Reducing Body Myopathy and Other FHL1-Related Muscular Disorders

Reducing Body Myopathy and Other FHL1-Related Muscular Disorders Joachim Schessl, MD, Sarah Feldkirchner, MSc, Christiana Kubny, MSc, and Benedikt Schoser, MD During the past 2 years, considerable progress in the field of four and a half LIM domain protein 1 (FHL1)-related myopathies has led to the identification of a growing number of FHL1 mutations. This genetic progress has uncovered crucial pathophysiological concepts, thus redefining clinical phenotypes. Important new characterizations include 4 distinct human myopathies: reducing body myopathy, X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, and scapuloperoneal myopathy. Additionally, FHL1 mutations have been discovered in rigid spine syndrome and in a single family with contractures, rigid spine, and cardiomyopathy. In this review, we focus on the clinical phenotypes, which we correlate with the novel genetic and histological findings encountered within FHL1-related myopathies. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given FHL1 mutation. Semin Pediatr Neurol 18:257-263 © 2011 Elsevier Inc. All rights reserved.

Four and a half LIM domain protein 1 (FHL1, also known as skeletal muscle LIM protein 1 or KyoT1) is a 32-kDa protein containing an N-terminal zinc finger/half LIM domain, followed by 4 complete LIM domains. LIM domains, first recognized in the 3 homeodomain transcription factors Lin-11, Isl-1, and Mac-3 (LIM), are cysteine-rich, tandem zinc-finger protein interaction motifs.1-5 There are 5 known mammalian members of the FHL family: FHL1–3 are expressed in striated and cardiac muscle.6-9 FHL1 is also expressed in further tissues, like ovary, kidney, lungs, and others.6,10-12 FHL2 is located in the placenta and ovary tissues.7 FHL4 is exclusively expressed by the seminiferous epithelium of the testis.13 FHL5 (ACT) is coordinately expressed with the activator of cyclic 3=,5=-adenosine monophosphate–responsive element modulator in the testis.14 The role of FHL is not yet completely understood, but it is suggested that FHL proteins seem to be involved in the regulation of transcription factors, From the Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University of Munich, Germany. J.S. and B.S. are supported by the German Research Association (DFG, FOR1228) and by a grant from the Ludwig-Maximilians-University of Munich (FöFoLe to J.S.). J.S. and B.S. are members of the German network on muscular dystrophies (MD-NET) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). MD-NET is a partner of TREAT-NMD. Address reprint requests to Joachim Schessl, MD, Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University of Munich, Ziemssenst 1A, 80336 Munich, Germany. E-mail: joachim.schessl@ med.uni-muenchen.de

1071-9091/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2011.10.007

cytoskeletal scaffolding, and biomedical stress response. In comparison with other FHL family members, the multifunctional roles of FHL2, such as cellular interactions, interaction partners, and subcellular localization with cytoplasmic and nuclear functions, are well known.7 FHL1 is a cysteine-rich double zinc-finger structure and localizes to the myofibrillar sarcomere and the sarcolemma in skeletal muscle. Little is known about the function of FHL1, but data suggest that it participates in muscle growth and differentiation, as well as in the assembly of the sarcomere, and that it is a regulator of the skeletal muscle mass.8,15 Known interactions of FHL1 include the slow and cardiac isoforms of the myosin-binding proteins C, ERK2, HPC2, RING1, and KBP1.8,16-19 Additionally, it has been shown that the FHL1 protein complex includes PDZ and LIM domain protein 1, gelsolin, and ␣-actinin 1.20 Three basic isoforms of FHL1, generated by alternative splicing, are known6,21: FHL1A, also known as skeletal muscle LIM protein 1, is the full-length protein; FHL1B, or SLIMMER, is composed of the first 3 LIM domains and a nuclear localization, as well as export signals and an RBP-J binding region; and FHL1C, or KyoT2, is the shortest isoform and contains only the first 2 LIM domains, as well as an RBP-J binding region, and interacts with PIAS1.19,22 FHL1 is encoded on Xq26.3, contains 280 amino acids, and spans over 3.6-kb width. All 4 introns disrupt the coding region at regular intervals near the start of each complete LIM motif, implying that exon duplication may be responsible for the tandem LIM domain repeats. 257

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Figure 1 Histological and ultrastructural appearance in reducing body myopathy. (A) Distribution of FHL1 immunoreactivity in muscle demonstrating FHL1-positive aggregates (arrows); scale bar 100 ␮m. (B) MenadioneNBT staining in the muscle with reactive intracytoplasmic bodies (arrows); scale bar 100 ␮m. (Color version of figure is available online.)

