age, Male
AC
CE
PCD
3 years of age, Female
- Whole exome seq: homozygous c.1188 T>G in SLC22A5.
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Lahrouchi, et al, 2017 [66]
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PCD
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- Whole exome seq: homozygous c.1316 dupT in exon 8 of SLC22A5.
- Carnitine (100mg/kg/day), MCT (30% total energy intake), and ↓ LCFAs. - Carnitine (200mg/kg/day)
- ↑ Activities of daily living - Exercise tolerance normalized to age matched controls (8 month follow-up)
- MS/MS: no free carnitine & only trace of total carnitine.
- Altered sensorium, increased frequency of seizures and global developmental delay with hypotonia.
- MS/MS: ↓ free carnitine
- Levocarnitine & levetiracetam
- Patient seizure free (2 months follow-up)
- Tonic-clonic seizures and deeply drowsy. Experienced a severe course of hypoglycemic encephalopathy. This was attributed to consumption of pivalic acidcontaining antibiotics.
-Serum: ↓ carnitine
- Midazolam, phenobarbital and phenytoin, 10% glucose bolus, hydrocortisone (5mg/kg/day),
- Blood glucose stable (35 day follow-up)
- Genetic analysis identified c.396G>A and c.539A>C variations in SLC22A5.
- L-carnitine (55 mg/kg/day, three divided doses).
- Patient transferred to rehabilitation medicine for status epilepticus, disabled visual fixation, impaired visual acuity and impaired locomotion and transitional movements.
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ACCEPTED MANUSCRIPT 9 months of age, Male
- Jaundice, failure to gain weight, mild motor developmental delay, frequent breathing problems, cardiomegaly and biventricular hypertrophy.
- MS/MS: ↓ free carnitine - Sanger Seq.: compound heterozygous mutations C.1354G>A and c.231_234del in SLC22A5.
Mahale, et al, 2016 [121]
8 months of age, Female
- Fever, loose stools, excessive irritability, lethargy, hepatomegaly and worsening sensorium.
- MS/MS revealed ↓ free carnitine (2.6mM/l).
PCD
Al-sharefi, et al, 2015 [122]
35 years of age, Female
- History of schizoaffective disorder, lithium-induced diabetes, insipidus and hyperthyroidism. Drowsiness, personality changes, fatigue, generalised weakness, and deteoriating mobility.
- Routine biochemistry diagnosed VHE.
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- On 3 week follow-up serum: ↓ free and total carnitine
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M
ED
9 years of age, Male
Yilmaz, Atay, et al, 2015 [124]
12 years of age, Male
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PCD
CE
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Mutlu-Albayrak, et al, 2015 [123]
PCD
Kumar, et al, 2015 [125]
3 months of age, Male
- Dysmorphic appearance, fatigue and hypertrophic cardiomyopathy.
- Prominent fatigue, upper extremity muscle weakness, and decreased deep tendon reflexes, congestive heart failure, hypoglycemic hypoketotic and encephalopathy secondary to PCD.
- Altered sensorium, fever, hypertonia, abnormal body movements,
- MS/MS revealed ↓ free carnitine - Genetic testing identified a homozygous c.1427 T>G mutation in SLC22A5 Serum: ↓ free carnitine
- Mechanical ventilator, intravenous fluids, and levocarnitine (100mg/kg/day, divided doses).
- Gradually improved in sensorium and was extubated (follow-up not stated).
- Sodium valproate (1000mg, divided in two doses). - Carnitine (2000mg/day, divided in two doses).
- Within 3 days mental status improved achieving a 10/10 abbreviated mental test score.
- Oral carnitine (200mg/kg/day)
- Clinical improvement was observed, particularly ↓ fatigue (2 month follow up)
- Oral carnitine (dosage not stated).
- It was reported that heart failure ceased (follow-up not stated)
- An SLC22A5 mutation was found (mutation details not stated).
- Serum: deficiency of free carnitine
- Jaundice cleared within days
- ↑ left ventricular ejection fraction. Liver size and enzymes normalized (3 month follow-up).
CR
PCD
PCD
- Oral Lcarnitine (100mg/kg/day)
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Deswal, et al, 2016 [120]
IP
PCD
- On 3 week follow-up fatigue and weakness persisted, after 2 weeks of carnitine this was resolved
- No post-treatment report on muscle function or hypoglycemic hypoketotic encephalopathy - Mechanical ventilation, intravenous fluids, antibiotics and
- Normalization of all clinical parameters reported (follow-up
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ACCEPTED MANUSCRIPT tachypnea, tachycardia and seizures and hepatomegaly.
Wang, et al, 2014 [127]
5 children (1-14 years of age, 1 Female and 4 Males)
- Upper airway infection, cardiac insufficiencies, including cardiomegaly and left ventricular hypertrophy
- Serum: ↓ free and total carnitine
- All patients presented with dyspnea, cardiomyopathy and enlargement of the left ventricle.
- Highthroughput seq.: heterozygous c.338G>A, c.760C>T and c.865C>T SLC22A5 mutations.
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IP
- Next gen. seq.: homozygous c.597_597delG mutation in SLC22A5
- L-carnitine (50-100 mg/kg/day p.o), plus digoxin, diuretics and vasodilators
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3 years of age, Male
3.5 years of age, Female
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Agnetti, et al, 2013 [65]
- Fatigue and marked pallor, cardiomegaly and severe congestive heart failure.
- Left ventricular function returned to normal and heart size normalized for all patients (4 month to2 year follow-up).
- Oral carnitine (3g/day to 2g/day after 6 months)
- This proband has been followed for 28 years. Over time heart size normalized, along with other ECG and echocardiographic parameters. Able to perform regular physical activity.
- Muscle biopsy: lipid storage
CE
PT
ED
PCD
Serum: mean value 1.37 ± 0.66 𝜇mol/L - Serum: ↓ carnitine
- Treatment suspension lead to recurrence of muscle symptoms, and dosing reintroduction restored function.
AC PCD
Kilic, et al, 2012 [128]
7 children (5F and 3M 5-12 Y/O)
- This patient has been followed for 14 years. Over time, improvements in cardiac functions were observed, including improvements in left ventricular ejection fraction. No further details given.
- L-carnitine (200-300 mg/day p.o), plus digoxin, diuretics and vasodilators
AN
PCD
Yilmaz, Seker, et al, 2015 [126]
not stated).
- L-carnitine (100mg/kg/day, in divided doses) and MCT ’s.
US
PCD
antiepileptic medication.
- Symptoms of heart failure, and cardiomyopathy (6 dilated, 1 hypertrophic).
Serum: mean value 2.63 ± 1.92 𝜇mol/L - SLC22A5 analysis: p.G411V,
- Oral carnitine (100-300mg/kg) with cardiac inotropic and diuretic agents
- All signs and symptoms of heart failure and cardiomyopathy were reversed in every case
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ACCEPTED MANUSCRIPT
20 years of age, Female
- Syncopal episode caused by ventricular tachycardia, and abnormal QT interval.
2 males (5 & 6 years)
- Skeletal myopathy and hypertrophic cardiomyopathy.
Serum: ↓ free carnitine
US
Kishimoto, et al, 2012 [64]
- Carnitine (3g increased to 4.2g/day)
- Both patients recovered muscle strength, and no longer fatigued easily after exercise.
22 years of age, Female
CE
Mazzini, et al, 2011 [130]
AC
PCD
PT
ED
M
AN
PCD
- Irregular heart rhythm, witnessed ventricular fibrillation arrest requiring resuscitation.
- Over 5 years cardiac symptoms and syncopal episodes persisted.
- Upon carnitine introduction syncopal episodes ceased, cardiac symptoms reversed and QT interval normalised (follow-up not stated).
- High dose carnitine (3,960mg/day).
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-Molecular analysis: c.95A>G and c.136C>G mutations in SLC22A5
- Metoprolol (50mg to 75/day), implanted defibrillator and mexiletine (450mg/day).
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De Biase, et al, 2012 [129]
(1 year follow- up).
IP
PCD
p.G152R, p.R254X, p.R282X, p.R289X, p.T 337Pfs12X mutations. - After newborn screened positive, serum: ↓ total and free carnitine
- Skeletal and endomyocardial muscle biopsies: lipid storage
- Echocardiographic parameters normalized (30 year follow-up).
- PCR analysis: homozygous mutation in SLC22A5 (no specifics). - Gene Seq.: A142S and R488H mutations on allele 1 and 1588G>T on allele 2 of SLC22A5
- Cardioverterdefibrillator implanted, oral levocarnitine (3g/day) and MCFA’s
- Heart rhythm normalised (6 month follow-up).
- No arrhythmias have been reported (22 month follow-up)
- Serum: ↓ Free and total carnitine
Endomyocardial
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ACCEPTED MANUSCRIPT biopsy: lipid storage
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary
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Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”,
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“Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
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Storage Disease with Myopathy”.
To be included in this review studies needed to meet the following criteria: Clinical case reports,
US
controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
AC
CE
PT
ED
M
AN
written articles published within the last seven years were assessed (2011-2017 inclusive).
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Figure 1
Figure 2
Figure 3
Emily R. Vasiljevski, Matthew A. Summers, David G. Little, Aaron Schindeler PII: DOI: Reference:
S0163-7827(18)30017-1 doi:10.1016/j.plipres.2018.08.001 JPLR 968
To appear in:
Progress in Lipid Research
Received date: Revised date: Accepted date:
4 April 2018 20 June 2018 6 August 2018
Please cite this article as: Emily R. Vasiljevski, Matthew A. Summers, David G. Little, Aaron Schindeler , Lipid storage myopathies: Current treatments and future directions. Jplr (2018), doi:10.1016/j.plipres.2018.08.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Lipid storage myopathies: Current treatments and future directions Emily R Vasiljevski
1,2
, Matthew A Summers
3,4
, David G Little
1. Orthopaedic Research & Biotechnology,
1,2
, Aaron Schindeler
1,2*
The Children’s Hospital at Westmead,
Westmead, NSW, Australia. 2. Discipline of Paediatrics & Child Heath, Faculty of Medicine, University of Sydney,
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Camperdown, NSW, Australia
3. Bone Biology Division, The Garvan Institute of Medical Research, Darlinghurst, NSW
4.
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Sydney, Australia
St Vincent’s Clinical School, University of New South Wales, Faculty of Medicine,
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Sydney, Australia.
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* Corresponding author
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Mailing address:
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Orthopaedic Research & Biotechnology, Research Building The Children's Hospital at Westmead
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Locked Bag 4001
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Westmead, NSW 2145, Australia Phone: +61-2-98451451
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Fax: +61-2-98453078
Email: [email protected]
Conflicts of interest Authors have no conflicts of interest to declare.
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ACCEPTED MANUSCRIPT
ABSTRACT Lipid storage myopathies (LSMs) are a heterogeneous group of genetic disorders that present with abnormal lipid storage in multiple body organs, typically muscle. Patients can clinically present with cardiomyopathy, skeletal muscle weakness, myalgia, and extreme fatigue. An early
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diagnosis is crucial, as some LSMs can be managed by simple nutraceutical supplementation.
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For example, high dosage L-carnitine is an effective intervention for patients with Primary
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Carnitine Deficiency (PCD). This review discusses the clinical features and management practices of PCD as well as Neutral Lipid Storage Disease (NLSD) and Multiple Acyl-CoA
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Dehydrogenase Deficiency (MADD). We provide a detailed summary of current clinical management strategies, highlighting issues of high-risk contraindicated treatments with case
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study examples not previously reviewed. Additionally, we outline current preclinical studies providing disease mechanistic insight. Lastly, we propose that a number of other conditions involving lipid metabolic dysfunction that are not classified as LSMs may share common
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features. These include Neurofibromatosis Type 1 (NF1) and autoimmune myopathies, including
AC
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Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM).
