MYH7-related myopathies: Clinical, histopathological and imaging findings in a cohort of Italian patients

Abstract

Background: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

Clinical and imaging hallmarks of the MYH7‐related myopathy with severe axial involvement

“…In this region, mutations causing hypertrophic or dilated cardiomyopathy as well as skeletal myopathy have been described already . Three of the patients in our series harbored novel mutations, and others were previously correlated with LDM . In Patient 4, 2 variants were identified in the cis state with confirmed segregation (p.Arg1608Ser and p.Ala1611Asp).…”

“…In 1 patient, EDX evaluation displayed a neurogenic pattern. Clinical and electrophysiological neurogenic changes were previously described …”

“…Finally, mutations in the globular head of the protein cause familial hypertrophic cardiomyopathy . Nevertheless, phenotypes featuring both cardiac and skeletal muscle involvement have been described, with mutations identified in the middle and the distal domains …”

“…Recently, a wider spectrum of clinical phenotypes associated with mutations in MYH7 has been described, including axial and proximal muscle involvement, dropped head, or rigid spine . These phenotypes overlap with other early‐onset axial myopathies, and therefore, the diagnosis may be challenging.…”

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

“…One was classified as “likely causal” (Supporting Information) with previous reports indicating pathogenicity for late onset distal myopathy (Fiorillo et al. ) and the other 17 were of “uncertain significance” (Table ). The relevance of these results will only become apparent when similar analyses are undertaken with larger samples.…”