Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease

Author’s Accepted Manuscript Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease Marianne C van Schie, Sjaam Jainandunsing, Jeanine E Roeters van Lennep www.elsevier.com/locate/ejphar

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S0014-2999(17)30633-7 https://doi.org/10.1016/j.ejphar.2017.09.046 EJP71432

To appear in: European Journal of Pharmacology Received date: 15 May 2017 Revised date: 5 September 2017 Accepted date: 28 September 2017 Cite this article as: Marianne C van Schie, Sjaam Jainandunsing and Jeanine E Roeters van Lennep, Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease, European Journal of Pharmacology, https://doi.org/10.1016/j.ejphar.2017.09.046 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 galley proof before it is published in its final citable 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.

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Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease Marianne C van Schie*, Sjaam Jainandunsing, Jeanine E Roeters van Lennep Department of Vascular medicine, Erasmus Medical Centre, Rotterdam, The Netherlands *

Correspondence to: Department of Internal Medicine, Erasmus MC – office D434, PO-box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 70 35960. [email protected]

Abstract Cholesterol is of vital importance for normal function of organisms. However, a high serum level is associated with an increased risk of cardiovascular disease. In this review an overview is presented of the different known monogenetic disorders of the cholesterol metabolism which lead to unfavourable lipid profiles form childhood onwards and premature cardiovascular disease. Since these monogenetic disorders have a large variety in clinical presentation, ranging from scarcely any to extreme premature cardiovascular disease, the frequency is underestimated and often the correct diagnosis is not made. This results into a missed opportunity for optimal treatment as well as for appropriate counselling of family members. Therefore, greater awareness among physicians is needed.

Keywords Premature cardiovascular disease, cholesterol metabolism, monogenetic disorders; Familial hypercholesterolemia, LDL-C, HDL-C

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1.Introduction Cholesterol plays an important role in the development and growth of eukaryotic cells. It is necessary for cell membrane synthesis and regulation of membrane fluidity. Cholesterol is also important for the synthesis of numerous molecules involved in the regulation of cell homeostasis and supplies building blocks for bile acids, vitamin D and steroid hormone synthesis. Cholesterol can be synthesized de novo or can be obtained from the diet. These pathways are interdependent, meaning that the synthesis of cholesterol is influenced via complex feedback mechanisms by the amount of dietary cholesterol and cellular requirements and vice versa (Russell, 1992). Another important factor in the maintenance of cholesterol homeostasis is the elimination of cholesterol by converting cholesterol in bile acids which are excreted by the body (Monte et al., 2009). More recently, transintestinal cholesterol efflux (TICE) has emerged as a novel non-biliary pathway for cholesterol excretion(van der Velde et al., 2010), and although rodent studies targeting TICE demonstrated that it is a potential target to reduce atherosclerosis(Lo Sasso et al., 2010; Yasuda et al., 2010), further mechanistic studies of the role of TICE and subsequently clinical studies in humans are required. Although cholesterol is of vital importance for normal function of organisms, elevated serum cholesterol levels, in particular low-density lipoprotein cholesterol (LDL-C) levels, are harmful as cholesterol rich lipoproteins play a pivotal role in the pathobiology of atherosclerosis and subsequent cardiovascular disease (CVD). Since a considerable part of mortality and morbidity

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is caused by CVD, hypercholesterolemia is a large contributor to the worldwide burden of disease. Cholesterol levels not only increase with age, but are also influenced by obesity, diabetes, the nephrotic syndrome, hypothyroidism, and the use of alcohol, anabolic steroids, glucocorticoids, highly active anti-retroviral therapy (HAART) and anti-psychotic drugs. In >90% of patients, dyslipidemia is a polygenetic/environmental disorder of which the expression is to a considerable extent influenced by diet and obesity and other environmental factors(Hegele, 2009). Interestingly, the strongest association between hypercholesterolemia and CVD is seen in individuals with monogenetic disorders of the cholesterol metabolism which are less common (Genest et al., 1992; Graham et al., 2005; Humphries et al., 2006; Khera et al., 2016; Neil et al., 2003). If untreated, a considerable number of these individuals will develop premature CVD which is defined as CVD occurring before 55 years of age in men and before 60 years of age in women. In contrast to the polygenetic/environmental dyslipidemia, most of these disorders do not require non-genetic factors for their expression. The monogenetic disorders are especially associated with CVD at a younger age compared to polygenetic/environmental dyslipidemia, as plaque formation as a result of dyslipidemia starts already in early childhood (Marks et al., 2003), therefore early detection and correct treatment are crucial for timely CVD prevention. In this review, we will give an overview of the different monogenetic disorders of cholesterol metabolism and their association with premature CVD.