Keywords: Lipid, metabolism, myopathy, diet
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Abbreviations: ABHD5, α/β-Hydrolase Domain-5; AC, adenylate cyclase; anti-ACVR2B, mouse monoclonal activin receptor type IIB; ATGL, adipose triglyceride lipase; BEZ, bezafibrate; CACT, carnitine translocase; CD36, cluster of differentiation 36; CGI-58,
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comparative gene identification-58; CoA, coenzyme A; CoQ10, co-enzyme Q10; CPT I,
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carnitine palmitoyltransferase I; CPT II, carnitine palmitoyltransferase II; DM, dermatomyositis;
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EM, electron microscopy;ETF, electron transfer flavoprotein; ETFDH, electron transfer flavoprotein dehydrogenase; ETF-QO, electron transfer flavoprotein -ubiquinone
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oxidoreductase; FABP4, fatty acid binding protein-4; FACS, fatty acyl-CoA synthetase; FADH2 , flavin adenine dinucleotide; FAT, fatty acid translocase; FATP, fatty acid transport protein; GC-
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MS/MS, gas chromatography - tandem mass spectrometry; HDL-C, high-density lipoproteincholesterol; HSL, hormone sensitive lipase; IBM, inclusion body myositis; IMCL,
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intramyocellular lipid; TCA, tricarboxylic acid; jvs, juvenile visceral steatosis; LSM, lipid storage myopathy; MADD, multiple acyl-CoA dehydrogenase deficiency; MCFA, medium chain
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fatty acids; MCT, medium chain triglycerides; MGL, monoglyceride lipase; MS/MS, tandem mass spectrometry; NADH, nicotinamide adenine dinucleotide; NaHB, sodium-D-L-3-
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hydroxybutyrate; NEFA, non-esterified fatty acid; NF1, neurofibromatosis type 1; NLSD-I, neutral lipid storage disease with ichthyosis; NLSD-M, neutral lipid storage disease with
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myopathy; OCTN2, organic cation/carnitine transporter 2; PCD, primary carnitine deficiency; PKA, protein kinase A; PM, polymyositis; PNPLA2, Patatin-like Phospholipase Domain
AC
Containing 2; PPAR, peroxisome proliferator-activated receptors; SLC22A5, Solute Carrier Family 22 Member 5; UDCA, ursodeoxycholic acid VHE, valproate hyperammonaemic encephalopathy; VLDL-C, very low-density lipoprotein-cholesterol; ↑, high/elevated; ↓, low/reduced.
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1.
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INTRODUCTION
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Lipid storage myopathies (LSMs) are a group of genetic disorders characterized by excessive and pathological lipid accumulation, chiefly within muscle fibers [1]. There are four classic LSMs with a defined genetic cause: Neutral Lipid Storage Disease with Myopathy (NLSD-M),
and
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Neutral Lipid Storage Disease with Ichthyosis (NLSD-I), Primary Carnitine Deficiency (PCD) Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) [2]. These conditions are
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associated with dysfunction in intracellular triacylglycerol catabolism, mitochondrial fatty acid oxidation, or transport of carnitine, acyl-carnitines, and/or long chain fatty acids [1]. Lipid
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dysmetabolism can cause a range of clinical features, but most commonly encompass a
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progressive myopathy with muscle weakness, myalgia, and fatigue [1]. Triacylglycerols are a broad category of non-polar lipid molecules made up of three fatty acids
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bound to a glycerol backbone. They are the predominant metabolic substrate utilized at rest, during routine activities, and for low to moderate-intensity exercise (30-65% maximal oxygen
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consumption). While most body triacylglycerol (>80%) is derived from sources of dietary fat, endogenous triacylglycerol synthesis occurs primarily in the adipocytes and liver; this is fueled
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by excess available glucose and/or precursors of hepatic gluconeogenesis [3]. In healthy individuals triacylglycerol is primarily stored in subcutaneous and visceral adipose tissue [4]. While minimal, skeletal muscle also contains triacylglycerol stores that can provide energy for muscle activity [5]. These are primarily stored in adipocytes situated between muscle fibers, but can also be present in small, lipid droplets within muscle fibers termed intramyocellular lipid (IMCL) inclusions [5]. Resting tissue IMCL levels can vary in response to environment and energy demand; indeed while increased muscle IMCL is a hallmark of metabolic disease, in elite endurance trained athletes IMCL stores are dramatically elevated as a response to chronic training (termed fat adaptation) [6].
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ACCEPTED MANUSCRIPT
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2.
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OVERVIEW OF FATTY ACID METABOLISM
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In order to contextualize the pathways dysregulated in lipid storage myopathy patients, it is important to define the normal mechanism for the breakdown of fats. In this section we provide a brief overview of the key pathways and enzymatic steps in fatty acid metabolism relevant to lipid
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storage diseases. For an in depth and complete review of metabolic biochemistry we recommend reviews by Zechner, et al, 2012 [7], Longo, et al, 2016 [8], Houten, et al, 2016 [9], and Letts and
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Sazanov, 2017 [10].
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Briefly, triacylglycerol stored in cells are hydrolyzed sequentially into glycerol and fatty acids via lipolytic pathways. Next, the fatty acids are transported across the mitochondrial membrane
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and then broken down by beta-oxidation to generate acetyl-CoA. Finally, within the mitochondria, acetyl-CoA molecules are used to fuel classical aerobic respiration pathways of
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the TCA cycle and the electron transport chain. Many of the key regulatory enzymes and factors
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2.1
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governing these processes are linked to lipid storage myopathies.
Intracellular lipolysis The enzyme adipose triglyceride lipase (ATGL) catalyzes the initial and often rate-limiting step of intracellular lipolysis [11]. This involves the conversion of a triacylglycerol molecule to diacylglycerol, which releases a fatty acid [11]. ATGL is predominately expressed in adipose tissue and to a lesser extent in non-adipose tissue including liver, heart and skeletal muscle [7]. It has been speculated that other neutral lipases may play a role in the initiation of lipolysis in nonadipose tissues [7].
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ACCEPTED MANUSCRIPT Diacylglycerols
are
subsequently
hydrolyzed
by
hormone
sensitive
lipase
(HSL),
to
monoacylglycerols, which are finally hydrolyzed by monoglyceride lipase (MGL) to liberate the final fatty acid [7]. HSL can also hydrolyse triacylglycerols and monoacylglycerols, but with lesser specificity [7]. Lipolysis occurs largely in response to energy demand, and is initiated by the release of
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hormones such as glucagon, epinephrine, and norepinephrine [7, 12]. In adipose tissue, these
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trigger the activation of adenylate cyclase (AC) and subsequently Protein Kinase A (PKA) [12]. PKA phosphorylates Perilipin-1 causing CGI-58 to dissociate from Perilipin 1 and induce ATGL
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activity [12] (Figure 1 A). In non-adipose tissue ATGL and its co-activator CGI-58 are recruited, and directly bind to Perilipin-5 to induce the hydrolysis of triacylglycerol to
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diacylglycerol [13, 14] (Figure 1 B).
2.2
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Fatty acid transport
After fatty acids are released into circulation, they are transported in the blood bound to serum
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albumin, a protein with high-affinity fatty acid binding sites [15]. When the fatty acid-albumin complex reaches the target cell, it is thought that the fatty acid then dissociates to begin the
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cellular uptake process [15, 16]. Several membrane-associated fatty acid binding transport proteins, in particular members of the Fatty Acid Transport Protein (FATP) family, promote the
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uptake of fatty acids into various cell types [17]. FATP rapidly translocate to the plasma membrane in response to insulin, and facilitate fatty acid transport across cellular membranes
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[17]. Additionally, Fatty Acid Translocase (FAT)/CD36 is another key fatty acid transporter at the plasma membrane, which modulates long-chain fatty acid oxidation during times of rapid energy demand [18].
2.3 Carnitine Shuttling of Fatty Acyl-Coenzyme A’s Once transport proteins take up the non-esterified fatty acids (NEFAs), the NEFAs are coupled with Coenzyme A (CoA) to form short-chain (
ACCEPTED MANUSCRIPT C24), or very Long-chain acyl-CoA (>C24), depending on the length of the fatty acid carbon chain [17]. This is catalyzed by a family of intracellular enzymes with different chain-length specificities, known as the Fatty Acyl-CoA Synthetase’s (FACS). This conjugation prevents NEFAs from re-entering the circulation and facilitates their transport across the mitochondrial membrane [17] (Figure 2).
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While short and medium-chain acyl-CoA can passively diffuse across the mitochondrial
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membrane, long-chain and very long-chain acyl-CoA require active transport via the Carnitine Shuttle system [8]. Carnitine Palmitoyltransferase I (CPT I) is a key enzymatic regulator of
acyl-CoAs.
Carnitine
Translocase
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carnitine bioactivity and catalyzes the binding of free carnitine and long chain/very long chain (CACT) then shuttles acylcarnitine across the inner
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mitochondrial membrane. Inside the mitochondrial matrix, the acylcarnitine is separated back into a long chain acyl-CoA and free carnitine by Carnitine Palmitoyltransferase II (CPT II)
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(Figure 2) [8].
The action of CPT I requires sufficient endogenous carnitine to be present [19]. Carnitine can be
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synthesized from lysine and methionine by kidney and liver cells, but this is insufficient and humans require carnitine intake from dietary sources [19]. Free carnitine (unbound to fatty acid
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CoA molecules) is circulated in the blood and is actively transported into tissues by tissuespecific plasma membrane carnitine transporters [20]. These include Organic Cation/Carnitine
2.4
AC
Beta-Oxidation
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Transporter 2 (OCTN2) (Figure 2) [20].
Beta-oxidation describes the enzymatic removal of carbon molecules from a fatty acid chain, beginning at the beta-carbon. This is catalyzed by a family of acyl-CoA dehydrogenases, which include short-, medium-, long-, and very long- chain acyl-CoA dehydrogenase [9, 21]. There are four enzymatic steps within a cycle, and each cycle liberates a 2-carbon acetyl-CoA molecule. The acetyl-CoA molecules can subsequently be metabolized via the tricarboxylic acid (TCA) cycle (also known as the Krebs or Citric acid cycle). The reduced intermediates, including
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ACCEPTED MANUSCRIPT Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FADH2 ), feed electrons from the 2-carbon acetyl-CoA to the electron transport chain [9] (Figure 3).
2.5 The Electron Transport Chain and Oxidative Phosphorylation
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The mitochondrial electron transport chain is a series of protein complexes that transfer electrons from electron donors, to electron acceptor molecules via a series of biochemical redox reactions
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[10]. Electrons are transferred to ubiquinone through electron acceptors including Electron Transfer Flavoprotein (ETF) and Electron Transfer Flavoprotein - Ubiquinone Oxidoreductase
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(ETF-QO) [22]. The respiratory chain and oxidative phosphorylation are not specific to lipid precursors, as acetyl-CoA is also a product of glucose and amino acid metabolism [23] (Figure
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3).
3.
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LIPID STORAGE MYOPATHIES
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Individuals with LSMs do not produce or produce inadequate amounts of crucial enzymes in the pathways just described. This results in intracellular lipid accumulation, which is associated with
quality of life.
