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Case report

Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy Nur Yüceyar a,1, Özgecan Ayhan b,1, Hatice Karasoy a, Aslıhan Tolun b,* b

a Ege University, School of Medicine, Department of Neurology, Izmir 35100, Turkey Bog˘aziçi University, Department of Molecular Biology and Genetics, KP 301, Bebek, Istanbul 34342, Turkey Received 20 November 2014; received in revised form 13 January 2015; accepted 20 January 2015

Abstract Myosin storage myopathy (MSM) is a protein aggregate myopathy caused by the accumulation of myosin in muscle fibres and results from MYH7 mutation. Although MYH7 mutation is also an established cause of variable cardiomyopathy with or without skeletal myopathy, cardiomyopathy with MSM is a rare combination. Here, we update the clinical findings in the two brothers that we previously reported as having recessively inherited MSM characterized by scapuloperoneal distribution of weakness and typical hyaline-like bodies in type 1 muscle fibres. One of the patients, weak from childhood but not severely symptomatic until 28 years of age, had an unusual combination of MSM, severe dilated cardiomyopathy, and respiratory impairment at the age of 44 years. We identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 in these patients as the second recessive MYH7 mutation reported to date. © 2015 Elsevier B.V. All rights reserved. Keywords: Myosin storage myopathy; Dilated cardiomyopathy; MYH7

1. Introduction Myosin storage myopathy (MSM; OMIM 608358) is a protein aggregate myopathy associated with hyaline-like accumulation of myosin in muscle fibres. MSM was the first skeletal muscle disease identified as a result of MYH7 mutation [1]. It was clinically defined in 1971 in a brother and sister with a congenital myopathy in which fine granular material that stained intensely with the myosin ATPase reaction had accumulated within the muscle fibres [2]. In this family, a heterozygous 5378T-C transition in exon 37 of gene MYH7 was later identified [3]. MYH7 encodes the cardiac beta-myosin heavy chain in muscle, and mutations responsible for MSM reside in the last four exons (exons 37–40) [4]. Other mutations in those exons lead to Laing distal myopathy with type 1 fibre hypotrophy (mutations in exons 32–38; OMIM 160500). Why different mutations cause different pathologic phenotypes is not known

* Corresponding author. Bog˘aziçi University, Department of Molecular Biology and Genetics, KP 301, Bebek, 34342 Istanbul, Turkey. Tel.: +90 212 359 6472; fax: +90 212 287 2468. E-mail address: [email protected] (A. Tolun). 1 These authors contributed equally to this work.

[5]. MYH7 mutations in several exons can lead to a variety of cardiopathies, including familial hypertrophic cardiomyopathy (OMIM 192600), dilated cardiomyopathy (OMIM 613426) and left ventricular non-compaction (LVNC) cardiomyopathy (OMIM 613426) [4]. MYH7 mutations are also among the causes of congenital myopathies with either multi-minicore (MMC) or congenital fibre type disproportion (CFTD) with variable cardiac involvement [6–9]. Almost all mutations reported to date have a dominant effect (heterozygous); they are either de novo mutations or inherited in a dominant fashion. In MSM, limb-girdle or scapuloperoneal muscles are predominantly affected with a slow progressive course, whereas in Laing distal myopathy primarily the dorsiflexor muscles of the toes and ankles are affected initially. In both of these myopathies, onset is from childhood to middle age, with mild to severe weakness affecting ambulation [4]. All of the reported MYH7 mutations that cause MSM are heterozygous, thus with a dominant effect, including L1779P, K1784delK, L1793P, R1845W, H1901L and X1936WfsX32; the exception is homozygous E1883K with a recessive effect [4,10,11]. Mutations in the distal rod region of MYHC associated with MSM could thus be dominant or recessive. More than 200 different heterozygous, missense mutations affecting the globular head domain of MYH7 have been

http://dx.doi.org/10.1016/j.nmd.2015.01.007 0960-8966/© 2015 Elsevier B.V. All rights reserved. Please cite this article in press as: Nur Yüceyar, Özgecan Ayhan, Hatice Karasoy, Aslıhan Tolun, Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.01.007