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2 Monogenetic disorders of the cholesterol metabolism (table 1). 2.1 Familial hypercholesterolemia Familial hypercholesterolemia (FH; OMIM (Online Mendelian Inheritance in Man) #143890) is the most common dyslipidemia caused by a monogenetic disorder. FH is characterized by increased low density lipoprotein cholesterol (LDL-C) levels, premature CVD, tendon xanthomata and/or lipoid arcus often in combination with a positive family history of hypercholesterolemia and premature CVD. The genetic defects are usually autosomal dominant inherited. LDL-C is cleared from the circulation after binding of the LDL particle via apolipoprotein B (apoB), the main protein of LDL, to the LDL receptor (LDLr). This complex is internalized in the hepatocyte. Once intracellular, the LDL-LDLr complex dissociates and LDLr is recycled and expressed again on the cell surface while the LDL particle will be degraded (Brown and Goldstein, 1986). Originally FH was defined as an inherited disorder characterized by the presence of loss-of-function mutations in the LDLr gene (LDLR ;OMIM #606945). Individuals with FH caused by mutations in LDLR, which is located on chromosome 19p13.2, are not capable of clearing LDL particles sufficiently because the LDLr is absent or is not working properly. More than 1600 different mutations in LDLR have been identified (Guardamagna et al., 2009). The severity of the phenotype characterized by LDL-C levels depends on the residual LDLr activity which can be categorized into five different classes of LDLR mutations (Hobbs et al., 1990). The class 1 mutations are null mutations because these results in a failure to synthesize any detectable LDLr protein. Classes 2 to 5 are classified as “defective” as some

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residual activity is present, with class 2: mutated LDL receptors are unable to transport from the endoplasmatic reticulum to the Golgi complex; class 3: mutated LDL receptors are transported to the cell membrane, but unable to bind LDL-C, class 4: mutated LDL receptors bound to LDL-C are unable to cluster in clathrin-coated pits and class 5: mutated LDL receptors fail to release LDL-C in the endosome and subsequently are not recycled back to the cell membrane, but are intracellularly degraded. However, nowadays it has been acknowledged that autosomal dominant FH is a more heterogeneous condition as a similar clinical phenotype is caused by loss-of-function mutations in the ApoB gene (APOB; OMIM #107730)affecting isoform ApoB-100, or gain of function mutations in the pro-protein convertase subtilisin kexin type 9 gene (PCSK9;OMIM #607786). APOB located on chromosome 2p24.1 codes for the main protein on LDL particles and is essential for LDL-LDLr complex formation. Loss of function mutations in APOB reduce the ability of LDL particles to interact with LDLr. In contrast with the large number of LDLR mutations, only a few mutations a within a relatively small coding region near p.3527 have been identified with as most common mutation the R3500Q and R3500W mutation (Andersen et al., 2016). PCSK9 is a protein that is expressed in the liver, and regulates LDLr recycling; PCSK9 attaches to the LDLr part on a LDL-LDLr complex and increases the affinity of LDLr for LDL significantly, resulting in an inability to release LDL in the endosome and intracellular degradation of LDLr(Durairaj et al., 2017). Gain of function mutations in PCSK9 located on chromosome 1p32.3, increase the degradation of LDLr intracellular leading to less expression of LDLr on the cell surface and reduced LDL-C clearance from the circulation (Soutar and Naoumova, 2007). Notably, also loss of function mutations in PCSK9- exist leading to the