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muscle weakness, myalgia and fatigue; these can have a profound impact on an individual’s
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Today, many lipid storage myopathies are effectively managed, but they are often reliant on an early and accurate diagnosis and can otherwise be lethal. A subset of lipid storage myopathies is still lacking in effective management strategies, and requires further extensive research.
3.1 Neutral lipid storage disease Neutral lipid storage diseases (NLSD) are rare (prevalence unknown with ~50 cases reported in the literature) autosomal recessive disorders of lipolysis. They are clinically heterogeneous;
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ACCEPTED MANUSCRIPT however classically present with myopathy (NLSD-M, OMIM: #610717) and/or ichthyosis (NLSD-I, OMIM: #275630), which is dry, thickened, scaly skin. NLSD is often diagnosed by the presence of lipid inclusions within leukocytes, which is assessed from a peripheral blood smear. These lipid inclusions were first described by Jordans in 1953, and are now commonly
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known as Jordans’ anomaly [24].
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Neutral Lipid Storage Disease with Myopathy (NLSD-M)
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3.1.1
NLSD-M is caused by mutations in the Patatin-like Phospholipase Domain Containing 2
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(PNPLA2) gene [25]. PNPLA2 encodes for Adipose Triglyceride Lipase (ATGL), the enzyme responsible for the first, often rate-limiting step of triacylglycerol hydrolysis. NLSD-M patients
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thus accumulate intracellular triacylglycerol depositions in most tissues, including the liver, and skeletal and cardiac muscle. Multiple mutations in PNPLA2 have been reported, and there is a
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suggestion that disease severity can correlate with specific mutations. For example, nonsense mutations in the C-terminal region often result in a less severe phenotype [26].
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NLSD-M patients present clinically with little to no obesity despite the underlying lipolytic deficiency [25]. They are affected in adulthood, and most commonly present with muscle
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weakness, exercise intolerance, myalgia and/or cardiomyopathy (Table 1). There is great variability in cardiac versus skeletal muscle involvement and severity. For example, the
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cardiomyopathy can be lethal or require a heart transplant to survive, while others exhibit a milder phenotype [27, 28]. Extrinsic factors such as diet and lifestyle are likely to influence
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disease severity and progression, however sex and other genetic factors may also be involved. Additional to Jordans’ anomaly, lipid storage in muscle and mutations in the PNPLA2 gene are also frequently used in diagnosis of NLSD-M (Table 1). There is no curative treatment for NLSD-M, and currently only dietary changes are recommended.
Dietary regimes focused on supplying sufficient carbohydrate for energy
production are the most encouraged (Table 1). This is likely due to one study reporting improvements in maximal oxygen uptake in patients following intravenous glucose delivery [29].
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ACCEPTED MANUSCRIPT A murine model of Pnpla2 deficiency has been developed [30]. Corresponding to the clinical phenotype, Pnpla2 deficient mice are not overly obese and are protected against weight gain on a high-fat diet whilst remaining insulin-sensitive [30-32]. Subsequent studies suggested that this was due to these mice having significantly less adipose tissue [33]. Pnpla2 deficient mouse hearts showed decreased mRNA expression of PPAR𝛼 and PPAR𝛿 target genes including multiple acyl-CoA dehydrogenases, and CPT and essential co-activators [34]. By lipolysis-
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independent PPAR activation using an agonist of PPAR-𝛼 (WY14643), mitochondrial defects
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and lethal cardiomyopathy could be reversed, and prevented premature death suggesting that
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treatment targeting this pathway could be beneficial in a clinical setting [34]. In contrast, a clinical study of triacylglycerol deposits in NLSD-M patients cardiac muscle showed an up
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regulation of PPAR expression [35]. Downstream gene expression of CD36 and Fatty Acid Binding Protein-4 (FABP4) was also markedly increased. It is still unclear whether these
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divergent results should be attributed to species differences [35]. Bezafibrate, a PPAR-𝛼 activator, has been tried in two NLSD-M patients because it is able to induce FATP and FACS
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expression in adipose tissue, subsequently promoting cellular NEFA uptake [36]. Although there was negligible overall clinical benefit, these patients showed a reduction in triacylglycerol
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accumulations in muscle and improved oxidative metabolism [35, 37, 38]. Additional long-term treatment studies are required to determine the therapeutic potential of Bezafibrate.
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Beta-blockers have also been tried in a clinical setting due to a partial rescue of patient myoblasts and fibroblasts reported in the literature [27]. However this was unsuccessful [35, 37]. Enzyme
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replacement therapy could be a potential treatment option, which has been under explored. Successful enzyme therapy has been observed in Fabry disease and Pompe disease [39], and may
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be applicable here.
3.1.2 Neutral Lipid Storage Disease with Ichthyosis (NLSD-I) NLSD-I, also known as Chanarin-Dorfman syndrome, is caused by mutations in the Comparative Gene Identification-58 (CGI-58) also annotated as α/β-Hydrolase Domain-5 (ABHD5) gene [25]. The CGI-58/ABHD5 protein interacts with factors associated with the surface of lipid droplets, including the perilipins, and co-activates ATGL [40, 41]. Some mutant 11
ACCEPTED MANUSCRIPT versions of CGI-58 have been shown to lose the ability to interact with perilipin; they are not recruited to lipid droplets and thus fail to activate ATGL [40, 41]. Patients with NLSD-I show a markedly different clinical phenotype and can be affected earlier in life compared to those with NLSD-M, despite CGI-58 and ATGL functioning in the same biochemical pathway [42]. NLSD-I can feature global developmental delay (including motor
feature
of the
condition
is
ichthyosis,
specifically
non-bullous
congenital
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characteristic
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function and IQ), hepatomegaly and intestinal disease, but not cardiomyopathy. However the
ichthyosiform erythroderma (Table 2). The underlying mechanism is believed to be the
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excessive incorporation of nonpolar lipids into the lamellar membrane. This is followed by the formation of a non-lamellar phase within the stratum corneum interstices (outer skin layer),
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which impairs barrier function [43]. Ichthyosis is not observed in patients with NLSD-M. This suggests an ATGL-independent function of CGI-58 in the skin, and potentially other organs.
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Seasonal fluctuation of ichthyosis have also been observed, leading to speculation that temperature elevation may affect ATGL activity or other lipolytic pathways [44, 45]. Both skin
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and liver biopsies frequently aid in the diagnosis of NLSD-I, as well as genetic sequencing of CGI-58/ABHD5 (Table 2).
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Similar to NLSD-M, there is no curative treatment for NLSD-I. Topical application of ureacontaining emollients, and dietary intervention are the mainstays for clinical treatment (Table 2).
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One of the original case reports for NLSD-I describes treatment with a gluten-free diet, which was reported to ameliorate gastrointestinal symptoms and slightly improve muscle strength [46].
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The patient was initially prescribed prednisone (25-30mg daily/ 1 year), vitamin D (5000 U daily/ 1 year), nystatin, and tetracycline however these had no effect [46]. Despite the beneficial
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response to a gluten-free diet, there have been no other reports involving this type of dietary intervention. A
combination
of high
carbohydrate,
low
fat
diet
supplemented
with medium-chain
triacylglycerols has shown to be a beneficial therapeutic dietary strategy (Table 2). There are several other recent case reports in the literature that outline other dietary interventions, including low fat [47, 48], LCFA-restricted [49] and protein-restricted carbohydrate-rich diets [50], however have no clinical report to treatment effects, and therefore have been excluded from Table 2. This suggests these dietary interventions may have had little therapeutic benefit.
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ACCEPTED MANUSCRIPT It is commonly advised throughout the literature that retinoids including acitretin should be avoided in cases where a NLSD-I patient has disturbed liver function. However, there are three recent reports where patients with impaired liver function have been prescribed acitretin [51-53]. In all cases, the individuals showed improvements in liver function, suggesting a review of clinical retinoid usage could be justified. Although retinoids may not be appropriate for all patients with impaired liver function, they could provide a viable treatment option provided they
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are used with caution and there is careful monitoring.
NLSD-I can be misdiagnosed as Sjogren-Larsson Syndrome, which also presents with ichthyosis
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[54]. Some clinical studies have shown in these patients the severity of itching is reduced with zileuton treatment [55]. This could be beneficial for NLSD-I patients but has yet to be
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investigated.
A Cgi58-/- knockout mouse model was generated in order to investigate the role of Cgi58 in
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triacylglycerol catabolism [56]. The study found Cgi58-/- mice failed to thrive and died within 16 hours after birth, in contrast to heterozygous Cgi58+/- mice, which were comparable to wildtype
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littermates. Cgi58-/- mice featured marked triacylglycerol levels in carcasses, hypoglycemia, hepatic steatosis, and lamellar ichthyosis associated with loss of skin permeability barrier
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function. Glucose injections, increased humidity and Vaseline® application failed to rectify the defects or extend the lifespan [56]. A more recent study in Cgi58-/- mice showed that the lethal
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skin barrier defect could be rescued by promoting Cgi-58 expression in the suprabasal epidermal
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3.2
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layers, a prerequisite for a functional skin permeability barrier [57].
Primary Carnitine Deficiency Primary Carnitine Deficiency (PCD, OMIM: #212140) is an autosomal recessive disorder caused by mutations in the Solute Carrier Family 22 Member 5 (SLC22A5) gene. The SLC22A5 gene encodes for the Organic Cation/Carnitine Transporter 2 (OCTN2) protein. It is responsible for the majority of cellular carnitine uptake, and does so in a sodium-dependent manner. The majority of PCD patient mutations in SLC22A5 have been shown to reduce transporter activity, and transporter activity has been shown to correlate with disease severity [58, 59].
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ACCEPTED MANUSCRIPT The incidence of PCD varies with a frequency of 1:3000-1:120,000 worldwide. It typically presents from early infancy or childhood, and chiefly manifests with liver, skeletal and cardiac muscle
involvement.
Patients
can
experience
episodes
of
hypoketotic
hypoglycemia,
hyperammonemia, hepatomegaly, and hepatic encephalopathy. Additionally, skeletal muscle weakness, impaired motor function, prominent fatigue and cardiomyopathy are also commonly reported (Table 3). Low levels of free and total carnitine indicated by routine biochemistry, or
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tandem mass spectrometry (MS/MS) suggests carnitine deficiency. In Australia, newborns are
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routinely screened for PCD by dried blood spot testing. Additionally, screening for mutations in
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the SLC22A5 gene can confirm a diagnosis (Table 3).
The cardiac and skeletal muscle function of PCD patients is rescued by pharmacological doses of
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carnitine (Table 3). Carnitine supplementation restores carnitine plasma levels, however muscle tissue carnitine concentration reaches only 5-10% of normal [60]. This is due to the persistent
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impairment of the OCTN2 carnitine membrane transporter that limits carnitine uptake in muscle to passive diffusion [61]. Nonetheless, the increases in muscle carnitine are sufficient to regain
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normal physiological function [60, 61]. Additionally, carnitine may act via antioxidant activity [62]. In skeletal muscle, reactive oxygen and nitrogen species are normally synthesised at low
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levels during force production. However, when reactive species accumulation overtakes tissue antioxidant capacity, then oxidative stress activates pathophysiologic signalling leading to
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reduced muscle strength capacity and fatigue [62].
L-carnitine has been shown to protect key
enzymes of the antioxidant defense system from further peroxidative damage [63].
carnitine
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Multiple long-term follow-up studies have been reported to ascertain the efficacy of lifetime supplementation
[64,
65]
showing
it’s
safe
and
effective.
