MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy

doi:10.1016/j.nmd.2007.01.010

Neuromuscular Disorders

Volume 17, Issue 4, April 2007, Pages 321-329

https://doi.org/10.1016/j.nmd.2007.01.010 Get rights and content

Abstract

In order to characterize, at the clinical, molecular and imaging level, myopathies due to MYH7 gene mutations, MYH7 gene analysis was conducted by RT-PCR/SSCP/sequencing in two patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapulo-peroneal myopathy of unknown etiology. MYH7 gene studies revealed the 5533C > T mutation (Arg1845Trp) in both myosin storage myopathy and in 2 of the 17 scapulo-peroneal patients studied. 5533C > T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in our cohort of patients included asymptomatic hyperCKemia, scapulo-peroneal myopathy and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies in only half of biopsied patients (2/4). In conclusion, phenotypic and histopathological variability may underlie MYH7 gene mutation and the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations.

Introduction

Myosin storage myopathy is a rare congenital myopathy characterized by slowly progressive muscle weakness and by the presence in muscle biopsy of subsarcolemmal eosinophilic formations called hyaline bodies (HB) in slow, oxidative (type I) fibers [1]. Similar pathological findings have also been reported earlier under different names [2], [3]. Recently Oldfords proposed the name of myosin storage myopathy for this entity, based on the findings in HBs of large inclusions consisting of slow heavy chain myosin (MyHC I) and on the identification of causative mutations in the MYH7 gene coding for MyHC I [4]. Subsequently, mutations in the MYH7 gene have been reported in a Saudi Arabian family [5], [6], in two isolated cases [7] and in one of the cases originally reported by Cancilla et al. [2], [8]. Interestingly, myosin storage myopathy is allelic to Laing early-onset distal myopathy (MPD1), clinically characterized by early onset and by selective weakness of the anterior tibial muscles followed by weakness of finger extensors [9], and to a common form of hypertrophic or dilated cardiomyopathy [10].

Clinical presentation in myosin storage myopathy includes hypotonia and delayed motor milestones [2], non-progressive weakness [1], [3], [6], [7], rapidly progressive muscle weakness with loss of ambulation and marked loss of subcutaneous fat [6], scapulo-peroneal muscular dystrophy [11], and slowly progressive muscle weakness, with winging of the scapulae and with or without pseudohypertrophy of the calves [4], [7]. Despite these various clinical presentations, muscle histopathology is uniform and is characterized by the presence of HBs in type I muscle fibers. HBs lack activity for glycogen and oxidative enzymes but retain reactivity for myofibrillar ATPase and ultrastructurally consist of granular or slightly filamentous storage material in the muscle fiber inclusion [1], [2], [3], [4], [5]. HBs positively immunostain for MyHC I [4], [5]. The mechanisms of formation of HBs and the functional consequences of myosin storage in muscle are not well understood, however it is likely that myosin storage myopathy may be caused by a defective assembly of the thick filaments [4]. Interestingly, the only three causative MYH7 gene mutations reported in myosin storage myopathy, L1793P [8], R1845W [4], [7], and H1901L [6], reside in the distal rod region of the myosin molecule involved with the interaction with other myosin molecules or with other proteins essential for alignment of the thick filaments [12].

Here we report clinical, muscle magnetic resonance imaging (MRI), and histopathological findings in patients with the MYH7 gene mutation.

Section snippets

Patients

About 6000 consecutive muscle biopsies from our Institution’s tissue bank were screened for patients who met the following clinical and/or histopathological criteria:

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muscle histopathology showing HBs in type I muscle fibers;
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muscle histopathology showing mixed myopathic and neurogenic changes and clinical phenotype consistent with a scapulo-peroneal myopathy.

Seventeen patients with scapulo-peroneal myopathy of unknown etiology and two patients showing HBs in their muscle biopsies were selected

Family A

This study was prompted by the clinical observation of patient II-12 (Fig. 1, Fig. 2 and Table 1). Individual II-12 was a 66-year-old man who presented with a history of progressive weakness since childhood. His early motor milestones were slightly retarded and he had always been clumsy. At 62 years he had difficulty climbing stairs, rising from a chair, and lifting weight with his upper limbs. Neurological examination showed a waddling gait with marked paresis on feet dorsiflexion (footdrop),

Discussion

The gene encoding the slow skeletal muscle fibers myosin heavy chain gene is mutated in myosin storage myopathy [4]. Mutations in the same gene also underlie Laing early onset distal myopathy (MPD1) [9] and a common form of both dilated and hypertrophic cardiomyopathy [10]. The clinical phenotype of myosin storage myopathy is quite heterogeneous, and variable age at onset, disease progression rate and severity have been reported [1], [2], [3], [4], [6], [7]. In spite of clinical heterogeneity,

Acknowledgements

Supported by grants from the Italian Telethon (# GTF02009) and EuroBioBank.