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opposite phenotype: increased number of LDLr on the cell surface, lower LDL-C levels and lower risk of CVD (Cohen et al., 2005) Recent research revealed that the estimated frequency of heterozygous FH, having a FH causing gene mutation from one parent, is more frequent than previously assumed. In the Caucasian non-founder populations the prevalence of heterozygous FH is more likely to be 1:250 instead of 1:500 (Benn et al., 2012; Sjouke et al., 2015). In the group of heterozygous FH individuals with an identified mutation, 93% of the mutations are in LDLR, 5% in APOB and 2% in PCSK9 (Talmud et al., 2013). Traditionally the diagnosis of homozygous FH was based on the presence of two similar mutations in LDLR (true homozygosity) inherited from both parents. However, since it is known that the underlying genetics of FH is more complex than previously acknowledged, this has consequences for the diagnosis of homozygous FH. Patients with two different (compound heterozygosity) mutations in one single gene or two mutations in two different genes (double heterozygosity) (Sjouke et al., 2016; Sjouke et al., 2015) are also regarded as having homozygous FH . In addition, homozygous FH can be diagnosed by clinical criteria consisting of an LDL-C >13 mmol/l in combination with tendon xanthomas <10 years of age or untreated elevated LDL-C levels consistent with heterozygous FH in both parents. Based on the current estimation of the prevalence of heterozygous FH, the predicted frequency of homozygous FH is 1: 300.000. (Cuchel et al., 2014; Sjouke et al., 2015). Characteristic of homozygous FH is the development of extremely premature cardiovascular events. Supravalvular aortic stenosis due to calcification of the aortic root (Kolansky et al., 2008; Rallidis et al., 1996) is found in approximately 50% of the patients with

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homozygous FH. Within the spectrum of homozygous FH patients, those with two null LDLR mutations and consequently no residual LDLr have the highest LDL-C levels, often >20 mmol/l. This form of homozygous FH is rare, but associated with a very poor prognosis, with CVD usually occurring before adolescence (Cuchel et al., 2014). Of note, homozygous FH patients with defective LDLR mutations (classes 2-5) often have an LDL-C <13 mmol/l and can phenotypically not be distinguished from severe heterozygous FH patients with one null mutation (Sjouke et al., 2015). Besides the autosomal dominant inherited FH, a recessive form of FH; autosomal recessive hypercholesterolemia (ARH; OMIM #603813) exists. This recessive inherited FH is caused by loss of function mutations in the low-density lipoprotein receptor Adaptor Protein 1 gene (LDLRAP1;OMIM #605747) (Garcia et al., 2001) located on chromosome 1p36.11. LDLRAP1 is involved in the endocytosis of the LDL-LDLr complex with mutations lead to impaired internalization of the complex. ARH is considered an exceedingly rare disorder in most countries, with the exception of the island of Sardinia (Italy), with a prevalence of 1:40.000 for homozygotes and compound heterozygotes, probably as the result of founder effect and allopatric speciation(Arca et al., 2002). The clinical phenotype of ARH is milder than that of LDLr-negative homozygous FH, as it resembles the clinical phenotype observed in LDLrdefective homozygous FH (Pisciotta et al., 2006). Although in the majority of FH patients, mutations in the previously mentioned genes are identified, in about 30% of patients with the clinical characteristics of FH, no mutation can be identified. Recently, a new genetic locus in the signal transducing adaptor family member 1 gene (STAP1;OMIM #604298) located on chromosome 4q13.2. associated with autosomal

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dominant FH has been identified by parametric linkage analysis and whole exome sequencing (Fouchier et al., 2014). The function of the encoded protein is still unknown.

2.2 Sitosterolemia An extremely rare autosomal recessive disease (80-100 cases around the world) with clinical resemblance to FH is sitosterolemia (OMIM #210250) (Kidambi and Patel, 2008). Like FH, sitosterolemia manifests with tendon xanthomas and premature CVD, although a milder phenotype without specific symptoms has also been described. In sitosterolemia plant sterol levels are increased. Mutations in the sterolin-1gene (ABCG5; OMIM #605459) and sterolin-2 gene (ABCG8; OMIM #605460) located on the chromosome 2p21, are responsible for the disease (Patel, 2014). ABCG5 and ABCG8 are expressed in both liver and intestine. In healthy individuals, the ABCG5 and ABCG8 transporters in the enterocyte promote efflux of most plant sterols back into the intestinal lumen. The remaining plant sterols are transported as part of chylomicrons to the liver and excreted into the bile by ABCG5 and ABCG8 transporters in the liver(Yoo, 2016). In patients with sitosterolemia the intestinal plant sterol absorption is increased and the hepatic excretion is decreased leading to high plant sterol plasma levels (Escola-Gil et al., 2014). e Mutations in ABCG5 and ABCG8, increase cholesterol and plant sterol absorption and decrease cholesterol and plant sterol excretion in bile. In patients with sitosterolemia plasma cholesterol levels vary, ranging from normal to severely increased. Other distinctive clinical features that can be found in patients with sitosterolemia are arthralgia, thrombocytopenia and hemolysis probably due to incorporation of plant sterols into the red blood cell membrane (Kidambi and Patel, 2008). The commonly used enzymatic assay for

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cholesterol measurement cannot differentiate between cholesterol and plant sterols. However, gas chromatography or high performance liquid chromatography can detect plant sterols and should be performed to differentiate between FH and sitosterolemia since the two diseases, as mentioned earlier, show clinical resemblance (Moghadasian et al., 2002) but require a different treatment which will be discussed later on in this review.