Notably
many
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underdeveloped countries lack newborn genetic screening, which can result in preventable mortalities of young children with PCD [66]. This highlights the importance of both newborn screening and early intervention before irreversible organ damage occurs [67]. Individuals who are heterozygous for SLC22A5 gene are reported to have mildly reduced plasma carnitine levels, and they can progressively develop benign cardiac hypertrophy. It is estimated these asymptomatic PCD individuals may encompass up to 1% of the population. It is unclear whether SLC22A5 heterozygosity leads to an increased risk of cardiomyopathy [68-71].
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ACCEPTED MANUSCRIPT The addition of sodium pivalate to the drinking water of rodents to induce a PCD phenotype is a well-established pre-clinical model. Pivalic acid and carnitine form a pivaloylcarnitine ester; this is excreted to induce carnitine deficiency [72]. This model has proven useful for studying the cardiac manifestations of carnitine deficiency syndromes, including asymptomatic PCD [72]. In the pivalic acid-treated rat model, -adrenergic stimulation of the myocardium resulted in a 50% mortality rate. This was rescued by carnitine supplementation [73]. The heterozygous juvenile
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visceral steatosis (jvs/+) mouse is an alternative genetic rodent model of asymptomatic PCD [74]. The jvs/+ mice are prone to cardiomyopathy and heart failure when challenged by
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surgically induced pressure overload on the heart [75]. These models justify further clinical research into the cardiac risks associated with asymptomatic PCD, and whether these individuals
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may benefit from prophylactic carnitine treatment.
3.2.1
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HIGH RISK: Pivalic acid containing antibiotics are contraindicated for PCD patients The death of five adults with PCD has recently been attributed to the consumption of antibiotics
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containing pivalic acid, a chemical that depletes carnitine by esterification [76]. These cases were reported in the Faroe Islands, an archipelago in the North Atlantic Ocean with the highest
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reported frequency of PCD worldwide (1:3000). Additionally, a recent case report associated pivalic acid containing antibiotics with an extremely severe hospital course for another patient
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[77]. Pivalic acid is commonly used to increase oral bioavailability of antibiotics, including pivampicillin and pivmecillinam. Current studies are estimating the prior mortality associated
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with pivalic acid in PCD patients, as well as determining the risk associated with these drugs in asymptomatic heterozygous individuals. As PCD is not widely recognized as a contraindication for prescription of antibiotics containing pivalic acid, this may continue to cause preventable deaths [76]. The following is a list of available pivalic acid containing antibiotics that should be avoided in suspected or diagnosed PCD individuals: Cefditoren pivoxil, cefcapene pivoxil, cefteram pivoxil, pivmecillinam and pivampicillin.
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ACCEPTED MANUSCRIPT 3.3 Multiple Acyl-Coenzyme A Dehydrogenase Deficiency (MADD) Multiple Acyl-Coenzyme A Dehydrogenase Deficiency (MADD, OMIM: #231680), also known as Glutaric Acidemia Type II, is an autosomal recessive genetic disorder caused predominately by mutations in the Electron Transfer Flavoprotein (ETFA, ETFB) or Electron
Electron Transfer Flavoprotein-Ubiquinone
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of Electron Transfer Flavoprotein (ETF) and
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Transfer Flavoprotein Dehydrogenase (ETFDH) genes. These genes encode the α and β subunits
Oxidoreductase (ETF-QO) respectively. Disruption of ETF and ETF-QO function impairs the
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transfer of electrons received from acyl-CoA dehydrogenases, compromising the β-oxidation of fatty acids [78].
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MADD has a clinically heterogeneous phenotype, but is classically characterized based on age at presentation. There are two types of neonatal-onset MADD, with (type I) or without (type II)
hepatomegaly,
non-ketotic
hypoglycemia,
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congenital anomalies. Neonatal-onset MADD is severe and often lethal, and can feature metabolic
acidosis,
hypotonia,
and
sometimes
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cardiomyopathy [79, 80]. Adult-onset MADD predominantly features muscle-related symptoms, including weakness, fatigue, and myalgia (Table 4). Excessive lipid build-up has been observed
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in muscle biopsies of patients with both neonatal and adult onset types [81, 82], which aids in diagnosis. Elevated urine organic acids, including glutaric acid, and acyl carnitines are also
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characteristic diagnostics. Finally, most cases report mutations in the three “classical” MADD genes (ETFA, ETFB and ETFDH), which confirm diagnosis. If a mutation cannot be identified
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then other genes associated with riboflavin transport, for example SLC52A1, SLC52A2 and SLC52A3, or FAD transport or synthesis, including SLC25A32 and FLAD1 can be investigated
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[83] (Table 4). MADD is associated with a genotype-phenotype correlation, with ETFA and ETFB mutations linked to early onset disease and ETFDH mutations late onset [80, 84, 85]. Most adult-onset patients are responsive to riboflavin supplementation (riboflavin responsive (RR)–MADD), which ameliorates symptoms. Carnitine, CoQ10, and vitamin B12 are also recommended to enhance clinical outcomes (Table 4). However, neonatal-onset MADD (mutations in ETFA and ETFB) is often lethal and cannot be treated [79]. There has been one treatment-outcome case report within the last 8 years detailing a patient with neonatal-onset MADD (confirmed mutation in the ETFA gene). The patient underwent sodium-D-L-3-
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ACCEPTED MANUSCRIPT hydroxybutyrate (NaHB) therapy, which improved clinical outcome (Table 4). NaHB therapy could be further investigated for treatment of neonatal-onset MADD. MADD has predominately been modeled in vitro using patient fibroblasts and genetically modified mammalian cell lines. Recently, bezafibrate, a fibrate drug commonly used to lower human serum lipid levels, has been tried [86] following promising findings of its application in
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other metabolic diseases [87-89]. Fibrates are known to induce FATP and FACS expression in
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adipose tissue, which promotes cellular NEFA uptake through PPAR activation [36]. In vitro, bezafibrate significantly reduced the levels of palmitoylcarnitine (C16) and octanoylcarnitine
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(C8), suggesting a possible improvement of 𝛽-oxidation capacity [86], which could be translatable. However, there has been one clinical report of bezafibrate treatment within the last 8
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years, and it was only found beneficial when supplemented with riboflavin [90]. Aside from in vitro studies, Zebra fish (Danio rerio) have been found to be a good in vivo model
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of MADD. They feature mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased glycolytic flux and hyperplastic neural progenitor cells [91, 92]. In an
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etfa-null Zebrafish model, increased Mechanistic Target of Rapamycin Complex 1 (mTORC1)
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signalling was treated with rapamycin, and this partially reversed the MADD- phenotype [92]. In an etfdh-null Zebrafish model, it was shown that the PPARγ-ERK pathway was up regulated, and
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a PPARγ agonist partially rescued the model [91]. However, the clinical relevance of these
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studies is yet to be ascertained.
3.3.1
MADD
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HIGH RISK: MADD patients are frequently misdiagnosed with polymyositis. patients
are
often
mistakenly
diagnosed
with polymyositis,
and
treated
with
glucocorticoids. Mistreatment with glucocorticoids was compared with riboflavin in a cohort of 45 patients with late-onset MADD. 18 were initially administered glucocorticoids (1mg/kg/day), and the remaining 27 patients took riboflavin (90-120mg/day) and coenzyme Q10 (60mg/day) for at least one month. Muscle strength was only improved in the riboflavin group [93]. Moreover, glucocorticoids have the potential to increase lipid levels and lipid accumulation,
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ACCEPTED MANUSCRIPT which would be particularly harmful in these patients. Potential adverse events include metabolic disorder, Cushing syndrome, and gastrointestinal ulcers [94].
3.3.2
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HIGH RISK: MADD patients are particularly sensitive to dietary changes
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Care also needs to be taken when advising MADD deficiency patients on dietary changes. A 2014 case study reported a 33-year old woman who presented with a history of progressive weakness
[78].
The patient was taking citalopram (20mg/day) and
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proximal muscle
hydrocodone/ibuprofen (7.5mg/200mg for pain, however still required hospital admission).
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Gabapentin (300mg 3 times daily) and hydrocodone/ibuprofen were further prescribed. Serum carnitine level was low, and carnitine supplements were given four times a day (1mg).
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Symptoms persisted. A cocktail of carnitine (4mg/twice daily), coenzyme Q10 (150mg twice daily) and riboflavin (100mg twice daily) was then given. However treatment failed to reverse
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symptoms, and respiratory function declined resulting in death. Notably, prior to death the patient revealed deliberate restriction of carbohydrate intake as a means of weight loss [78],
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potentially exacerbating metabolic decline.
These studies highlight the shortfalls that can still occur in the clinical care of MADD deficiency,
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due to either misdiagnosis or neglecting an appropriate clinical interrogation of dietary practices.
METABOLIC INVOLVEMENT IN CLASSICALLY NON-METABOLIC SYNDROMES In a clinical and genetic analysis study of LSMs only 24% of cases were attributed to mutations in the ‘classic’ LSM genes, including PNPLA2, CGI-58 or ABHD5, SLC22A5, ETF-A, ETF-B and ETF-DH [2]. Thus, we speculate that some LSMs may be associated with genes not previously associated
with metabolic disorders, including Neurofibromatosis type 1 and
autoimmune myopathies.
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4.1 Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 1 (NF1) is a complex, multi-system autosomal dominant genetic disorder affecting ~1:3000 individuals. Individuals with NF1 present with a spectrum of
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characteristic clinical and sub-clinical features including a high tumor burden, skin pigment
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abnormalities, osseous dysplasias, and cognitive abnormalities. While there are many anecdotal
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reports of reduced muscle strength, high fatigability, and decreased motor function in NF1, these have historically been attributed to neuromuscular causes [95]. However, several recent seminal studies have highlighted the prevalence and impact of muscle weakness in well-described
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paediatric cohorts [96] and revealed a biological mechanism using genetic mouse models [97,
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98].
Most notably, murine Nf1 knockout muscle [97] and human NF1 muscle biopsies [99] exhibit
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substantively elevated levels of intramyocellular lipid. A 2018 study has revealed that this is associated with an increase in long-chain fatty acids in a murine model and that the muscle lipid
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phenotype could be rescued by a reduced long-chain fatty acid diet and L-carnitine supplementation [99]. These data suggest that NF1 shares many features of a LSM both in terms
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of muscle function and histology, and may be potentially treated using a targeted metabolic
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4.2
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intervention.
Autoimmune myopathies Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM) are a rare and heterogeneous group of autoimmune myopathies with a combined prevalence of 15-32 cases per 100,000 [100]. These diseases are characterised by muscle weakness and fatigue [101-103]. An abnormal immune response has been implicated by the infiltrations of inflammatory cells in histopathology of muscle biopsies. High levels of serum triacylglycerol, non- high-density lipoprotein-cholesterol (non HDL-C), and very low-density lipoprotein-cholesterol (VLDL-C) are common to PM/DM patients [102, 19
ACCEPTED MANUSCRIPT 103]. Intramyocellular lipid droplets have been observed in PM patient muscle tissue [104]. Similarly, accumulations of free (non-esterified) cholesterol are found in the muscle fibers of patients with IBM [101]. Potential mechanisms for muscle dysfunction and fatigue include impaired fatty acid metabolism and reduced energy bioavailability and/or lipotoxicity. In a clinical setting patients respond poorly to immune therapy [105], despite being the
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traditional approach to autoimmune myopathies treatment. For example, the phase IIb/III multi-
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center international study for Bimagrumab, an anti-ACVR2B monoclonal antibody to improve muscle performance failed to achieve its primary outcome goals [106]. Therefore, a need to
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develop another targeted therapy for autoimmune myopathies is necessary. Triheptanoin oil is a medium odd-chain fatty acid-enriched oil that has been speculated to improve muscle and
is
currently
registered
for
phase
I
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performance
trial
for
treatment
of IBM
[ACTRN12614000082606]. Statins are potent cholesterol-lowering drugs, which may benefit
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patients with PM/DM/IBM [107]. While they may affect lipid droplet formation, statins have also been associated with muscle pain, weakness and fatigue [108]. It is unknown whether statins
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have a positive or negative affect on muscle in the context of PM/DM/IBM [107]. There are cases of PM/DM, which have been triggered by prior exposure to statin use, and these were
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associated with a more aggressive clinical course [109].