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identified to date as responsible for hypertrophic cardiomyopathy [12]. Dilated cardiomyopathy and LVNC are less frequent cardiac manifestations of MHY7 mutation [4], and cardiac involvement can include arrhythmias, sudden cardiac death, and restrictive cardiomyopathy [6,12]. Alternatively, MYH7 mutation can cause a pure skeletal myopathy or a combination of skeletal myopathy and cardiomyopathy [4,5]. Previously we reported a family with autosomal recessive MSM [13]. We have now identified a homozygous mutation c.5458C>T (p.R1820W) in MYH7 exon 37. Our study family is the second case of recessive MSM to be reported, and one of the patients has an unusual combination of skeletal myopathy and severe dilated cardiomyopathy and respiratory weakness. 2. Case report The clinical features and histopathologic findings in the two brothers were reported previously [13]. Briefly, the older patient (index patient), a 44-year-old man, was weak in childhood but not severely symptomatic until the age of 28 years. His 40-yearold brother was asymptomatic until the age of 33 years. Two sisters and the parents were unaffected. Both patients had scapuloperoneal weakness and atrophy. Muscle biopsies showed variation in fibre size with marked type I fibre predominance. The most striking finding was subsarcolemmal hyalinized structures in 25–30% of the type I fibres, which did not react with periodic acid Schiff and oxidative enzymes but stained positive for ATPase at pH 4.3. The older patient had a long face, high arched palate and decreased cardiac systolic function. His medical history included diabetes mellitus for 15 years; one sister and the father also had diabetes. We recently re-evaluated the patients and now summarize the developments in the clinical features in the past 12 years. At age 44 years, the older patient had some clinical symptoms of cardiac failure, and his echocardiogram displayed left ventricular systolic and diastolic dysfunction; left ventricular end diastolic diameter was 6.3 cm (normal range, 3.7–5.6 cm), left ventricular end systolic diameter was 5.5 cm (normal range, 2.3–3.9 cm), and global left ventricular hypokinesia with a left ventricle ejection fraction of 30%. His electrocardiogram displayed ST segment depression in leads V5–V6 and findings compatible with left ventricular hypertrophy with normal sinus rhythm. Measurements of the maximal wall thickness in multiple myocardial segments, including septal/posterior wall thickness, were within normal limits; the posterior wall thickness was 1.0 cm (normal range, 0.6–1.1 cm) and the interventricular septal wall thickness was 1.0 cm (normal range, 0.6–1.1 cm). On the echocardiogram, the appearance of the compacted muscular wall of the ventricles was not compatible with LVNC or hypertrophic cardiomyopathy. Dilated cardiomyopathy was diagnosed based on these echocardiographic findings, indicative of left ventricular enlargement and reduced systolic function. A year later the patient was put under medical treatment. He had exertional dyspnoea and discomfort while lying supine at night, which could be due to cardiac dysfunction or diaphragmatic muscle weakness. Pulmonary function tests revealed a restrictive type of respiratory insufficiency. At the