2.3 CYP450 subfamily mutations As mentioned in the introduction, conversion of cholesterol in bile acids is important for cholesterol elimination. Mutations in proteins involved in this process have also been related to dyslipidemia and premature atherosclerosis. Thus far, mutations in two proteins have been identified. Firstly, the sterol 27-hydroxylase protein, which is encoded from the sterol 27-hydroxylase gene (CYP27A1;OMIM #606530) and located on chromosome 2q35, is involved in bile acid formation. It is a mitochondrial enzyme expressed in almost all cells of the body (Bjorkhem and Hansson, 2010). Mutations in CYP27A1 cause the disease cerebrotendinous xanthomatosis (CTX; OMIM #213700) which is a rare, recessive inborn error of metabolism. To date, more than 57 pathogenic variants have been identified. Due to deficiency of sterol 27-hydroxylase, the cholesterol is not converted into bile acids but into increasing amounts of plasma bile alcohol and cholestanol, and subsequently cholestanol accumulation occurs in tissues throughout the body, predominantly in tendons and brain xanthomas. (Bjorkhem and Hansson, 2010). The mean age at onset of symptoms is 19 years. However, it takes on average an additional 16 years before CTX is diagnosed (Pilo-de-la-Fuente et al., 2011).The prevalence of CTX varies

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considerably between different ethnic populations ranging from 1: 135.000 to 1:460.000 in Europeans and 1:36.000 to 1:75.600 in South Asians (Appadurai et al., 2015). The manifestation of CTX is diverse as multiple organs may be involved. It may present with infantile-onset diarrhea or childhood onset cataract which is the first finding in 75% of affected individuals. In the second or third decade of life, patients develop xanthomas in tendons and in the central nervous system. As a consequence, patients may develop neurological symptoms such as dementia, behavioral changes and pyramidal sings. In CTX patients, premature atherosclerosis and CVD have also been described. Amongst others, despite normal cholesterol levels, alterations of plasma lipids and lipoproteins towards an atherogenic profile, with highly increased 27-hydroxycholesterol and decreased HDL-C levels as main characteristics, has been suggested to play a role in the development of premature atherosclerosis (Bjorkhem et al., 1994; Weingartner et al., 2010). The second protein is cholesterol 7α- hydroxylase (CYP7A1) encoded by the CYP7A1 gene (OMIM #118455) located on chromosome 8q12.1. This protein is only expressed in the liver (Russell, 2003). It is a microsomal enzyme that initiates the synthesis of bile acids in the classical pathway of bile acid formation. Decreased CYP7A1 activity due to a mutation in the encoding gene is associated with increased intrahepatic cholesterol content, due to decreased cholesterol catabolism and synthesis of bile acids. This increase in hepatic cholesterol levels downregulates hepatic LDL receptors, resulting in increased LDL-C plasma levels. Increased triglyceride levels have also been described in individuals with homozygous CYP7A1 mutations (Pullinger et al., 2002). Individuals with CYP7A1 loss of function mutation have an increased risk

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of premature atherosclerosis. It appears to be an autosomal co-dominant disorder (Hofman et al., 2005; Pullinger et al., 2002; Pullinger et al., 2003).

2.4 Lysosomal acid lipase deficiency A rare condition associated with premature atherosclerosis is lysosomal acid lipase (LAL) deficiency, an autosomal recessive inborn error of metabolism caused by mutations of the Lipase A gene (LIPA; OMIM #613497)located on chromosome 10q23.31 (Hoffman et al., 1993). Due to these mutations, LAL activity is reduced resulting in accumulation of cholesterol esters and triglycerides in lysosomes. The lysosomal accumulation leads to less free intracellular cholesterol resulting in increased synthesis of endogenous cholesterol. Subsequently, as a result it is not a previously believed increased upregulation of LDLr, but an increase in VLDL-C which results in hypercholesterolemia in individuals with LAL deficiency. Also, less free intracellular cholesterol downregulates proteins involved in HDL-C efflux into our bloodstream. The net effect is increased circulating LDL-C and decreased circulating HDL-C particles (Bowden et al., 2011; Maciejko, 2017; Reiner et al., 2014). The phenotypic expression of LAL deficiency is wide and depends largely on the residual LAL activity. Patients with the infantile-onset form known as Wolman disease (WD; OMIM #278000) with a residual LAL activity <5% are most severely affected. These infants have steatorrhea and malabsorption due to increased deposition of lipids along the gastrointestinal wall. In addition, they have hepatomegaly due to steatosis which may progress to liver failure. Furthermore, enlarged adrenal glands with calcification, a typical finding in WD, can lead to adrenal