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5. CONCLUSION
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Lipid Storage Myopathies (LSMs) represent a diverse class of metabolic disorders that result in lipid accumulation and impaired muscle function. The underlying causes of disease have been linked to genes associated with triacylglycerol lipolysis, fatty acid transport, and beta-oxidation. Based on the different and often highly effective treatments available for LSM, early and correct diagnosis is imperative. Conditions such as MADD deficiency are associated with a higher than acceptable rate of misdiagnosis, which can result in delays to treatment and high morbidity. For PCD, understanding the risks associated with pivalic acid-containing antibiotics is critical to reduce mortality in this patient population. Finally, conditions such as NF1 and PM/DM/IBM have not been historically classified as LSMs, but exhibit many features common to LSMs. Thus
20
ACCEPTED MANUSCRIPT there may be justification to reevaluate the current classification systems to accommodate these related conditions.
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ACKNOWLEDGEMENT
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We thank Ms Fiona Tea for her assistance with graphical design of the Figures during
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manuscript revision.
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Mosegaard, S., et al., An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Mol. Genet. Metab. 122 (2017) 182-188. Vattemi, G., C. Gellera, and G. Tomelleri, Riboflavin responsive multiple acyl-CoA
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132.
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dehydrogenase deficiency: delayed hypersensitivity reaction and efficacy of low dose
133.
Creanza, A., et al., Successful pregnancy in a young woman with multiple acyl-coa
Pooja, M., et al., Multiple Acyl CoA dehydrogenase deficiency: Uncommon yet treatable
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disorder. Neurol. India. 65 (2017) p. 177. 135.
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dehydrogenase deficiency. JIMD Rep, 2017. 134.
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intermittent supplementation. Eur. J. Neurol. 24 (2017) 41-42.
Vengalil, S., et al., Fatty acid oxidation defects presenting as primary myopathy and
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prominent dropped head syndrome. Neuromuscul. Disord. 27 (2017) 986-996. Fu, H.-x., et al., Significant clinical heterogeneity with similar ETFDH genotype in three
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Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. Neurol. Sci. 37 (2016) 1099-1105.
Wang, Z., et al., Severe sensory neuropathy in patients with adult-onset multiple acyl-
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CoA dehydrogenase deficiency. Neuromuscul. Disord. 26 (2015). 170-175. Peng, Y., et al., Bent spine syndrome as an initial manifestation of late-onset multiple
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acyl-CoA dehydrogenase deficiency: a case report and literature review. BMC Neurol. 15
139.
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(2015) 114.
Zhuo, Z., et al., A case of late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (MADD) with a novel mutation in ETFDH gene. J. Neurol. Sci. 353 (2015) 84-86.
140.
Wen, B., et al., Multiple acyl-CoA dehydrogenation deficiency as decreased acylcarnitine profile in serum. Neurol. Sci. 36 (2015) 853-9.
141.
Ersoy, E.O., et al., Glutaric aciduria type 2 presenting with acute respiratory failure in an adult. Respir. Med. Case Rep. 15 (2015) 92-94.
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Gautschi, M., et al., Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy. Pediatr. Res. 2015. 77(1-1): p. 91-8.
143.
Rosenbohm, A., et al., Novel ETFDH mutation and imaging findings in an adult with glutaric aciduria type II. Muscle & Nerve. 49 (2014) 446-450.
144.
Zhu, M., et al., Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients. J. Hum. Genet. 59 (2014)
Wen, B., et al., Increased muscle coenzyme Q10 in riboflavin responsive MADD with
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145.
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256-61.
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ETFDH gene mutations due to secondary mitochondrial proliferation. Mol. Genet. Metab. 109 (2013) 154-60.
Zhao, Z.N., et al., A case of late onset riboflavin responsive multiple acyl-coa
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146.
dehydrogenase deficiency with novel mutations in ETFDH gene. CNS Neurosci. Ther.
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18 (2012) 952-954.
Trakadis, Y., et al., Pregnancy of a patient with multiple Acyl-CoA dehydrogenation
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deficiency (MADD). Mol. Genet. Metab. 106 (2012) 491-494. Cotelli, M.S., et al., Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency
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with unknown genetic defect. Neurol. Sci. 33 (2012) 1383-1387. Rosa, M., et al., Developmental evolution in a patient with multiple acyl-coenzymeA
(2011) 203-205.
Izumi, R., et al., A case of late onset riboflavin-responsive multiple acyl-CoA
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dehydrogenase deficiency under pharmacological treatment. Eur. J. Paediatr. Neurol. 16
dehydrogenase deficiency manifesting as recurrent rhabdomyolysis and acute renal
151.
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failure. Internal medicine (Tokyo, Japan) 50 (2011) 2663. Kaminsky, P., et al., Subacute myopathy in a mature patient due to multiple acyl coenzyme a dehydrogenase deficiency. Muscle & Nerve. 43 (2011) 444-446.
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Figure 1: Intracellular lipolysis. A) In adipose tissue, Protein Kinase A (PKA) signaling phosphorylates Perilipin -1, which causes CGI-58 to dissociate from Perilipin-1 and bind to Adipose Triglyceride Lipase (ATGL). ATGL catalyses the initial, rate-limiting step of lipolysis by converting a triglyceride to a diglyceride by releasing a bound fatty acid. Subsequently, diglycerides are hydrolysed by Hormone Sensitive Lipase (HSL) releasing a second fatty acid, and Monoglyceride Lipase (MGL) hydrolyses monoglycerides to liberate the last fatty a cid from the glycerol back bone. B) In non-adipose tissue lipid droplets, ATGL and CGI-58 are recruited by Perilipin-5 to form a complex, and this triggers the sequential hydrolysis of triglycerides to liberate all three fatty acids from the glycerol backbone. The release of free fatty acids into circulation is tightly regulated, and once released into the vasculature the free fatty
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acids are bound to albumin and transported as a complex to target tissue.
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Figure 2: Cellular uptake and the Carnitine Shuttling System. Once the free fatty acid-albumin bound complex reaches the target cell, the free fatty acid is transported across the cellular membrane by a Fatty Acid Transport Proteins (FATP). During times of rapid oxidative demand Fatty Acid Translocase (FAT/CD36) is also involved. Once inside the cytoplasm, it is then processed into a fatty acid acyl CoA molecule by Fatty Acyl-Coenzyme A Synthetase (FACS). The OCTN2 transporter is responsible for cellular uptake of carnitine. Carnitine is used by Carnitine Palmitoyltransferase 1 (CPT I) to synthesize an acylcarnitine molecule, which is shuttled across the inner mitochondrial membrane by Carnitine Translocase (CACT). Finally, acyl carnitine is converted back into carnitine, and a fatty acid acyl-CoA molecule by Carnitine Palmitoyltransferase 2 (CPT II) for beta-oxidation within the mitochondrial matrix.
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Figure 3: Beta oxidation and the Electron Transport Chain. Beta oxidation is the catabolic process by which a fatty acyl-CoA molecule is broken down within the mitochondrial matrix to produce 1) an acetyl CoA molecule that feeds into the Krebs cycle and 2) NADH and FADH 2 which act as reducing agents and transfer electrons across the Electron Transport Chain (ETC) complexes. The initial rate-limiting step of beta oxidation is catalyzed by a class of enzymes, knowns as the Acyl-CoA Dehydrogenases. These enzymes transfer electrons to the electron acceptors Electron Transfer Flavoprotein (ETF) and Electron Trans fer Flavoprotein-Ubiquinone Oxioreductase (ETF-UO). They then transfer the electrons to complex 1, Ubiquinone, of the electron transport chain (ETC). The ETC involves a series of 5 protein complexes, transferring electrons through a series of redox reactions to the ATPSynthase (complex 5) resulting in the phosphorylation of ADP into ATP.
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Table 4: Treatment-outcome case reports of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) patients since 2011
Author/yea r
Patien t
Clinical presentation
Diagnostic testing
Treatment
Transient MADD
Mosegaard, et al 2017 [131]
Newborn, Female
- Lethargy, hypotonia, hyperammonemia, metabolic lactic acidosis and encephalopathy.
- Urine: excretion of lactate, ketones, dicarboxylic acids and traces of glutaric acid
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Lipid Storage myopath y
- Riboflavin (200mg/day, 2 divided doses), fat and protein restricted diet, avoidance of fasting, carnitine substitution
Hyperammonemi a and metabolic lactic acidosis did not recur (30 month follow-up).
- Riboflavin (100mg/day slowly lowered to 20mg/day).
- Muscle weakness had completely resolved (22 years follow-up)
40 years of age, Female
- Diffuse myalgia, muscle stiffness, exercise intolerance and progressive weakness.
MADD
Creanza, et al, 2017 [133]
18 years of age, Female
- Preganant
- Riboflavin was discontinued and normal psychometric development pursued.
- PCR analysis: heterozygous intronic c.1134 + 11G>A variation in SLC52A1 - Muscle biopsy: atrophic fibres and lipid storage
- Gene screening: no mutations in ETFA, ETFB or ETFDH.
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Vattemi, et al, 2017 [132]
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- Newborn screening: ↑ acyl carnitines (C6-C18)
MADD
Clinical outcomes
- Urine organic acids: typical dicarboxylic aciduria.
- Gene analysis: compound heterozygosity in ETFDH c.1074G>C
- ↑ carbohydrate, ↓ fat, six meal diet, and riboflavin (100mg/day), pyridoxine (300mg/day), Lcarnitine (up to 4g/day during third trimester) and protein supplements (up to 30g/day during
- T reatment withdrawal resulted in muscular symptoms, resolved upon riboflavin reintroduction. - Pregnancy progressed and patient gave birth without complications
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Pooja, et al, 2017 [134]
24 years of age, Male
- MS/MS: ↑ medium and long chain acyl carnitines
- Exertion-induced weakness and fatigue
- During delivery and postoperative period carnitine (3g/day) and an isotonic solution (with 10% dextrose) was administered. - Riboflavin (100mg/day), CoQ10 (60mg/day) and carnitine (500mg/day)
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MADD
second trimester) throughout pregnancy
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and c.1073G>A in exon 9.
- Dramatic improvement in exercise tolerance (6 month follow up).
