A new de novo missense mutation in MYH2 expands clinical and genetic findings in hereditary myosin myopathies

Abstract

Congenital myopathy related to mutations in myosin MyHC IIa gene (MYH2) is a rare neuromuscular disease. A single dominant missense mutation has been reported so far in a family in which the affected members had congenital joint contractures at birth, external ophthalmoplegia and proximal muscle weakness. Afterward only additional 4 recessive mutations have been identified in 5 patients presenting a mild non-progressive early-onset myopathy associated with ophthalmoparesis. We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia. We describe clinical, histopathological and muscle imaging findings expanding the clinical and genetic spectrum of MYH2-related myopathy.

Fig. 1

Muscle biopsy. Quadriceps muscle biopsy shows marked variability in fiber size with proliferation of perimysial and endomysial connective tissue without inflammation and necrosis (A). Hystochemistry for cytocorme c-oxidase does not show disorganization of the intermyofibrillar network (B). Immunochemistry for Myosin isoforms shows type I fibers predominance (monoclonal antibodies against slow type I fibers, Leica Microsystems) (C). In (D) are shown the rare and hypotrophic type II fibers (monoclonal antibody against fast type fast IIa and IIx fibers, mAb A4.74, Hybridoma Bank, The University of Iowa, Department of Biology, Iowa City).

Fig. 2

Muscle MRI. Axial T1-weighted fast spin echo sequences of pelvic girdle, thigh and calf muscles. At the pelvic level is an evident predominant involvement of gluteus maximus and tensor fascia lata (A). At the thigh vastus lateralis, rectus femoris, semitendinosus and gracilis are mainly involved (B). At calf level there are marked changes in the lateral head of the gastrocnemius and minor involvement of soleus (C).

Fig. 3

Sequence alignment of MyHC IIa isoform among different species. Figure shows multiple sequence alignment of MyHC IIa across species in the amino acid region 1840–1900 of the human protein. The site of the L1870P mutation is indicated by an arrow. Invariant residues are grayed.