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insufficiency. WD infants normally do not survive beyond the first year of life(Reiner et al., 2014). All later onset LAL deficiency (from early childhood to late adulthood) is known as cholesterol ester storage disease (CESD; OMIM #278000). These patients may have a phenotypic expression resembling WD, but more often have a milder phenotype as they have more residual LAL activity. Besides the dyslipidemia, CESD patient may have hepatomegaly with steatosis, elevated transaminases and xanthelasma. The main source of morbidity in the late onset CESD patient group is due to premature cardiovascular events such as myocardial infarction and ischemic stroke(Bowden et al., 2011). The exact prevalence of LAL deficiency is not known and probably underestimated since CESD is often a subclinical disease. In one German study the prevalence was estimated to be 1:50.000 for CESD and 1:350.000 for WD (Muntoni et al., 2007).

2.5 Familial dysbetalipoproteinemia Familial dysbetalipoproteinemia (FDBL; OMIM #617347) is a mixed hyperlipidemia characterized by increased levels of total cholesterol and triglycerides due to the accumulation of chylomicron and very low-density lipoprotein (VLDL) remnant particles (Hopkins et al., 2014; Marais et al., 2014). FDBL is an autosomal recessive inherited and associated with an increased risk of premature CVD (Hopkins et al., 2009; Mahley, 2016). Apolipoprotein E (apoE) plays a central role in the development of FDBL. The ApoE protein, encoded by the APOE gene (OMIM #107741) located on chromosome 19q13.32, has three main allelic variants, namely E2, E3 and E4. Individuals who are homozygous for the E2 variant

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(APOE2/E2) may develop FDBL (Bennet et al., 2007). Some rare mutations in APOE associated with an autosomal dominant form of FDBL also exist (de Villiers et al., 1997). Compared to apoE3 and apoE4, apoE2 has a lower affinity for the hepatic LDLr, which removes chylomicron and VLDL remnants from the circulation. Especially those individuals who have an APOE2/E2 genotype show an impaired chylomicron and VLDL remnants clearance. As a consequence, the remnant particles circulate longer and become abnormally cholesterol-enriched due to core lipid exchange with LDL and HDL particles. These modified remnant particles are highly atherogenic. About 1% of the general population has the APOE2/E2 genotype, but only approximately 15% of these individuals will develop the clinical syndrome (Mahley et al., 1999). Other factors such as diabetes mellitus, alcohol, estrogen deficiency, hypothyroidism and obesity are required to provoke the full clinical syndrome. Interestingly, only about 30% of patients with the FDBL phenotype have the APOE2/E2 genotype indicating that other unknown factors must contribute to the pathobiology of this remnant lipoprotein disorder (Hopkins et al., 2014).

3 Low high density lipoprotein cholesterol disorders Several monogenetic disorders of the lipid metabolism are associated with low high density lipoprotein cholesterol (HDL-C) levels. In this review, familial hypo-alphalipoproteinemia, Tangier disease and lecithin cholesterol acyltransferase (LCAT) deficiency will be discussed (table 2). 3.1 Familial hypo-alphalipoproteinemia (OMIM #604091) is a rare heterogeneous autosomal dominant inherited lipid disorder. Apolipoprotein A1 (apoA1), apolipoprotein C3