FHL1 is the causative gene for a disease spectrum of up to 4 distinct diseases of the muscle, and many of the respective mutations affect highly conserved amino acid residues, mostly cysteine within the LIM domain.23 We established FHL1 as the causative gene for reducing body myopathy (RBM), using laser microdissection of the inclusions followed by proteomic analysis.24 Currently, further FHL1 gene mutations have been detected in RBM. FHL1 mutations have also been detected in a late-onset X-linked scapulo-axio-peroneal myopathy characterized by postural muscle atrophy with rigid spine syndrome (RSS) along with pseudoathleticism/ hypertrophy termed X-linked myopathy with postural muscle atrophy (XMPMA), in Emery-Dreifuss muscular dystrophy (EDMD), and in X-linked dominant scapuloperoneal myopathy (X-SM) (Fig 1).25-32 An FHL1 mutation has also been identified in a single patient with RSS and in a single family with contractures, rigid spine, and cardiomyopathy.33,34 In 1 family, a mutation of the FHL1 gene was also reported as the cause of an adult-onset X-SM.27 Following our first report, muscle biopsies from patients of this family were re-examined and also found to contain menadione-nitro-blue-tetrazolium (NBT)–positive inclusions (Michio Hirano, personal communication, 2008), suggesting that this family represents the milder end of RBM.24,27 This review will point out the recent activities and developments in understanding FHL1 mutations as the causative gene for human diseases of the muscle.

Reducing Body Myopathy

radic female patients with early-childhood onset. One sporadic patient was a severely affected boy, with loss of ambulation at the age of 18 months and cardiac arrest at the age of 3 years. Eight familial cases of RBM have been reported so far, of which 5 are without molecular confirmation.24,27,31,39,40,46,48 The reported families with RBM revealed no male-to-male transmission, consistent with the X-chromosomal location of FHL1. Until now, in all family reports, the male patients were more significantly affected than the female family members. Described female carriers can be asymptomatic or suffer from mild proximal muscle weakness.24,28,29 The clinical features of RBM range from mild muscle weakness, especially proximal and periscapular, to progressive and severe muscle weakness with loss of ambulation within the first 7 years of life, and death in early childhood because of respiratory failure.29 A magnetic resonance imaging study in 4 RBM patients showed a distinctive pattern of muscle involvement with alteration of posterior-medial and soleus muscles while sparing the hypertrophic-appearing glutei muscles.49 Rigid spine, scoliosis, and contractures, especially of the Achilles tendon, are common features in patients with RBM. With progression of the disease, antigravity strength was lost, and swallowing difficulties were present. Facial involvement with asymmetric ptosis occurred in 1 patient at a late stage. Dilated cardiomyopathy is reported in patients with RBM. Some patients developed respiratory insufficiency, thus requiring ventilatory support on a continuing basis or only overnight. One patient reportedly died of respiratory complications.

Clinical Features

Muscle Histopathology

RBM is a rare X-linked dominant disorder of muscle, causing progressive muscular weakness and characteristic intracytoplasmatic myofiber inclusions, first described nearly 40 years ago.35 However, the etiology remained unknown until early 2008. RBM is the most severe myopathy caused by a mutation in the FHL1 gene. Clinical manifestations of RBM have ranged from fatal early onset through childhood onset to adult-onset cases and, therefore, represent a wide clinical spectrum.29,35-48 Most reported severe cases represent spo-

The most distinctive histopathological feature of RBM, the intracytoplasmic inclusion bodies, which reduce NBT and, thus, stain strongly with the menadione-NBT stain, are therefore named reducing bodies, giving the disease its name (Fig 1B). In a large series of RBM patients, cytoplasmic bodies were frequent. Muscle biopsies also display a myopathic pattern, like variability of fiber diameters and fiber degeneration, especially in sections with a high number of aggregates. Rimmed vacuoles are occasionally seen. Immunohistochemi-

FHL1-related muscular disorders cally, numerous proteins, including FHL1, have been reported to stain positive with the inclusions (Fig 1A).24,9,50 The FHL1-positive aggregates were often in close association with the nucleus. There seems to be an increase of aggregates in biopsies at different times during the course of disease, suggesting a correlation between aggregate formation and clinical severity. Ultrastructural analysis confirms the electrondense appearance of aggregates and close association to the myonuclei.

