Case reportA novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies
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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Signs and Symptoms in Congenital Myopathies
2019, Seminars in Pediatric NeurologyCitation Excerpt :It is generally reported as a milder myopathy and is characteristic in its combination of distal involvement with slowly progressive scoliosis.50 Clarke et al reported a phenotype with distal and axial contractures similar to the ones reported in COL6-related myopathies.44 Lastly, rare cases of autosomal dominant CNM caused by mutations in DNM2 have been described with a pronounced distal involvement at onset, with mild facial weakness, ptosis, and external eye movement restriction.57
A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain
2018, Neuromuscular DisordersLaing distal myopathy with a novel mutation in exon 34 of the MYH7 gene
2016, Neuromuscular DisordersThe most prevalent freeman-sheldon syndrome mutations in the embryonic myosin motor share functional defects
2016, Journal of Biological ChemistryClinical massively parallel sequencing for the diagnosis of myopathies
2015, Revue NeurologiqueCitation Excerpt :Mutations in TPM2, previously associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B, were also found by exome sequencing in core-rod myopathy or distal arthrogryposis types 7 [49]. MYH7-associated phenotypic spectrum has also been recently enlarged thanks to massively parallel sequencing approaches [50–53]. Finally, whereas mutations is ISPD gene were known to cause of a severe form of congenital muscular dystrophy Walker-Warburg syndrome [21], exome sequencing revealed that mutations in this gene are also associated with milder dystroglycanopathy phenotypes, ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy [22].