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

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Abstract

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.

Introduction

MYH7 encodes slow/β-cardiac myosin heavy chain, a class II myosin found in cardiac and type I skeletal myofibers [1]. It is a critical component of the force generation apparatus in both heart and skeletal muscle. Mutations in MYH7 are an established cause of cardiomyopathy [2] and of an expanding range of skeletal myopathies that includes Laing distal myopathy [3], [4], myosin storage myopathy [5], [6], [7], [8], congenital fiber type disproportion (CFTD) [9], [10], myopathy with serpiginous cytoplasmic bodies and myofibrillar changes [11], and core myopathy (including multi-minicore disease) [12], [13]. Mostly these disorders follow autosomal dominant inheritance although a family with autosomal recessive myosin storage has been reported [14]. Mutations for the different disorders cluster in different parts of the protein with some overlap. For example, most cardiomyopathy mutations are located in the myosin head and neck domains [15] while skeletal myopathy mutations are usually in the distal regions of the rod domain [16].

Until recently, MYH7 has been an uncommon cause of skeletal myopathy, associated with a narrow range of clinical and histological phenotypes. Recent case reports link MYH7 mutations to several new histological and clinical patterns of disease [9], [10], [11], [17], [18], and it is possible that mutations in MYH7 may be responsible for a significant proportion of a wide range of skeletal myopathies. We present two new cases that support this hypothesis. These two unrelated patients have a previously unreported MYH7 mutation (p.Leu1597Arg) and have strikingly different clinical and histological presentations. These cases thus broaden the known spectrum of MYH7 myopathy and also show that the same mutation can cause highly variable clinical and histological phenotypes that include axial myopathy and multiminicore disease.

Section snippets

Case 1

This female patient (currently age 32 years old) has prominent and multiple joint contractures and generalized weakness that is most notable in the distal musculature. She presented with toe walking at age 2 years and required multiple Achilles tendon lengthening surgeries between ages 11–14 years. From age 19 years she developed progressive weakness and contractures. At age 32 years, she could walk only short distances and had prominent contractures of the finger flexors (Fig 1A), neck flexors, and

Discussion

We present strong evidence that a heterozygous p.Leu1597Arg MYH7 change is the cause of myopathy in two unrelated probands with distinct clinical and histopathological presentations. This evidence includes the fact that the variant is not present in large control datasets and that it arose de novo in both individuals in association with a congenital myopathy phenotype, which is very unlikely to occur by chance. This missense change is located within the light meromyosin (LMM) region, similar to

Acknowledgements

This research has been supported by Australian National Health and Medical Research Council grants 1022707 and 1031893 (KN & NC), and 1035828 (NC). It was additionally supported in part through the Taubman Medical Institute and the Department of Pediatrics at the University of Michigan. Partial support was also derived from NIH K08AR054835 (JJD) and MDA186999 (JJD).

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