Genetics Until now, 12 FHL1 mutations have been reported in 22 RMB patients from 16 different families (Fig 2).24,28,29,31 All mutations are located in the LIM domain 2, affecting highly conserved zinc-coordinating cysteine and histidine residues and thereby affecting all 3 splice forms of FHL1 (FHL1A, B, C).6,21,23,29 There are 11 missense mutations (C101F, C104R, W122S, H123Y/L/Q, C132F, C150Y/R, C153Y/R) and 1 deletion (del102-104KGC). Mutations in the hotspot H123 seem to result in a clinically more severe phenotype, indicating that these mutations disrupt the structure of the LIM domain. Mutations in the C150 and C153 residue were associated with a comparatively milder manifestation, suggesting that these mutations cause a less severe disruption of the LIM domain. However, a different mutation in C150 was reported in a female RBM patient with infantile onset and a severe, progressive, finally fatal course.31 The W122S mutation of the FHL1 gene was reported as the cause of an adultonset X-SM.27 Muscle biopsies from patients of this family were re-examined and were also found to contain menadione-NBT–positive inclusions (Michio Hirano, personal communication, 2008), suggesting that this family represents the milder clinical end of RBM. Noteworthy, a second FHL1 mutation at the same position (W122C) in X-SM was detected in

259 a family with a milder phenotype and also FHL1-positive cytoplasmic inclusions in the muscle biopsy.25

X-Linked Myopathy With Postural Muscle Atrophy Clinical Features So far, 8 families are reported to present XMPMA caused by FHL1 mutations: 5 unrelated German families, 1 Austrian family, 1 British family, and 1 Croatian family.30,32 Clinical assessment in all known patients revealed the characteristic XMPMA phenotype: all patients confirm an initially pseudoathletic appearance with early-onset neck rigidity and Achilles tendon shortening in their teens, followed by the formation of a scapulo-axio-peroneal syndrome with postural muscle atrophy, and scapular winging, as well as development of an additional proximal weakness in a limb-girdle distribution pattern, gait difficulties, and respiratory insufficiency in sporadic patients at older age. Older patients revealed mild to moderate scoliosis and dull deep lower back pain. Creatine kinase (CK) levels ranged from normal to 2.800 U/L (normal, ⬍180 U/L). The age of onset of symptoms ranged between 6 and 75 years. All the older patients reported an obvious disease progression in their late 30s. Initially mild but gradually progressive pulmonary insufficiency may be an important life-limiting feature. None of the patients revealed cardiac arrhythmia or cardiomyopathy. Nevertheless, detailed cardiac investigations are warranted. In women as affected mutation carriers, cardiac rhythm alterations may be found late in life. In 2 men, a rare aneurysm of the sinuses of Valsalva was found and treated by surgery. Whether this is related to the FHL1 mutation remains open. Finally, some women may present with mild proximal myopathy, kyphoscoliosis, reduced exercise tolerance, and hy-

Figure 2 Schematic representation and mutations in FHL1opathies. (A) Schematic representation of the domain structure of FHL1, containing an N-terminal zinc finger/half LIM domain, followed by 4 complete LIM domains. (B) Location of the missense, insertion, and deletion mutations in the LIM domains 2, 3, and 4 of the FHL1 gene so far reported in FHL1opathies within the consensus sequence C-X2-C-X16-23-C/H-X2-4-C/H/E –X2– C-X2-C-X16-21-C/H-X13-C/H/D (X denotes any amino acid). Mutations in the distal exons of the FHL1 gene of patients with XMPMA (V280M, c.688⫹1G¡A intron) and EDMD (X281E, C273LfsX11, 11-229delinsG, D112FfsX51, K157VfsX36, and X62, K124RfsX6), usually insertions or deletions resulting in a frameshift and truncated protein, are not shown.