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- Urine: ↑ 2-hydroxy glutaric acid, 2hydroxy adipic acid and palmitic acid
6 adults (17-40 years of age, 1 Female and 5 Males)
- Exertional myalgia, and muscle weakness
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Vengalil, et al, 2017 [135]
Fu et al. 2016 [136]
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MADD
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MADD
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- Muscle biopsy: lipid storage
MADD
Behin, et al, 2016 [82]
23 years of age, 68 years of age and 15 years of age, Male
13 Adults (21-55 years of age, 8 Female and 5
- Muscle weakness and exercise intolerance
- Exercise intolerance, myalgia and muscle weakness
- MS/MS: ↑ acylcarnitines and carnitine
- Muscle biopsy: lipid storage
- Initially received a course of oral steroids (for polymyositis) - Riboflavin, CoQ10 and carnitine and restriction of fat intake.
- Gene analysis: 3 compound heterozygous variants of EFTDH including c.892C>T, c.453delA and c.449_453delTAACA ,
- Prednisolone (60 mg per day) (for polymyositis)
- Muscle biopsy: lipid storage
- All treated with L-carnitine, 11 with riboflavin, 4 with CoQ10, 1 with MCT ’s, all on adapted diet
- Proton pump inhibitors (for irritable bowel syndrome)
- No definitive benefits of oral steroids. - All patients reported alleviation of symptoms:fatigue , muscle weakness, dysphagia, myalgia and dropped head syndrome (follow-up period not stated). - Ongoing myalgia and weakness with prednisolone (8 year follow up). - Symptom free with riboflavin (6 month follow up)
- Riboflavin (6090mg/day) and CoQ10 (60mg/day) - Followed up for up to 27 years there was a good response, 11/13 continued to display minor
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6 Adults (33-54 years of age, 1 Female and 5 Male)
- Proximal limb weakness and sensory neuropathy, particularly distal limb numbness
- Muscle biopsy: myofibre size variability and lipid storage
- Riboflavin (60mg/day), carnitine (2g/day) and CoQ10 (100mg/day), vitamin B12 (500ug/day)
- Strength returned (two weeks follow-up)
- Riboflavin (60mg/day), after 3 weeks dropped down to riboflavin (30mg/day), CoQ10 (100mg/day) and vitamin B12 (500ug/day)
- Spine and dropped head completely resolved 93 week follow-up)
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Wang, et al, 2016 [137]
and limited fat intake
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MADD
- Gene analysis: ETFDH mutations including c.250G>A, c.571G>A, c.622G>C, c.877C>G, c.1732C>T, c.79C>T, c.406-2A>G, C.1366C>T, c.877C>G, c.245C>T and c.769T>C.
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Male)
- 2/6 patients reported none to mild alleviation of sensory disturbances (18 month follow-up).
46 years of age, Male
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Peng, et al, 2015 [138]
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MADD
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- Urine: ↑ 2hydroxyglutaric acid, 2hydroxyadipic acid, 3-hydroxypropanoic acid and ethylmalonic acid.
symptoms of exercise intolerance
- Bent spine, dropped head and numbness
- Next gen. seq.: c.242T>C, c.770A>G, c.1227A>C, c.65A>G, c.920C>G and c.1450T>C in ETFDH - Urine: ↑ glutarate, 2-hydroxyglutaric acid, 3hydroxyglutaric acid, glyceric acid and 2-hydroxyadipic acid. - Serum: ↑ acylcarnitines
- Muscle strength improved and mild alleviation of numbness after persistent administration (6 month follow-up)
- Muscle biopsy: lipid storage
- Gene screening: c.770A>G in exon 7, and c.920C>G in
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ACCEPTED MANUSCRIPT exon 8 of EFTDH. 9 years of age, Female
- Muscle weakness, intermittent vomiting and hepatosplenomegal y
- Muscle biopsy: lipid storage
- Riboflavin (100mg/day) and L-carnitine (50mg/kg/day), ↑ calorie ↓ fat diet
- MS/MS: ↑ ethylmalonate, glutarate, 2hydroxyglutaric acid, adipic acid and suberic acid.
- Muscle strength restored (1 month follow-up) - Liver and spleen size normalised (3 month follow-up)
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Zhuo, et al, 2015 [139]
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MADD
24 years of age, Male
- General fatigue, weakness, muscle pain, intermittent nausea and vomiting
- Muscle biopsy: myofibre size variability and lipid storage
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Wen, et al, 2015 [140]
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MADD
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- Gene seq.: compound heterozygous mutations c.389A>T in exon 3 and c.736G>A in exon 7 of EFTDH
CE Ersoy, et al, 2015 [141]
19 years of age, Female
- L-carnitine (2g/day) and Riboflavin (30mg)
- Progressive muscle weakness, dyspnea and hepatomegaly
- MS/MS: and organic acid analysis: ↑ acyl carnitines
- Muscle weakness and exercise intolerance persisted with prednisone (40 day follow-up)
-Muscle weakness mildly improved with carnitine (24 day follow-up)
- Seq. analysis: compound heterozygous mutations c.1211T>C in exon 10 and c. 1450T>C in exon 11 of ETFDH.
AC MADD
- Serum: ↑ acyl carnitines
- Prednisone therapy (60mg/day) (for polymyostitis)
- Exercise intolerance and muscle weakness dramatically improved, and eventually all symptoms resolved (2 year follow-up). - Carnitine (1g), riboflavin (100mg) and CoQ10 (100mg), hemodialysis and physiotherapy
Progressive recovery with the ability to walk and swallow dramatically improving (4
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ACCEPTED MANUSCRIPT month followup). Gautschi, et al, 2015 [142]
2.5 years of age, Male
- Progressive muscle weakness, severe metabolic decompensation, hypoglycemia and diffuse leukodystrophy.
- Serum: acylcarnitines and urinary organic acids suggestive of MADD
- Racemic mixture of NaHB (3-4% of daily caloric need)
25 years of age, Female
- Erythematous rash, rhabdomyolysis, and progressive quadriparesis becoming bedbound
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Rosenbohm, et al, 2014 [143]
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- Gene analysis: homozygous mutation c.1106G>C in exon 9 of EFTDH.
- A fat and protein restricted diet and carnitine, riboflavin (100mg/day) and ubiquinone (510mg/kgBW/day) .
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MADD
Shioya, et al, 2014 [90]
31 years of age, Male
- MS/MS: ↑ some long chain acylcarnitines, adipic, suberic, sebacic, 2hydroxyglutaric and ethylmalonic acid
- Motor function improved, mood and behaviour normalized and vocabulary increased. There was some indigestion and dehydration (1 month of NaHB treatment)
- Catch up of development continuing (3 year follow-up) - Riboflavin (200mg/day), CoQ10 (15mg/kg/day), a diet with ↓ fat (10-15%), ↑ carb, and medium protein levels (10%)
- Almost complete recovery, 10kg of weight was regained and strength improved (9 month follow-up)
- L-carnitine, and riboflavin (105mg/day) or BEZ (8.2mg/kg/day).
- When riboflavin was added to the L-carnitine and BEZ, symptoms completely resolved (21 month followup).
- Gene sequencing: homozygous c.1544G>T mutation in ETFDH.
AC MADD
- Muscle biopsy: lipid storage
- Patient did not respond to riboflavin
- Muscle weakness and limb fatigability
- Muscle biopsy: lipid storage
- Serum: ↑ acyl carnitines - Urine: ↑ 2-OHglutarate, ethylmalonate, 3-
- Riboflavin was added to L-
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ACCEPTED MANUSCRIPT carnitine and BEZ treatment.
OH-propionate
- Muscle weakness, exercise intolerance, myalgia and recurrent vomiting after fatty meals
- Muscle biopsy: lipid storage
- Mutation screening of ETFA, ETFB and ETFDH: 13 heterozygous changes in ETFDH of each patient, including c.3G>C, c.389A>T, c.524G>A, c.715G>A, c.770A>G, c.821G>A, c.1084G>A, c.1211T>C, c.1227A>C, c.1395T>G, c.1399G>A, c.l773_1774delAT, c.1828G>A, c.295C>T, c.303T>A, c.518T>G, c.1586A>G and c.1810G>T
AN M ED CE
PT MADD
Van Rijt, et al, 2014 [84]
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MADD
Wen, et al, 2013 [145]
Newborn, Female
34 Adults (6-50 years of age, 18
- L-carnitine (2g/day), riboflavin (60mg/day), CoQ10 (90mg/day).
IP
13 adults (26-57 years of age, 4 Females and 9 Males)
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Zhu, et al, 2014 [144]
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MADD
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- Gene analysis: compound heterozygous missense mutations (890G>T/W297L and 950C>G/P317R) in ETFDH.
- Hypoglycemia, developmental delay, severe tachyarrhythmias and progressive cardiomyopathy.
- Gene analysis: homozygosity for a mutation in ETFA (specific mutation not stated).
- All adults showed proximal muscle weakness and
- Muscle biopsy: lipid storage
- Muscle weakness, myalgia and exercise intolerance were completely resolved (1 month follow-up)
- Less responsive patients (3) were administered a higher dose of riboflavin (120mg/day) and prednisone (30mg/day)
- Frequent feedings, restriction of fat, riboflavin, CoQ10. - NaHB was added (increased from 450mg/kg/day to 900mg/kg/day and finally 2600mg/kg/day). - CoQ10 (60mg/day), and after two weeks
- Following the highest dosage of NaHB clinical improvement observed (followup not stated)
- Partial recovery of muscle weakness with
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ACCEPTED MANUSCRIPT Females, 16 Males)
exercise intolerance
riboflavin therapy
55 years of age, Male
- Osphyalgia, muscle weaknesss, difficulty walking, fatigue, swallowing and speaking anorexia and intermittent nausea
- Muscle biopsy: lipid storage
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Zhao, et al, 2012 [146]
- Riboflavin (100mg/day) and ↓ protein/fat and ↑ carb diet
- Symptoms subsided and exercise intolerance improved within a few weeks (6 year follow-up)
- Intravenous carnitine (660mg 3 times daily), riboflavin (100mg), intravenous 10% dextrose and ondansetron, commercial oral rehydration
- Recurrent vomiting associated with fatigue resolved by treatment. Gastrienteritis improved with oral rehydration solution. Gave birth to a child by
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MADD
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Gene analysis: ETFDH gene mutations at c.1227A>C, c.242T>C, c.770A>G, c.380T>G, c.122T>C, c.1436G>C, c.1295T>A, c.389A>T, c.250G>A, c.256C>T and c.251C>T.
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- Serum and urine: changes consistent with MADD.
CoQ10 (2 week follow-up), and on the addition of riboflavin muscle strength almost returned too normal (2 month follow-up).
Trakadis, et al, 2012 [147]
24 years of age, Female
- MS/MS: ↑ acyl carnitines
- Gene analysis: compound heterozygous mutations including c.1522C>A and c.1583_1584insA in ETFDH.
AC MADD
- Urine: abnormal excretion of glutarate, methylmalonic acid and 2hydroxyglutaric acids
- Pregnant haha this is not a disease.
Was she doing a standard preg test or something?
- At diagnosis blood acyl-carnitine and urinary organic acid profiles were consistent with MADD.
- PCR and
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- Muscle biopsy: lipid storage
- Riboflavin (100mg/daily) and ↓ fatty acid, ↓ protein and ↑ carbs diet
- Able to walk normally with no significant weakness (1 year follow-up)
- Carnitine (1gr/day) and after one month additional riboflavin (100mg/day) and ubiquinone (50mg/day) treatment
- Modest improvement of limb weakness with carnitine (1 month follow-up)
- Riboflavin (100mg/day), Lcarnitine (50mg/kg/day) and ↓ fat diet
- Muscle weakness and fatigue gradually improved (3 week follow-up)
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- Waddling and stepping gait, reduced reflexes and muscle weakness
- Intravenous carnitine (During delivery -1000mg every 8 hours, after delivery – 1320mg and reduced back to pre-delivery levels)
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20 years of age, Male
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Cotelli, et al, 2012 [148]
solution during pregnancy.