age of 46 years, he was admitted to the intensive care unit with a diagnosis of cardiorespiratory failure. He had severe respiratory impairment with a forced vital capacity of 0.45 of normal and dilated cardiomyopathy with a left ventricular ejection fraction of approximately 20%. He required ventilator assistance and inotropic therapy for 2 weeks. Digoxin was initiated after emergency treatment of heart failure. He tolerated the cardiac condition well without requiring ventilator assistance until he was admitted to the intensive care unit at the age of 50 years for urgent tracheotomy and mechanical ventilation due to severe congestive cardiac failure and hypercapnic respiratory failure. After 3 months of hospitalization, he was discharged with a home bilevel positive airway pressure device for management of nocturnal hypoventilation. He has been using the device during sleep and requiring aspiration during the day for 7 years, since the first episode of cardiorespiratory failure. There has been a slow progression of his scapuloperoneal type weakness with normal creatine kinase levels over the past 12 years. At age 56 years, the patient is still ambulatory at home and able to rise with support from the chair but unable to sit up from the supine position without using his arms, suggesting mild truncal weakness. The most recent examination disclosed symmetrical wasting of the sternocleidomastoideus, trapezius, supraspinatus, pectoralis, deltoid, triceps, biceps, paravertebral and tibialis muscles. He had scapular winging and spinal rigidity pronounced in the cervical spine. Using the Medical Research Council (MRC) grading system, shoulder abductors (MRC2), elbow flexors (MRC2) and ankle dorsiflexors (MRC0) were found to be the most severely affected muscles compared with the finger abductors and extensors (MRC−4), knee extensors (MRC−4) and ankle plantar flexors (MRC−4). Other muscles were only slightly affected (MRC+4). In summary, over the course of 12 years (from 44 to 56 years of age), the disease has progressed and cardiomyopathy and respiratory distress have become the predominant features besides the scapuloperoneal muscle weakness. The dilated cardiomyopathy is not accompanied by significant conduction system disease or arrhythmia. At the age of 40 years, the younger patient had moderate weakness and mild atrophy in the shoulder girdle and peroneal muscles, like his brother, but without any clinical or laboratory evidence of cardiorespiratory impairment. On the annual echogram at the age of 45 years, left ventricular diastolic dysfunction with an ejection fraction of approximately 50% and mitral valve prolapse were detected without any cardiac symptoms. The measurements for the maximal wall thickness in multiple myocardial segments were within normal limits. Over the last 7 years, his condition has remained stable. At the most recent examination at the age of 52 years, no predominant changes in the scapuloperoneal type muscle atrophy and weakness were observed. The manual muscle test results were as follows: MRC3 in the shoulder abductors and elbow flexors, and MRC4 in the shoulder adductors, finger abductorsextensors and ankle dorsiflexors. He had discomfort while lying supine at night, which could be due to evolving cardiac dysfunction or diaphragmatic muscle weakness.

Please cite this article in press as: Nur Yüceyar, Özgecan Ayhan, Hatice Karasoy, Aslıhan Tolun, Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.01.007

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Table 1 Reported cases of skeletal muscle myopathy due to MYH7 mutation that are associated with cardiomyopathy. Number of families

Mutation

Protein

Affected muscles (other findings)

Histo

CI

References

2 2 1 1 1 1 1 1 1 1 1

c.5378T>C c.23014C>T c.24012G>A c.5458C>T c.1408C>T c.1902G>A c.2348G>C c.4399C>G c.4763G>C c.5291_5293delAAG c.5566G>A

p.L1793P p.R1845W p.E1883K p.R1820W p.T441M p.V606M p.R783P p.L1467V p.R1588P p.K1729del p.E1856K

Proximal (adult or childhood onset) Scapuloperoneal Proximal, axial, respiratory Scapuloperoneal, respiratory Distal (contractures) Distal hypertrophic myopathy Distal (childhood onset) Proximal Distal Distal, facial, axial, proximal (skeletal deformities) Distal > proximal myopathy

MSM MSM MSM MSM nsMP nsMP CFTD MMCD MMCD CFTD Neurogenic

hCMP, LVNC hCMP hCMP dCMP hCMP hCMP dCMP, CTP SCD Yes dCMP dCMP

[16] [17] [11] Present study [14] [15] [18] [6] [6] [8] [19]

CI, cardiac involvement; Histo, histologic manifestations; nsMP, non-specific myopathy; CFTD, congenital fibre type disproportion; MMCD, multi-minicore disease; MSM, myosin storage myopathy; SCD, sudden cardiac death; CMP, cardiomyopathy; dCMP, dilated cardiomyopathy; hCMP, hypertrophic cardiomyopathy; LVNC, left ventricular non-compaction; CTP, cardiac transplantation. Homozygous mutations are in bold type.