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260 perCKemia, corresponding to an X-linked dominant mode of inheritance.30,32

Muscle Histopathology Muscle pathology mostly presented a moderate myopathy with only mild fibrosis and granular myofiber degeneration. In some biopsies, rimmed autophagic vacuoles, increased fiber size variation, and fiber hypertrophy were reported. Interestingly, a common feature concerning modified Gomori’s trichrome staining was the presence of cytoplasmic bodies in some samples. Reducing bodies have not been detected so far. Anti-FHL1 staining revealed a loss of cytoplasmic staining in some biopsies; accumulation of FHL1-positive material was not seen. In 1 biopsy from a 40-year-old patient, apart from cytoplasmic bodies and an increase in desmin expression, atypical reducing bodies with blue inclusions in the menadione-linked ␣-glycerophosphatase dehydrogenase were detected.30 Therefore, it is possible that older XMPMA patients may develop reducing bodies.

Genetics In XMPMA, the commonly found C224W mutation replaces a highly conserved cysteine within the fourth LIM domain of FHL1 without affecting the FHL1C isoform (Fig 1).32 The H246Y mutation substitutes a completely conserved histidine residue, which is involved in the coordination of the central Zn2⫹ ion of the fourth LIM domain. The effect of the H246Y mutation on FHL1 is likely to be identical to that of the C224W mutation because it will lead to destabilization of the fourth LIM domain and thereby affect the folding and secondary protein structure. The splice site mutation p.A168GfsX195, located behind the second LIM domain, only affects FHL1A and FHL1B. The amino acid substitution of the V280M mutation only affects FHL1B and is located between the nuclear export signal and the RBP-J binding domain of this isoform.

Emery-Dreifuss Muscular Dystrophy Clinical Features EDMD is a rare myopathy with characteristic early joint contractures, rigid spine, childhood onset of muscle wasting, and weakness mostly with a scapuloperoneal distribution pattern, as well as late-onset cardiac involvement, such as cardiomyopathies, arrhythmias, and conduction defects.26,51 Death in EDMD patients is mostly because of sudden cardiac failure.52 Until now, 6 subtypes of EDMD have been identified: 5 subtypes are caused by mutations in the nuclear membrane proteins emerin (EDMD type 1), lamin A/C (EDMD type 2 and 3), and nesprin (EDMD type 4 and 5)53,54; EDMD type 6 is caused by mutations in the FHL1 gene.26 In EDMD type 6, onset of the disease was in childhood or adulthood (4 – 48 years of age). First symptoms were joint contractures in 4 cases, muscle weakness in 1 patient, and both symptoms combined in 2 patients. The course of disease was progressive in all cases reported. Common features in the

course of disease were muscle weakness and wasting (pelvic, peroneal, scapular muscles). Four patients had additional axial muscle weakness/atrophy, and 2 patients suffered from facial involvement. Limb-joint contractures, neck stiffness, and rigid spine were commonly observed. Noteworthy, dysphonic voices in 3 patients suggested vocal cord palsy. In some patients, swallowing difficulties, muscle hypertrophy, and ptosis could be observed. CK levels were normal or moderately elevated (6 times normal). Cardiac involvement of variable extent was reported in all patients. Cardiac hypertrophy was the most prominent feature, followed by arrhythmias and conduction defects. Two patients died a sudden death, and in 2 further patients, respiratory impairment was significant, requiring noninvasive ventilation.

Muscle Histopathology Muscle biopsies showed either nonspecific myopathic changes or a dystrophic pattern. Fiber size variation and increase of interstitial tissue were common features. In 1 patient, additionally rimmed vacuoles and internalization of nuclei were observed. No reducing bodies were reported, and no aggregates were seen by immunostaining. FHL1 immunoreactivity was clearly reduced. Interestingly, the FHL1 immunoreactivity still seen in the biopsy tissue was situated close to the nucleus.