- ESI-MS/MS: ↑ long and medium-chain carnitine esters
C-section. Remained stable with no hypoglycemia or acidosis during or after delivery.
US
MADD
bidirectional DNA seq.: homozygous c. 1601C>T mutation in exon 12 of ETFDH.
Rosa, et al, 2012 [149]
7 months of age, Male
- Developmental delay and muscle weakness
AC MADD
Izumu, et al, 2011 [150]
56 years of age, Male
- PCR analysis: No identified mutations - MS/MS: ↑ short, medium and long chain acylcarnitines
- Urine: ↑ ethylmalonic, glutaric, OHcaproic, adipic, suberic and sebacic acids
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PT
MADD
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- Urine: ↑ hydroxyglutaric and ethyl-malonic acid
- Fatigability, muscle weakness, myalgia, weight loss and dysarthria.
- Muscle biopsy: lipid storage
- Serum: ↑ free carnitine and acylcarnitine - Urine: ↑ glutarate
- Improved motor function, and effect of therapy on intellectual disability (6 month follow-up)
- No relapse of rhabdomyolysis and returned to
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ACCEPTED MANUSCRIPT normal daily activity (6 month follow-up)
Kaminsky, et al, 2011 [151]
55 years of age, Female
- Severe myalgia, muscle weakness,
- Muscle biopsy: lipid storage
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MADD
IP
- Gene analysis: compound heterozygous missense ETDH mutation c.1211T>C in exon 10 and c. 1786G>A in exon 13.
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and 2-OH-glutarate
Able to walk normally and myalgia resolved (6 month followup)
-PCR analysis: heterozygous c.877C>G in ETFDH
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- MS/MS: ↑ short, medium and longchain acylcarnitine
- Riboflavin (30mg/day), Lcarnitine (50mg/kg/day) and a ↓ fat, ↓ protein, ↑ carb diet
PT
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary
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Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”, “Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
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Storage Disease with Myopathy”. To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including unconfirmed diagnoses, or non-intervention observational studies were not included. Only Englishwritten articles published within the last seven years were assessed (2011-2017 inclusive).
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ACCEPTED MANUSCRIPT Table 2: Treatment-outcome case reports of Neutral Lipid Storage Disease with Ichthyosis (NLSD-I) patients since 2011. Confirmation diagnostic testing
Arora, et al, 2017 [53]
8 years of age, Male
- Generalised scaling, erythema, distended abdomen, hepatomegaly, reduced tone and muscle weakness
- Skin biopsy: Hyperkeratosis, lipid storage.
Verma, et al, 2017 [113]
17 years of age, Male
- Nephritis, proteinuria and ichthyosiform erythroderma
- T opical emollients and acitretin (10mg/day)
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- Parents were unwilling for genetic analysis.
Treatment
T
Clinical presentatio n
- 4-mm punch biopsy: Acanthotic dermatitis. -Liver biopsy: macrocellular hepatosteatosis and Jordans anomaly.
AN
NLSD-I
Patient (age and gender )
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NLSD-I
Author and year
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Lipid Storage myopath y
29 months of age, Female
Developmentally delayed in all spheres, generalized scaling of the whole body, abdominal distension, central hypotonia and hepatomegaly - On and off fever, progressive abdominal distension, hepatomegaly and generalised erythroderma
- Peripheral blood smear: Jordans anomaly
- Motor development delay, slight hypotonia, and generalised ichthyosiform squamae and excoriations
- Peripheral blood smear: Jordans anomaly
ED
Gupta, et al, 2016 [114]
Waheed, et al, 2016 [115]
1 year of age, Male
Huigen, et al, 2015 [54]
18 months of age, Female and Age not clear, Male
AC
NLSD-I
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PT
NLSD-I
NLSD-I
- Significant pruritic ichthyosis and
- Liver biopsy: distorted globular architecture and ballooning - Gene analysis: homozygous nonsense mutation c.297>C in exon 3 of ABHD5.
- Blood smear: Jordans anomaly - Liver biopsy: Moderate to severe steatosis, ballooning and pericellular fibrosis
- Gene analysis: homozygous mutations c.47+1G>A in intron 1 (patient 1), c.594insC in exon 4 (patient 2) of ABHD5
- Scaling and erythema reduced - Liver enzymes have normalised - Muscle weakness is static
- Prednisolone (tapering dose of 0.5mg/kg-1 ) and diuretics -Petroleum jelly, and a ↓ fat diet with, moderatecarbs
M
- Bidirectional Sanger seq.: homozygous missense mutation c.752>C. of ABHD5.
Reporte d clinical outcome s
- ↓ fat, ↓ protein, ↑ MCT ’s and ↑ carb diet - UDCA, vitamin E and local emollients
- Advised a ↓ fat, ↓ protein, ↑ MCT’s and ↑ carb diet and emollients
- Diverse emollients and MCT diet
- Kidney functioning normally. - Proteinuria persisted. Erythroderma severity unchanged (1 year followup) - Repeat lipid profile showed almost similar levels (6 month follow-up)
Improvement in clinical condition was reported (no specific detail; 3 month follow-up). - Motor and cognitive development normalized (2 year followup). - At seven years of age hepatomegaly vanished. It
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Newborn, Female
- Congenital ichthyosis, and hepatomegaly (from 2 years of age).
- Peripheral blood smear: Jordans anomaly - Liver biopsy: Severe macro and micro-vesicular steatosis
- Liver biopsy: diffuse micro and macro-vesicular steatosis
- Peripheral blood smear: Jordans anomaly
- Progressive upper abdominal distension, generalised ichthyosis and hepatomegaly.
- Peripheral blood smear: Jordans anomaly
AN
18 months of age, Male
- Aquaphor® ointment applied from birth
- Liver biopsy: macrovesicular steatosis, cirrhosis and steatohepatitis - Skin biopsy: Hyperkeratosis
- Hydrocortisone topical from 2 years old - ↓ fat diet with MCT ’s and UDCA and vitamin E initiated at 4 years and 9 old. - Oral acitretin (10mg biweekly) and a diet with ↑ MCT ’s and ↓ LCFAs.
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Srinivasarag havan, et al, 2013 [51]
US
- Gene analysis: 3955bp homozygous deletion associated with a 26bp insertion (NG_007090.3: g.43728907_43732862del3955ins 26) in ABHD5. NLSD-I
- ↓ fat diet and topical emollients/treatme nt
T
Missaglia, et al, 2014 [117]
29 years of age, Female
CR
NLSD-I
Kazemi, et al, 2015 [116]
IP
NLSD-I
erythrodermia, mild diffuse bilateral cataract and hepatomegaly - Generalised skin scaling, mild erythema, brown hyperpigmentatio n and hyperkeratosis
Israeli, et al, 2012 [52]
2 years of age, female
- Generalised skin scaling, mildly distended abdomen and hepatomegaly.
- Peripheral blood smear: Jordans anomaly - Skin biopsy: Compact orthokeratosis, irregular acanthosis and papillomatosis. - Direct seq. analysis: homozygous transition located within an intron 6 (c.960 + 5G>A) of ABHD5
- Moderate amounts of carb, and MCT ’s, and oral acitretin (0.5mg/kg/day)
- Skin lesions were significantly reduced, and liver function tests improved, e.g. aspartate transaminase decreased (2 month follow-up) - Dramatic improvement s of the skin condition and liver function tests were observed (2 month follow-up)
AC
CE
PT
NLSD-I
ED
- Genetics: homozygous c.5063C>G in ABHD5.
was reported the diet was ineffective and discontinued. T ransaminase s levels continually fluctuating (follow-up period and outcomes not detailed). Improvement s of liver size and skin condition following dietary treatment, UDCA and vitamin E (1 year followup).
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”, “Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid Storage Disease with Myopathy”. To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including
47
ACCEPTED MANUSCRIPT unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
AC
CE
PT
ED
M
AN
US
CR
IP
T
written articles published within the last seven years were assessed (2011-2017 inclusive).
48
ACCEPTED MANUSCRIPT
Table 1: Treatment-outcome case reports of Neutral Lipid Storage Disease with Myopathy (NLSD-M) patients since 2011
Clinical
Diagnostic testing
T
Patient
Clinical outcomes
Treatment
IP
Author/year
CE
PT
ED
M
AN
US
CR
Presentation
AC
Lipid Storage myopathy
49
ACCEPTED MANUSCRIPT
26 years of age, Male
- Syncope, shortness of breath, muscle weakness, severe dilated biventricular cardiomyopathy.
- Muscle weakness, walking difficulties, left ventricular dilation, ↓ left ventricular systolic function
- Muscle biopsy: lipid storage - Sanger seq.: homozygous missense mutation c.497A>G in PNPLA2.
- Muscle biopsy: lipid storage - Gene analysis: homozygous deletion of seven nucleotides in exon 7 (c.41_47_delGCTGCGG) of PNPLA2
- Beta-blocker, ACE inhibitor, Eplerenone, warfarin and a defibrillator was implanted
- Enalapril (5mg bid) and ivabradine (7.5mg/di)
T
Pasanisi, et al, 2016 [110]
22 years of age, Male
Pennisi, et al, 2015 [111]
72 years of age, Female
- Exercise intolerance, myalgia and muscle weakness.
- Peripheral blood smear: Jordans anomaly. - Muscle biopsy: mild non-specific myopathic changes - Gene analysis: c.497A>G in exon 5 and c.1442C>T in exon 10 of PNPLA2.
- Salbutamol (4mg, two divided doses), dexamethasone, (25mg/day), and phenofibrate (160mg/day)
Kaneko, et al, 2014 [112]
59 years of age, Male
AC
CE
NLSD-M
PT
ED
M
AN
NLSD-M
US
CR
NLSD-M
Muggenthaler, et al, 2016 [37]
IP
NLSD-M
NLSD-M
NLSD-M
Perrin, et al, 2013 [26]
Van De Weijer, et al, 2013 [38]
17 years of age, Male
37 and 39 years of age, Female
- Muscle weakness, cardiomegaly with dilation of the left ventricle and decreased ejection fraction.
- Fatigue, increased difficulties in running and walking, and myalgia after prolonged exercise.
- Progressive muscle weakness, diffuse hypokinesia of the left and right ventricles of the heart with ↓ ejection
- Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly - Gene analysis: Homozygous c.576delC PNPLA2 mutation.
- Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly. - Gene analysis: homozygous mutation c. 865C>T in exon 7 of PNPLA2 - Muscle biopsy: lipid storage - Peripheral blood smear: Jordans anomaly
- Beta-blockers, ACE inhibitors and diuretics, -Intensive care and cardiovascular treatment
- Initial improvements in shortness of breath - Condition deteoriated and patient required cardiac implantation (follow-up not stated). - Ejection fraction ↑ - Improved exercise capacity (oxygen consumption increased from 48 to 57% of the predicted value) (18 month follow-up) - Salbutamol was not tolerated and dexamethasone was stopped after no clinical improvement (2 month followup)
- ↓ myalgia and fatigue with phenofibrate treatment (follow-up not stated). - Over 10 years cardiac function deteoriated. Patient was discharged and received medication in outpatient settings.
- Oral Carnitine (1g/daily)
- No significant clinical improvement was observed and treatment ceased (6 month follow-up).