The family history did not include any early deaths that could possibly be of cardiac origin. The genetic studies comprised disease gene mapping and subsequent mutation analysis. A genome scan was performed for the mother, the two patients and the two healthy sisters using 730,000 single nucleotide polymorphism (SNP) markers. Linkage analysis was performed using Allegro v1.2c, assuming autosomal recessive inheritance. The parents denied consanguinity and were assumed to be second cousins. Four loci yielded a maximal logarithm of the odds (LOD) score of 2.65, and the MYH7 gene was within one of these loci. Sequence analysis for the last four MYH7 exons (exons 37–40) identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 (Supplementary Figure S1). The two affected brothers were homozygous for the mutation and the sisters were not; the mother was heterozygous. All the online tools we used predicted the mutation as damaging (Polyphen score was 0.98, Mutation Taster predicted it as disease causing with a prediction probability of 0.99, and the SIFT score was 0). A population control panel of 120 individuals was screened for the mutation using HRM curve analysis to detect a normal sequence variant with a frequency of 0.01 with a power of 80% [3], and the mutation was not found. In addition, the mutation was not found in the Turkish EVS (in 353 unrelated persons) and EVS databases. Informed consent was obtained from all participants. The Bog˘aziçi University Institutional Review Board for Research with Human Participants approved the study protocol. 3. Discussion Cardiac beta-myosin heavy chain, encoded by MYH7, is expressed in cardiac muscle and all slow skeletal muscle fibres. Myosin is a major component of both heart and skeletal muscles and plays a role in muscle contractibility, converting chemical energy into mechanical force. Myosin exists as a dimer of globular heads linked to an alpha helical coiled-coil rod domain. Each head domain contains an ATP hydrolysis and actin binding site, which is required for motor activity, and the rod is involved

in thick filament formation [4]. Mutations in the head domain were associated only with cardiomyopathy until other patients with both cardiomyopathy and distal myopathy were reported [5,14,15]. Mutations in the rod domain are also associated with diseases involving both cardiac and skeletal myopathies [4]. Reported cases of skeletal muscle myopathy due to MYH7 mutation that are associated with cardiomyopathy are listed in Table 1. Distal myopathy [5,14,15,18,19], MSM [11,16,17] and congenital myopathy with MMC [6] or CFTD [8,19] resulting from MYH7 mutation with dilated, hypertrophic or LVNC cardiomyopathy have recently been reported. All but one of the reported MYH7 mutations that cause skeletal myopathy with cardiac involvement are heterozygous. In a British family, homozygous missense mutation E1883K (exon 38) was identified in the three sibs who developed MSM with hypertrophic cardiomyopathy and respiratory failure [11]. The authors suggested that the cardiomyopathy and type II respiratory failure in the patients were due to the recessive effect of the mutation, as the previously reported patients with MSM were all heterozygous for MYH7 mutations and did not have these clinical features. However, cardiomyopathy with MSM due to MYH7 mutation is not unique to recessive inheritance. A woman with MSM caused by a heterozygous L1793P mutation (exon 37) developed hypertrophic cardiomyopathy and her daughter with the same mutation had early (at age 3 months) symptomatic LVNC [16]. Also, two brothers with MSM due to heterozygous mutation R1845W (exon 37) had slowly progressive proximal myopathy [17]. One of the brothers also had nocturnal hypoventilation, respiratory muscle weakness and sleep apnoea as well as left ventricular dysfunction attributed to hypertrophic cardiomyopathy. Our older patient has been weak from childhood, and severe dilated cardiomyopathy and respiratory impairment evolved in the fourth decade. He had no echocardiographic findings characteristic of antecedent cardiac hypertrophy or LVNC with prominent trabeculations and deep endocardial recesses. His brother has moderate weakness and recently mild cardiac symptoms were detected. Variability in cardiac manifestations or intrafamilial variation can occur in MYH7 mutation, as in our