The corresponding author has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred
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Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus
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Hyaline body myopathy: case report
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Familial myopathy with probable lysis of myofibrils in type I fibers
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Hyaline bodies in skeletal muscle of a patient with a mild chronic non-progressive congenital myopathy
Clin Neuropathol
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Myosin storage myopathy associated with a heterozygous missense mutation in MYH7
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MYH7-related disorders in two Bulgarian families: Novel variants in the same region associated with different clinical manifestation and disease penetrance
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One of them most probably affects the assembly competence domain, part of LMM, which is responsible for the filament formation [20,21]. In the first family the novel MYH7 variant c.5746C>T was identified in individuals with a broad variability of the phenotype, which has been described in previous reports [17,22,23]. Dilated cardiomyopathy is the common feature in both affected members with pronounced anticipation, as the child died due to heart failure at the age of 2 years and 4 months while the father passed away in his fourth decade.
Pathogenic variants in MYH7 cause a wide range of cardiac and skeletal muscle diseases with childhood or adult onset. These include dilated and/or hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, congenital myopathies with multi-minicores and myofiber type disproportion, myosin storage myopathy, Laing distal myopathy and others (scapulo-peroneal or limb-girdle muscle forms). Here we report the results from molecular genetic analyses (NGS and Sanger sequencing) of 4 patients in two families with variable neuromuscular phenotypes with or without cardiac involvement. Interestingly, variants in MYH7 gene appeared to be the cause in all the cases. A novel nonsense variant c.5746C>T, p.(Gln1916Ter) was found in the patient in Family 1 who deceased at the age of 2 years 4 months with the clinical diagnosis of dilated cardiomyopathy, whose father died before the age of 40 years, due to cardiac failure with clinical diagnosis of suspected limb-girdle muscular dystrophy. A splice acceptor variant c.5560–2A>C in MYH7 was detected in the second proband and her sister, with late onset distal myopathy without cardiac involvement. These different phenotypes (muscular involvement with severe cardiomyopathy and pure late onset neuromuscular phenotype without heart involvement) may result from novel MYH7 variants, which most probably impact the LMM (light meromyosin) domain's function of the mature protein.
POPDC2 a novel susceptibility gene for conduction disorders
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Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2^W188⁎), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K_2P) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2^W188⁎ causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2^W188⁎ knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2^W188⁎ loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.
Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G>A (p.E1856K) with high interfamilial cardiac variability and putative anticipation
2014, Neuromuscular Disorders
Myosin-heavy-chain 7 (MYH7)-myopathy manifests clinically with a distal, scapuloperoneal, limb-girdle (proximal), or axial distribution and may involve the respiratory muscles. Cardiac involvement is frequent, ranging from relaxation impairment to severe dilative cardiomyopathy. Progression and earlier onset of cardiac disease in successive generations with MYH7-myopathy is unreported. In a five-generation family MYH7-myopathy due to the novel c.5566G > A (p.E1856 K) mutation manifested with late-onset, distal > proximal myopathy and variable degree of cardiac involvement. The index patient developed distal myopathy since age 49 y and anginal chest pain. Her mother had distal myopathy and impaired myocardial relaxation. The daughter of the index patient had discrete myopathy but left ventricular hypertrabeculation/noncompaction and ventricular arrhythmias requiring an implantable cardioverter defibrillator. The granddaughter of the index patient had infantile dilated cardiomyopathy without overt myopathy. Cardiac involvement may be present in MYH7-myopathy and may be progressive between the generations, ranging from relaxation abnormality to noncompaction, ventricular arrhythmias, and dilated cardiomyopathy.
A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies
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MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated.
Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement
2012, Neuromuscular Disorders
Citation Excerpt :
Lastly, it has been suggested that mutations concerning the distal rod domain of the beta myosin heavy chain may be associated with a wider clinico-pathological spectrum [24]. The muscle MR imaging findings in the index case in Family 1 confirmed the previous report of predominant distal lower limb involvement and the predominant hamstring involvement within the thigh, although the previously reported selective semitendinosus sparing was not observed [21]. Interestingly, the marked soleus involvement observed in our patient corresponds to the high level of beta myosin heavy chain expression documented in this muscle [47].
Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the “core myopathies”) have been mainly associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the selenoprotein N (SEPN1) gene. A proportion of cases remain unresolved. Mutations in MYH7 encoding the beta myosin heavy chain protein have been implicated in cardiac and, less frequently, skeletal muscle disorders.
Here we report four patients from two families with a histopathological diagnosis of MmD, presenting in childhood with slowly progressive muscle weakness, more proximal in Family 1 and more distal in Family 2, and variable degrees of cardiorespiratory impairment evolving later in life. There was also a strong family history of sudden death in the first family. Muscle biopsies obtained in early childhood showed multiple minicores as the most prominent feature. Sequencing of the MYH7 gene revealed heterozygous missense mutations, c.4399C>G; p.Leu1467Val (exon 32) in Family 1 and c.4763G>C; p.Arg1588Pro (exon 34) in Family 2.
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Neuromuscular Disorders

Abstract

Introduction

Section snippets

Patients

Family A

Discussion

Acknowledgements

References (17)

Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred

Neuromuscul Disord

Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1)

Am J Hum Genet

Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus

Neuromuscul Disord

Early onset chromosome 14-linked distal myopathy (Laing)

Neuromuscul Disord

Hyaline body myopathy: case report

Neuromuscul Disord

Familial myopathy with probable lysis of myofibrils in type I fibers

Neurology

Hyaline bodies in skeletal muscle of a patient with a mild chronic non-progressive congenital myopathy

Clin Neuropathol

Myosin storage myopathy associated with a heterozygous missense mutation in MYH7

Ann Neurol

Cited by (45)

MYH7-related disorders in two Bulgarian families: Novel variants in the same region associated with different clinical manifestation and disease penetrance

POPDC2 a novel susceptibility gene for conduction disorders

Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G>A (p.E1856K) with high interfamilial cardiac variability and putative anticipation

A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies

Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement

Myositis mimics in scleroderma: A case series of neuromuscular diseases that can co-exist in scleroderma