Genetics Seven families with different FHL1 mutations, differently affecting the 3 FHL1 protein isoforms, have been identified.26 There are 2 missense mutations affecting highly conserved cysteine residues (p.C276Y and p.C209R), 1 mutation with loss of the stop codon (p.X281E), and 4 out-of-frame deletions and insertions, truncating the C-terminus and differently affecting the 3 FHL1 isoforms (p.C273LfsX11, p.K157VfsX36, p.K124RfsX6, p.111-229delinsG/p.D112FX51) (Fig 1). The C276Y missense mutation is only affecting LIM domain 4 (only present in the full-length isoform A), whereas the mutation C209R is present in isoforms A and B. Noteworthy, the missense mutation C209R was also discovered in the family described by Knoblauch et al presenting with rigid spine, contractures, and hypertrophic cardiomyopathy (as explained later).33

X-Linked Scapuloperoneal Myopathy Clinical Features The major characteristics of scapuloperoneal syndromes are progressive weakness in the shoulder girdle and peroneal muscles. Scapuloperoneal myopathy can be caused by mutations in the sarcomeric myosin heavy chain and desmin genes, whereas the X-linked form is caused by FHL1 mutations.25,27,55,56 The age of onset in patients with the X-SM is between 20 and 40 years. So far, 2 large families with FHL1 mutations have been characterized, presenting with early foot drop, scapular winging, and proximal weakness of legs and arms. Most male patients become wheelchair-bound at some stage of the course of disease and are more severely

FHL1-related muscular disorders affected than female family members. Cardiac involvement is reported in some patients.

261 in the second LIM domain, affecting a cysteine residue of FHL1 similar to mutations causing RBM, was identified (Fig 2).34

Muscle Histopathology In 2 muscle biopsies of the family described by Quinzii et al, desmin-positive cytoplasmic bodies were detected.27 The muscle biopsies from these patients were re-examined, and menadione-NBT–positive inclusions were found (Michio Hirano, personal communication, 2008). In the second reported family by Chen et al, the muscle biopsy revealed myopathic changes with rimmed vacuoles, fiber size variation, centrally located nuclei, and some atrophic fibers.25 Intrasarcoplasmic eosinophilic inclusions were present in some fibers. Immunostaining revealed FHL1-positive cytoplasmic inclusions. A menadione-NBT staining was not performed in these patients. These findings suggest that this is also a protein aggregation disorder of the muscle, and these families may represent the milder end of the RBM phenotype.

Genetics Two mutations are known so far: W122S and W122C (Fig 2). The first mutation in the FHL1 gene (W122S) was discovered in a large family, and the second FHL1 mutation (W122C) was detected in a family with a milder phenotype.25,27 Presenting similar histopathological features of RBM, these mutations are also located in the second LIM domain, but do not affect a zinc-binding residue, although a highly conserved tryptophan residue may affect the stability of the structure of the LIM domain.

Rigid Spine Syndrome Clinical Features Thus far, the only reported case of RSS caused by an FHL1 mutation is a 16-year-old male patient with age of clinical onset at 13 years, who developed scoliosis followed by rigid spine.34 Muscle atrophy and weakness were present in proximal lower limbs, pelvic girdle, sternomastoid, trapezius, and paravertebral muscles combined with winging of scapulae and Gowers sign. He also presented several joint contractures. The serum CK level was mildly elevated, and respiratory functions were slightly impaired. The clinical features of this patient and the histopathological evidence of reducing bodies in his biopsy suggest that this single RSS is a milder form of an FHL1opathy, most likely RBM. This would interestingly expand the phenotype in RBM caused by FHL1 mutations.

Muscle Histopathology The biopsy showed fiber size variation and rimmed vacuoles. Interestingly, in some fibers, reducing bodies were seen in the menadione-NBT staining. Anti-FHL1 staining was increased in some muscle fibers.

FHL1 Mutation Causing Contractures and Hypertrophic Cardiomyopathy Clinical Feature In the reported family, 9 male patients showed contractures at the ankle or knee as well as the rigid spine syndrome.33 The age of clinical onset was from childhood and the third decade of life. Only 1 patient was reported to have muscle weakness, but none had muscle atrophy. Serum CK was normal or elevated up to 3 times. Many patients showed hypertrophic cardiomyopathies, and 2 patients revealed left ventricular hypertrophy and cardiac fibrosis. One patient had atrial fibrillation. No female family member had muscle weakness or elevated serum CK levels. One female presented with left ventricular hypertrophy, and 2 other women showed a slightly noticeable finger-ground distance.

Muscle Histopathology Cytoplasmic bodies were present in the 3 biopsies reported. Interestingly, also anti-FHL1– positive aggregates were seen in some fibers. Additionally, 1 patient showed marked fiber size variation and necrotic and regenerating fibers.