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(apoC3) and apolipoprotein A4 (apoA4) are encoded by the APOA1/APOC3/APOA4/APOA5 gene cluster located on chromosome 11q23.3 (OMIM #107680). The phenotype of familial apoA1 deficiency disorder depend on the affected genes in the cluster. Some affected individuals lack apoA1, apoC3 and apoA4, others lack apoA1 and apoC3 due to complete or partial deletion of the gene cluster. Individuals with only deficiency of apoA1 due to nonsense mutations have also been described (Santos et al., 2008; Schaefer et al., 2016; Schaefer et al., 2010). These individuals have undetectable apoA1 plasma levels, marked HLD-C deficiency but normal triglyceride and LDL-C levels. Heterozygous affected individuals have HDL-C levels 50% of normal. Individuals with homozygous mutations resulting in combined apoA1/apoC3/apoA4 deficiency have undetectable ApoA-1 plasma levels, marked HDL-C deficiency, low triglycerides (due to apoC3 deficiency) and normal LDL-C levels. Heterozygous individuals have lipid plasma levels which are 50% of normal. Individuals with apoA1/apoC3 deficiency have a similar lipid profile compared to individuals with apoA1/apoC3/apoA4 deficiency. Although data on CVD in patients for this rare disease is lacking, their lipid profile might increase the risk of premature atherosclerosis. Other clinical manifestations include tubero-eruptive, planar and tendon xanthomas, corneal arcus and corneal opacification depending on the specific gene mutation. APOA-I gene variants other than nonsense mutations leading to undetectable apoA1 levels are also described. These are frameshifts or point mutations which lead to amino acid substitutions and as a result premature termination of apoA1 transcription causing a truncated protein (Santos et al., 2008; Schaefer et al., 2016; Schaefer et al., 2010). These gene variants which are autosomal dominant inherited, alter the function of the apoA1 protein leading to normal or reduced HDL-C levels and consequently normal or reduced LCAT activity since apoA1

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is necessary for LCAT activation. Remarkably, low HDL-C in combination with decreased LCAT activity is not linked with premature atherosclerosis, while low HDL-C in combinations with normal LCAT activity is associated with premature atherosclerosis. Depending on the genetic variant, corneal opacification may also occur. 3.2 Tangier disease (OMIM #205400) is an autosomal recessive disease caused by mutations in the ATP-Binding Cassette transporter A1 gene (ABCA1;OMIM #600046) located on chromosome 9q31.1 which encodes for the cholesterol efflux regulatory protein (ABCA1) (Santos et al., 2008; Schaefer et al., 2016; Schaefer et al., 2010). To date, 185 cases have been described in the literature(Schaefer et al., 2016). ABCA1 is important in reverse cholesterol transport as it facilitates the efflux of cholesterol and phospholipids from peripheral cells and the liver to very small lipid poor apoA1 particles (preβ-1HDL particles). This is the first step in the formation of mature HDL-C particles (Rothblat and Phillips, 2010). This process cannot take place in patients with homozygous ABCA1 mutations. These patients have a reduction of apoA1 level as the poorly lipidated apoA1 particles are rapidly catabolized by the kidney and mature HDL-C is scarcely formed. In addition, moderate hypertriglyceridemia is present and LDL-C levels are decreased due to increased catabolism of cholesteryl ester-poor LDL particles. Due to impaired cholesterol efflux, cholesterol esters accumulate in many tissues throughout the body. Consequently, affected individuals may present with hepatosplenomegaly, enlarged tonsils, mild corneal opacification, neuropathy and premature atherosclerosis. However, the severity of the phenotypic manifestations is variable. It appears that individuals with normal LDL-C levels instead of low LDL-C levels have an increased risk of premature CVD(Schaefer et al., 2016). Individuals who are heterozygous for an ABCA1 mutation have 50% lower HDL-C concentrations

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and 50% of the cholesterol efflux capacity compared to non-affected individuals. It is unclear whether the risk of premature atherosclerosis in heterozygote individuals is increased or not as conflicting data are reported (Santos et al., 2008). 3.3 LCAT deficiency is another rare (prevalence <1: 1.000.000) autosomal recessive inherited disorder of the lipid metabolism. LCAT has a pivotal role in lipoprotein metabolism (Ossoli et al., 2016) as it converts free cholesterol to cholesteryl esters leading to the maturation of small immature discoidal pre-HDL particles into larger mature spherical HDL particles which comprise most of the plasma HDL. Mature HDL particles have a longer plasma half-life than small pre-HDL which are rapidly catabolized by the kidney and are therefore essential for effective reverse cholesterol transport. ApoA1, the main protein on HDL particles, is the best LCAT activator. However, other proteins like apoE, apoC3 or apoB containing particles such as LDL can activate LCAT as well, as cholesterol is also being esterified by LCAT in these lipoproteins(Calabresi et al., 2012). Due to mutations in the LCAT gene (OMIM #606967) located on chromosome 16q22.1, LCAT is deficient and no mature HDL-C particles are being formed. Homozygous carriers of mutations in the LCAT gene have familial LCAT deficiency (FLD; OMIM #245900) or fish-eye disease (FED; OMIM #136120). In FLD, variants in LCAT result in failure of cholesterol esterification of HDL and apoB-containing particles (total LCAT deficiency), whereas in FED this is only the case for HDL particles leading to a less severe phenotype (partial LCAT deficiency). Both syndromes are characterized by very low HDL-C and decreased apoA-I levels. FLD patients also have low LDL-C levels due to an increased catabolism, a decrease in cholesteryl esters and an increase in circulating free cholesterol. The only clinical symptom in FED patients is corneal opacification whereas individuals with FLD often present with renal insufficiency, corneal