- Implantable cardioverter defibrillator in patient one and BEZ treatement
- No improvements in grip strength or cardiac
50
ACCEPTED MANUSCRIPT fraction.
in both patients (Bezalip, Actavis, 400mg/daily).
function (7 month followup)
- Some improvement in leg strength.
- The only notable difference was cardiac and muscle fat content.
US
CR
IP
T
- Mild myopathy and reduced exercise intolerance (heterozygote carrier).
- Gene seq. analysis: deletion causing a frame shift at amino acid position 270 in PNPLA2 of both patients. Additionally patient one has a missense mutation 548C>T .
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and
AN
ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”,
M
“Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
ED
Storage Disease with Myopathy”.
To be included in this review studies needed to meet the following criteria: Clinical case reports, controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including
PT
unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
AC
CE
written articles published within the last seven years were assessed (2011-2017 inclusive).
51
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
Table 3: Treatment-outcome case reports of Primary Carnitine Deficiency (PCD) patients since 2011
52
ACCEPTED MANUSCRIPT
Patient
PCD
Ravindranath, et al, 2017 [118]
8 months of age, Male
Clinical presentation
Diagnostic testing
Treatment
- Recurrent vomiting, lethargy, jaundice, enlarged liver, nonketotic hypoglycemia and hyperammonemia
- MS/MS: ↓ free & total carnitine & medium-chain dicarboxylic aciduria.
- Intravenous dextrose, sodium benzoate,& uncooked cornstarch in water
Clinical outcomes - No episodes of hypoglycemia ammonia levels & liver function normalized (4 month follow-up).
T
Author/year
CR
IP
Lipid storage myopathy
3 years of age, Female
- Progressive fatigue, shortness of breath, pallor of skin and conjunctivae and left ventricular hypertrophy.
ED PCD
Jun, et al, 2016 [77]
PT
Ganigara, et al, 2017 [119]
8 years of age, Male
AC
CE
PCD
3 years of age, Female
- Whole exome seq: homozygous c.1188 T>G in SLC22A5.
AN
Lahrouchi, et al, 2017 [66]
M
PCD
US
- Whole exome seq: homozygous c.1316 dupT in exon 8 of SLC22A5.
- Carnitine (100mg/kg/day), MCT (30% total energy intake), and ↓ LCFAs. - Carnitine (200mg/kg/day)
- ↑ Activities of daily living - Exercise tolerance normalized to age matched controls (8 month follow-up)
- MS/MS: no free carnitine & only trace of total carnitine.
- Altered sensorium, increased frequency of seizures and global developmental delay with hypotonia.
- MS/MS: ↓ free carnitine
- Levocarnitine & levetiracetam
- Patient seizure free (2 months follow-up)
- Tonic-clonic seizures and deeply drowsy. Experienced a severe course of hypoglycemic encephalopathy. This was attributed to consumption of pivalic acidcontaining antibiotics.
-Serum: ↓ carnitine
- Midazolam, phenobarbital and phenytoin, 10% glucose bolus, hydrocortisone (5mg/kg/day),
- Blood glucose stable (35 day follow-up)
- Genetic analysis identified c.396G>A and c.539A>C variations in SLC22A5.
- L-carnitine (55 mg/kg/day, three divided doses).
- Patient transferred to rehabilitation medicine for status epilepticus, disabled visual fixation, impaired visual acuity and impaired locomotion and transitional movements.
53
ACCEPTED MANUSCRIPT 9 months of age, Male
- Jaundice, failure to gain weight, mild motor developmental delay, frequent breathing problems, cardiomegaly and biventricular hypertrophy.
- MS/MS: ↓ free carnitine - Sanger Seq.: compound heterozygous mutations C.1354G>A and c.231_234del in SLC22A5.
Mahale, et al, 2016 [121]
8 months of age, Female
- Fever, loose stools, excessive irritability, lethargy, hepatomegaly and worsening sensorium.
- MS/MS revealed ↓ free carnitine (2.6mM/l).
PCD
Al-sharefi, et al, 2015 [122]
35 years of age, Female
- History of schizoaffective disorder, lithium-induced diabetes, insipidus and hyperthyroidism. Drowsiness, personality changes, fatigue, generalised weakness, and deteoriating mobility.
- Routine biochemistry diagnosed VHE.
US
- On 3 week follow-up serum: ↓ free and total carnitine
AN
M
ED
9 years of age, Male
Yilmaz, Atay, et al, 2015 [124]
12 years of age, Male
AC
PCD
CE
PT
Mutlu-Albayrak, et al, 2015 [123]
PCD
Kumar, et al, 2015 [125]
3 months of age, Male
- Dysmorphic appearance, fatigue and hypertrophic cardiomyopathy.
- Prominent fatigue, upper extremity muscle weakness, and decreased deep tendon reflexes, congestive heart failure, hypoglycemic hypoketotic and encephalopathy secondary to PCD.
- Altered sensorium, fever, hypertonia, abnormal body movements,
- MS/MS revealed ↓ free carnitine - Genetic testing identified a homozygous c.1427 T>G mutation in SLC22A5 Serum: ↓ free carnitine
- Mechanical ventilator, intravenous fluids, and levocarnitine (100mg/kg/day, divided doses).
- Gradually improved in sensorium and was extubated (follow-up not stated).
- Sodium valproate (1000mg, divided in two doses). - Carnitine (2000mg/day, divided in two doses).
- Within 3 days mental status improved achieving a 10/10 abbreviated mental test score.
- Oral carnitine (200mg/kg/day)
- Clinical improvement was observed, particularly ↓ fatigue (2 month follow up)
- Oral carnitine (dosage not stated).
- It was reported that heart failure ceased (follow-up not stated)
- An SLC22A5 mutation was found (mutation details not stated).
- Serum: deficiency of free carnitine
- Jaundice cleared within days
- ↑ left ventricular ejection fraction. Liver size and enzymes normalized (3 month follow-up).
CR
PCD
PCD
- Oral Lcarnitine (100mg/kg/day)
T
Deswal, et al, 2016 [120]
IP
PCD
- On 3 week follow-up fatigue and weakness persisted, after 2 weeks of carnitine this was resolved
- No post-treatment report on muscle function or hypoglycemic hypoketotic encephalopathy - Mechanical ventilation, intravenous fluids, antibiotics and
- Normalization of all clinical parameters reported (follow-up
54
ACCEPTED MANUSCRIPT tachypnea, tachycardia and seizures and hepatomegaly.
Wang, et al, 2014 [127]
5 children (1-14 years of age, 1 Female and 4 Males)
- Upper airway infection, cardiac insufficiencies, including cardiomegaly and left ventricular hypertrophy
- Serum: ↓ free and total carnitine
- All patients presented with dyspnea, cardiomyopathy and enlargement of the left ventricle.
- Highthroughput seq.: heterozygous c.338G>A, c.760C>T and c.865C>T SLC22A5 mutations.
T
IP
- Next gen. seq.: homozygous c.597_597delG mutation in SLC22A5
- L-carnitine (50-100 mg/kg/day p.o), plus digoxin, diuretics and vasodilators
CR
3 years of age, Male
3.5 years of age, Female
M
Agnetti, et al, 2013 [65]
- Fatigue and marked pallor, cardiomegaly and severe congestive heart failure.
- Left ventricular function returned to normal and heart size normalized for all patients (4 month to2 year follow-up).
- Oral carnitine (3g/day to 2g/day after 6 months)
- This proband has been followed for 28 years. Over time heart size normalized, along with other ECG and echocardiographic parameters. Able to perform regular physical activity.
- Muscle biopsy: lipid storage
CE
PT
ED
PCD
Serum: mean value 1.37 ± 0.66 𝜇mol/L - Serum: ↓ carnitine
- Treatment suspension lead to recurrence of muscle symptoms, and dosing reintroduction restored function.
AC PCD
Kilic, et al, 2012 [128]
7 children (5F and 3M 5-12 Y/O)
- This patient has been followed for 14 years. Over time, improvements in cardiac functions were observed, including improvements in left ventricular ejection fraction. No further details given.
- L-carnitine (200-300 mg/day p.o), plus digoxin, diuretics and vasodilators
AN
PCD
Yilmaz, Seker, et al, 2015 [126]
not stated).
- L-carnitine (100mg/kg/day, in divided doses) and MCT ’s.
US
PCD
antiepileptic medication.
- Symptoms of heart failure, and cardiomyopathy (6 dilated, 1 hypertrophic).
Serum: mean value 2.63 ± 1.92 𝜇mol/L - SLC22A5 analysis: p.G411V,
- Oral carnitine (100-300mg/kg) with cardiac inotropic and diuretic agents
- All signs and symptoms of heart failure and cardiomyopathy were reversed in every case
55
ACCEPTED MANUSCRIPT
20 years of age, Female
- Syncopal episode caused by ventricular tachycardia, and abnormal QT interval.
2 males (5 & 6 years)
- Skeletal myopathy and hypertrophic cardiomyopathy.
Serum: ↓ free carnitine
US
Kishimoto, et al, 2012 [64]
- Carnitine (3g increased to 4.2g/day)
- Both patients recovered muscle strength, and no longer fatigued easily after exercise.
22 years of age, Female
CE
Mazzini, et al, 2011 [130]
AC
PCD
PT
ED
M
AN
PCD
- Irregular heart rhythm, witnessed ventricular fibrillation arrest requiring resuscitation.
- Over 5 years cardiac symptoms and syncopal episodes persisted.
- Upon carnitine introduction syncopal episodes ceased, cardiac symptoms reversed and QT interval normalised (follow-up not stated).
- High dose carnitine (3,960mg/day).
CR
-Molecular analysis: c.95A>G and c.136C>G mutations in SLC22A5
- Metoprolol (50mg to 75/day), implanted defibrillator and mexiletine (450mg/day).
T
De Biase, et al, 2012 [129]
(1 year follow- up).
IP
PCD
p.G152R, p.R254X, p.R282X, p.R289X, p.T 337Pfs12X mutations. - After newborn screened positive, serum: ↓ total and free carnitine
- Skeletal and endomyocardial muscle biopsies: lipid storage
- Echocardiographic parameters normalized (30 year follow-up).
- PCR analysis: homozygous mutation in SLC22A5 (no specifics). - Gene Seq.: A142S and R488H mutations on allele 1 and 1588G>T on allele 2 of SLC22A5
- Cardioverterdefibrillator implanted, oral levocarnitine (3g/day) and MCFA’s
- Heart rhythm normalised (6 month follow-up).
- No arrhythmias have been reported (22 month follow-up)
- Serum: ↓ Free and total carnitine
Endomyocardial
56
ACCEPTED MANUSCRIPT biopsy: lipid storage
Table notes: We searched for articles in the Medline via OvidSP (1946-Present), PubMed, Scopus and ProQuest Research Library databases using the following strategy, combining terms with OR: “Primary
T
Carnitine Deficiency” “Multiple Acyl-CoA Dehydrogenase Deficiency”, “Glutaric Acidemia Type II”,
IP
“Neutral Lipid Storage disease with Ichthyosis”, “Chanarin-Dorfman Syndrome” and “Neutral Lipid
CR
Storage Disease with Myopathy”.
To be included in this review studies needed to meet the following criteria: Clinical case reports,
US
controlled and/or uncontrolled clinical trials involving an intervention and follow-up. Reports including unconfirmed diagnoses, or non-intervention observational studies were not included. Only English-
AC
CE
PT
ED
M
AN
written articles published within the last seven years were assessed (2011-2017 inclusive).
57
Figure 1
Figure 2
Figure 3