G.O.3: Severe congenital actin related myofibrillar myopathy

Abstract

Mutations in ACTA1 have been associated with nemaline myopathy, intranuclear rod myopathy, actin myopathy, cap myopathy, and congenital fiber type disproportion. Myofibrillar myopathies (MFM) are morphologically distinct but genetically heterogeneous muscular dystrophies arising from mutations in Z-disk related proteins. A 26-month-old boy was hypotonic and weak at birth, had significantly delayed motor development, and was mechanically ventilated and tube-fed since birth. At age 26 months he had cup-shaped low-set ears, a high-arched palate, contractures of the metacarpophalangeal and proximal interphalangeal joints, and facial diplegia with diffuse muscle weakness and reduced tendon reflexes, but had good head control and could sit with support. The EMG showed prominent fibrillation potentials and myopathic motor unit potentials. The muscle biopsy revealed abnormal variation in fiber size, fiber splitting, increased internal nuclei, vacuolar change, myofibrillar disorganization, hyaline structures, focal decreases of oxidative enzyme activity as well as scattered necrotic and regenerating fibers with marked increase of endomysial and perimysial connective tissue. Many structurally abnormal fibers displayed ectopic or abnormal expression of desmin, alphaB-crystallin, myotilin, dystrophin, and NCAM. Whole exome sequencing demonstrated a previously published in-frame insertion of two amino acids in ACTA1 . The mutant actin was expressed at ∼11% of wild-type in COS7 and C2 cells. C2 cells expressing mutant actin displayed cytoplasmic actin aggregates of different sizes whereas cells expressing wild-type actin displayed mostly filamentous actin. We conclude that (1) mutations in ACTA1 can cause MFM pathology; (2) MFM can be present at birth; (3) mutations in ACTA1 should be considered in patients with severe congenital hypotonia associated with muscle weakness and MFM pathology.