Genetics & Molecular Medicine

Abstract

The DES R415W Mutation: Clinicopathological Report of Four Patients

Sadaf Khorasanizadeh, Qian Wu, Marie L. Rivera-Zengotita, Kevin J. Felice

The myofibrillar myopathies are a heterogeneous group of genetic disorders characterized pathologically by the disruption of myofibrils and accumulation of degradation products in intracellular inclusions. Most patients present with progressive limb muscle weakness – distal, proximal or both. Cardiomyopathy – dilated or hypertrophic – can be an isolated feature or may develop concurrently with the skeletal myopathy. Mutations in the DES gene account for approximately 7% of genetically-determined myofibrillar myopathies. DES encodes for the intermediate filament protein desmin which is an essential component of the extra-sarcomeric cytoskeleton in cardiac, skeletal and smooth muscle cells. Since the first report of DES gene mutations as a cause of a familial and skeletal myopathy in two families in 1998, 126 pathogenic mutations have been documented – including 24 involving the tail domain. The tail domain mutation, DES R415W, was previously described in a 30-year-old patient with leg weakness. Over the past 10 years, we have diagnosed and cared for four patients with progressive skeletal myopathy and muscle histopathology consistent with myofibrillar myopathy – all harboring the DES R415W mutation. In this report, we describe the clinicopathological findings in these four patients. In summary, we report four patients with the DES R415W mutation. This tail domain mutation causes a late-onset myopathy primarily affecting the lower extremities. Respiratory muscle weakness, mild hyperCKemia, and sensory neuropathy – but not overt cardiac involvement – are associated features.

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