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opacification and hemolytic anemia due to a shorter lifespan of erythrocytes caused by intracellular deposition of free cholesterol and phosphatidylcholine. In patients with renal insufficiency, biopsy of the kidney shows glomerulopathy with lipid deposition. Although renal failure is the major cause of morbidity and mortality in the FLD patients. The exact pathobiology of renal failure in LCAT deficient patients remains to be elucidated (Saeedi et al., 2015). Whether LCAT deficiency is associated with atherosclerosis, is still a subject of debate (Calabresi et al., 2012; Ossoli et al., 2016).

4. Discussion In this comprehensive review, we aimed to describe the identified monogenetic disorders of the cholesterol metabolism and their association with premature CVD. The review shows that mutations in genes, encoding proteins involved in different components of the cholesterol metabolism, may lead to dyslipidemia and an increased risk of premature CVD. However, not for all genes the mechanism by which the mutation leads to an increased risk of premature CVD is has been clarified. The review also shows that not all genetic factors have yet been discovered. Due to a large variability in penetration, the clinical presentation of individuals with a similar genetic background is heterogeneous and can vary between a near normal lipid profile to severe dyslipidemia. Therefore, it is not always straightforward to distinguish between a polygenetic/environmental or monogenetic origin of dyslipidemia. Most likely, the frequency of the monogenetic lipid disorders is currently underestimated. Another complicating factor is that due to overlapping clinical features it can be difficult to differentiate between specific

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monogenetic disorders, for example sitosterolemia may be mistaken for FH or CTX and vice versa. Early diagnosis of the correct monogenetic disorder is important since individuals with a monogenetic dyslipidemia in general have a higher risk of premature CVD compared to individuals with the a similar lipid profile without a monogenetic cause, because the former have a lifelong exposure to the dyslipidemia (Marks et al., 2003). In addition, literature shows that different monogenetic disorder may require a different treatment in order to adequately reduce the risk of CVD. Although for most patients with hypercholesterolemia, including those with FH, statin treatment is the golden standard, for patients with sitosterolemia statins are not so effective(Kidambi and Patel, 2008). On the other hand, hypercholesterolemia in these patients is highly responsive to a low-plant sterol diet in combination with ezetimibe. Likewise, in patients with CTX chenodeoxycholic acid (bile acids) is first choice treatment and in patients with CYP7A1 deficiency ezetimibe is the best treatment option (Nie et al., 2014). A final argument for the necessity of early and correct diagnosis is that this can help to counsel family members. In case of autosomal inheritance, first-degree relatives have a 50% risk of being carrier of the pathogenic mutation. In most monogenetic lipid disorders, appropriate treatment is available. Currently FH is the only monogenetic lipid disorder for which screening programs have been initiated. Different types of FH screening programs have been established worldwide such as cascade screening (the Netherlands, Scotland) and universal new born screening (Slovenia, Slovakia) to detect FH patients at a young age. Diagnosis of FH at an early age is clinical relevant as statins can be safely used as lipid-lowering treatment in children from the age of eight years onwards, and is often started at an even younger age in children with

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homozygous FH. Therefore, early diagnosis is important to enable timely lipid-lowering treatment to prevent premature CVD. 5. Conclusion In conclusion, knowledge about the various monogenetic disorders of the cholesterol metabolism is essential for a correct diagnosis and treatment which may lead to a significant reduction of CVD in this specific group of patients and their affected family members.

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Tables:

Table 1 Monogenetic disorders of the cholesterol metabolism. Disease

Gene

Encode

Mode of

Prevalenc Main

CV

Other possible

affected

d

inheritanc e

lipoprotein

D

clinical features

protein

e

affected

risk

He 1:250

LDL-C 



Tendon

hypercholesterolemi

Ho

LDL-C 



xanthomas. Arcus

a

1:300.000

genotype general populatio n

Familial

LDLR

LDLr

AD

LDL-C 



Tendon, planar

He

LDL-C 



and tuberous

AD

1:1200

LDL-C 



xanthomas in

AR

Not

LDL-C



childhood.