Please cite this article in press as: Nur Yüceyar, Özgecan Ayhan, Hatice Karasoy, Aslıhan Tolun, Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.01.007

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patients [5,8,16,17]. Earlier onset and faster progression of cardiac disease in successive generations, similar to anticipation, with MYH7 myopathy has also been described in one family [19]. Our study family (the older patient) is the second family with MSM with a recessive MYH7 mutation and severe cardiomyopathy, but the cardiac condition in our patient is dilated and not hypertrophic cardiomyopathy in contrast to the previously reported recessive family [11]. In the previously reported patients with MSM with MYH7 mutation, cardiac involvement was also characterized by either hypertrophic cardiomyopathy or LVNC [16,17]. However, MYH7 is the most frequently mutated gene in a familial dilated myopathy study population [20]. Dilated cardiomyopathy and skeletal myopathy due to MYH7 mutation are also reported in families with autosomal dominant transmission and non-specific histopathologic findings [19] or CFTD [8,18] (Table 1). A 25-year old woman with heterozygous missense mutation p.R783P (exon 21) had cardiac transplantation at age 15 years [18]. The mutation resides in the essential light chain binding region of the protein, previously shown to be mutated only in hypertrophic cardiomyopathy. Respiratory muscle weakness necessitating ventilator assistance, as in our older patient, was also reported for some patients with skeletal myopathy due to MYH7 mutation [1,2,4,5,11,17]. Our older patient was weak in childhood and had a long face and high arched palate, indicating a possible congenital myopathy. MYH7 mutations have also been identified in congenital myopathies with MMC or CFTD with cardiac involvement [6,8,18]. However, the histopathologic findings in our patients did not have any characteristics of these congenital myopathies. We previously reported an incorrect locus for our study family, due to the inadequacy of the method used at the time and the unreported parental consanguinity in the family. The parents denied consanguinity, so we assumed that they were third cousins and found a single locus, compatible with the assumed distant consanguinity. But the recent linkage analysis yielded a maximal LOD score of 2.65 at four loci >600 kb, ranging from 3 mega bases (Mb) to 6.4 Mb, indicating a rather close consanguinity. The previous mapping was performed using genotype data for 156 autosomal microsatellite markers, which were considered adequate at the time. In the present study, we used dense SNP markers and found that the known gene for MSM is at a candidate locus. The previously reported locus at 3p is the second largest locus in Mb and the locus of MYH7 (14q11) is the fourth largest. Some MYH7 mutations cause cardiomyopathy without any clinical signs of skeletal myopathy, some cause skeletal myopathy without cardiomyopathy, and a few are associated with combined myopathy of skeletal and cardiac muscles. It is not obvious why different phenotypes result from different MYH7 mutations even if they affect the same part of the protein [5]. The fact that cardiomyopathy is not very rare in MYH7 myopathies indicates that a careful cardiac evaluation is essential for all patients with MYH7 myopathy. Our older