Genetics In this family, a single base-pair substitution c.625T⬎C (p.C209R) in exon 6 in the third LIM domain of the FHL1 gene was identified (Fig 2).33 This mutation exchanges a highly conserved cysteine residue for arginine. Noteworthy, the missense mutation C209R was also discovered in the family described by Gueneau et al, with an EDMD phenotype (as explained previously).26

Therapeutic Strategies Thus far, unfortunately, there are no curative therapeutic options available for patients with FHL1 mutations. The clinical care of patients with FHL1 mutations has to be managed by an interdisciplinary team. Long-term physical and occupational therapy should be prescribed to maintain the patient’s independence as long as possible. Regular sleep studies and pulmonary function testing are important to reveal nocturnal hypoventilation resulting from restrictive lung disease and weakness of respiratory muscles, including the diaphragm. Possible cardiac involvement including severe cardiac arrhythmia in the FHL1 disorders requires regular cardiac monitoring. In addition, social workers should help adjust the patient’s individuality and personal environment.

Genetics

Discussion

In this patient, a hemizygous, in-frame, 9-base pair deletion mutation at c.451-459delGTGACTTGC (p.151-153delVTC)

Since 2008, 26 different mutations in the FHL1 gene have been identified in human myopathies. Currently, FHL1 gene

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262 mutations have been detected in RBM, XMPMA, EDMD, X-SM, and RSS, as well as in a single family with contractures, rigid spine, and cardiomyopathy. Despite differences in the clinical presentation, X-SM and RSS, both caused by FHL1 mutations in the second LIM domain, present similar histopathological features, such as cytoplasmic inclusions, suggesting that they represent the milder end of the RBM phenotype. Therefore, RBM represents the largest group of FHL1opathies presenting with a broad phenotypic spectrum, ranging from a severe fatal course with early onset to very mild features with late onset. In addition to specific inclusions and protein aggregation, the histopathology of RBM and XMPMA, also in the family with the FHL1 missense mutation C209R with contractures and hypertrophic cardiomyopathy, encompasses the spectrum of myofibrillar myopathies (MFM), with evidence of granulofilamentous material and Z-line alterations. Therefore, the RBM group including X-SM and RSS caused by FHL1 mutations, XMPMA, and the condition of the family with the FHL1 missense mutation C209R with contractures and hypertrophic cardiomyopathy are protein aggregation disorders of the muscle and should be classified as MFM. MFM are progressive and devastating diseases of human skeletal muscle that often lead to premature death. Histopathologically, they are characterized by desminpositive protein aggregates and myofibrillar degeneration. Although part of the MFM is caused by mutations in genes encoding sarcomeric and extrasarcomeric proteins (desmin, filamin C, plectin, valosin-containing protein, Z-band alternatively spliced PDZ motif– containing protein, BAG 3, myotilin, and ␣B-crystallin), adding FHL1 as the latest protein, a large number of these diseases are caused by still unresolved gene defects. The FHL1 missense mutation C209R in the EDMD does not show any intracytoplasmic bodies, although it is the same mutation described in the family by Knoblauch et al, with contractures and hypertrophic cardiomyopathy. This would suggest that FHL1opathies can be classified as MFM (mostly with reducing bodies) with a wide spectrum of clinical phenotypes, and EDMD subtypes without protein aggregation. Genetically, it appears that FHL1 mutations affecting all 3 isoforms of the FHL1 protein result in a more severe phenotype, disrupting the whole FHL1 protein. Mutations in the FHL1 gene affecting only a single isoform present with a clinically milder form, suggesting a preserved FHL1 protein function. Further studies on FHL1 functions will be needed to understand the role of FHL1 and the resulting pathological functions and mechanisms. Although there are clear differences in clinical manifestation, the common features of all described FHL1opathies are the presence of mostly scapuloperoneal muscle weakness, rigid spine, cardiac involvement, and cytoplasmic bodies in the muscle biopsy. Encountering these features in a patient, one may consider screening for an FHL1 mutation. Until now, only few families and patients are reported with mutations in the FHL1 gene causing a myopathy. Further studies and FHL1 families will probably expand the knowledge of clinical phenotypes and broaden the clinical and histopathological spectrum.

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