APOB

ApoB

AD

PCSK9

PCSK9

AD

STAP1

STAP1

LDLRAP1

LDLRAP 1

lipoides.

known

Premature aortic

Not

valve stenosis.

known Ho Very

24

rare Ho 1:40.000 in founder populatio n Sitosterolemia

ABCG5

ABCG5

AR

For both

Plant

ABCG8

ABCG8

AR

genes

sterols



Elevated cholesterol.

together

Tendon or

80-100

tuberous

cases

xanthomas.

worldwid

Arthralgia.

e.

Haemolytic anaemia. Thrombocytopen ia.

Cerebrotendinous xanthomatosis

CYP27A1

CYP27A 1

AR

Ho:

Cholestenol 

Normal to low

1:135.000  Bile

cholesterol.

European

Infantil onset

alcohol

s

diarrhea.

Ho:

Childhood onset

25

1:36.000

cateract. Tendon

South

and central

Asians

nervous system xanthomas resulting in neurological symptoms.

CYP7A1 deficiency

CYP7A1

CYP7A1

AD

Not

LDL-C



known

TG may also be elvevated in homozygous individuals.

LAL deficieny 1. Wolman disease

LIPA

LAL

AR

LDL-C Ho

HDL-C

-

1:350.000 TG

Vomiting. 

2. Cholesterol ester storage disease

Hepatomegaly.

Diarrhea. Failure

Ho

to thrive. Adrenal

1:50.000

calcification. Xanthelasma. Hepatomegaly with steatosis. Cirrhosis. Splenomegaly.

26

Diarrhea and weight loss. Familial

APOE2/E

dysbetalipoproteine

2

mia

ApoE



AR

Ho 1:100

10% AD

of which

arterial disease.

15%

Tubero-eruptive

develope

and palmar

full

xanthomas.

TC TG

Peripheral

clinical syndrome . LDLr; low density lipoprotein receptor. ApoB; apolipoprotein B. PCSK9; pro-protein convertase subtilisin kexin type 9. STAP1; signal transducing adaptor family member 1. LDLRAP1; lowdensity lipoprotein receptor Adaptor Protein 1. ABCG5; sterolin-1. ABCG8; sterolin-2. CYP27A1; sterol 27-hydroxylase. CYP7A1; cholesterol 7α- hydroxylase. LIPA; lipase A. LAL; lysosomal acid lipase. ApoE; apolipoprotein E. AD; autosomal dominant. AR; autosomal recessive. He; Heterozygous. Ho; Homozygous. LDL-C; low density lipoprotein cholesterol. HDL-C; high density lipoprotein cholesterol. TG; triglycerides. TC; total cholesterol. CVD; cardiovascular disease.

27

Table 2. Monogenetic HDL related disorders. Disease

Gene

Encode Mode of

Prevalence

Main

CV

Other possible

affecte

d

genotype

lipoprote

D

clinical features

d

protein ce

general

in

risk

population

affected

Not known

HDL-C

inheritan

AD



Familial hypo-

A-I/C-

ApoA-I

Low TG. Fat

alphalipoproteine

III/A-IV

ApoC-

malabsorption.

mia

cluster

III

Planar, tendon

ApoA-

xanthomas.

IV

Corneal arcus. Corneal opacification. Decreased LCAT activity.

Tangier disease

ABCA1

CERP

AR

185 cases

HDL-C



worldwide

Elevated TG. Low LDL-C. Hepatosplenomeg aly. Enlarged tonsils. Corneal opacification. Neuropathy.

LCAT deficiency

LCAT

LCAT

AR

Ho

HDL-C

CD

Low LDL-C.

28

1. Familial LCAT deficiency 2. Fish-eye disease

<1:1.000.0

Corneal

00

opacification. Renal insufficiency. Hemolytic anaemia.

LCAT; lecithin cholesterol acyltranferase. ApoA-I; apolipoprotein A-I. ApoC-III; apolipoprotein CIII. ApoA-IV; apolipoprotein A-IV. ABCA1; ATP-Binding Cassette transporter A1. CERP; cholesterol efflux regulatory protein. AD; autosomal dominant. AR; autosomal recessive. Ho; Homozygous. LDL-C; low density lipoprotein cholesterol. HDL-C; high density lipoprotein cholesterol. TG; triglycerides. CVD; cardiovascular disease. CD; conflicting data