patient with an unusual combination of dilated cardiomyopathy and MSM with scapuloperoneal distribution further widens the broad spectrum of clinical phenotypes associated with MSM due to MYH7 mutation and provides further evidence that MYH7 is likely responsible for a greater proportion of cardiomyopathies associated with skeletal myopathy. In addition, the manifestations of the novel homozygous missense mutation identified here further demonstrate the intrafamilial phenotypic variability of MYH7 mutation. Acknowledgements We thank the family members for their cooperation and Dr Meral Kayıkçıog˘lu for the cardiologic evaluation. We are grateful to TUBITAK Advanced Genomics and Bioinformatics Group (IGBAM) for sharing the Turkish exome sequence database with us. This work was partially supported by the Bog˘aziçi University Research Fund, grant number 6655. Appendix: Supplementary material Supplementary data to this article can be found online at doi:10.1016/j.nmd.2015.01.007. References [1] Tajsharghi H, Thornell LE, Lindberg C, et al. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003;54:494–500. [2] Cancilla PA, Kalyanaraman K, Verity MA, et al. Familial myopathy with probable lysis of myofibrils in type I fibers. Neurology 1971;21:579–85. [3] Dye DE, Azzarelli B, Goebel HH, et al. Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred. Neuromuscul Disord 2006;16:357–60. [4] Tajsharghi H, Oldfors A. Myosinopathies: pathology and mechanisms. Acta Neuropathol 2013;125:3–18. [5] Lamont JP, Wallefeld W, Hilton-Jones D, et al. Novel mutations widen the phenotypic spectrum of slow skeletal/β cardiac myosin (MYH7) distal myopathy. Hum Mutat 2014;35:868–79. [6] Cullup T, Lamont PJ, Cirak S, et al. Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement. Neuromuscul Disord 2012;22:1096–104. [7] Ortolano S, Tarrıo R, Blanco-Arias P, et al. A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy. Neuromuscul Disord 2011;21:254–62. [8] Muelas N, Hackman P, Luque H, et al. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology 2010;75:732–41. [9] Clarke NF, Amburgey K, Teener J, et al. A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies. Neuromuscul Disord 2013;23:432–6. [10] Chai J, Liu C, Lai P, et al. Myosin storage myopathy with a novel slow-skeletal myosin (MYH7) mutation in a Chinese patient. Neuromuscul Disord 2007;17:838. [11] Tajsharghi H, Oldfors A, Macleod DP, et al. Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy. Neurology 2007;68:962. [12] Walsh R, Ruthland C, Thomas R, et al. Cardiomyopathy, a systematic review of disease-causing mutation in myosin heavy chain and their phonotypic manifestation. Cardiology 2010;115:49–60. [13] Onengüt S, Ug˘ur SA, Karasoy H, et al. Identification of a locus for an autosomal recessive hyaline body myopathy at chromosome 3p22.2-p21.32. Neuromuscul Disord 2004;14:4–9. [14] Darin N, Tajsharghi H, Ostman-Smith I, et al. New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH7. Neurology 2007;68:2041–2.

Please cite this article in press as: Nur Yüceyar, Özgecan Ayhan, Hatice Karasoy, Aslıhan Tolun, Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.01.007

ARTICLE IN PRESS N. Yüceyar et al. / Neuromuscular Disorders ■■ (2015) ■■–■■ [15] Overeem S, Schelhaas HJ, Blijham PJ, et al. Symptomatic distal myopathy with cardiomyopathy due to a MYH7 mutation. Neuromuscul Disord 2007;17:490–3. [16] Uro-Coste E, Arné-Bes MC, Pellissier JF, et al. Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 Leu1793pro mutation. Neuromuscul Disord 2009;19:163–6. [17] Shingde MV, Spring PJ, Maxwell A, et al. Myosin storage (hyaline body) myopathy: a case report. Neuromuscul Disord 2006;16:882–6. [18] Homayoun H, Khavandgar S, Hoover JM, et al. Novel mutation in MYH7 gene associated with distal myopathy and cardiomyopathy. Neuromuscul Disord 2011;21:219–22.

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[19] Finsterer J, Brandau O, Stollberger C, et al. Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G > A (p.E1856K) with high interfamilial cardiac variability and putative anticipation. Neuromuscul Disord 2014;24:721–5. [20] Villard E, Duboscq-Bidot L, Charron P, et al. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur Heart J 2005;26:794–803.

Please cite this article in press as: Nur Yüceyar, Özgecan Ayhan, Hatice Karasoy, Aslıhan Tolun, Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: Scapuloperoneal and respiratory weakness with dilated cardiomyopathy, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.01.007