Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles

Abstract

We describe a new myopathy in a large family with 19 affected cases. Inheritance was autosomal dominant. Characteristic clinical features were congenital joint contractures, which normalized during early childhood, external ophthalmoplegia, and proximal muscle weakness. Muscle atrophy was most prominent in the pectoralis and quadriceps muscles. The clinical course was nonprogressive in childhood, but most adult cases experienced deterioration of muscle function, starting from 30 to 50 years of age. The major histopathological change of skeletal muscle in childhood was focal disorganization of myofilaments. In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments. These findings suggests that this new disease should be classified as a variant of hereditary inclusion body myopathy.

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

“…The morphological changes were mainly restricted to type 2A fibers, which were either absent or varied in size and showed structural changes. 8,10,18 A later study of patients of three unrelated families with a recessive myopathy, ophthalmoplegia and the absence of type 2A muscle fibers revealed that all patients were compound heterozygous for truncating mutations in MYH2. 11 More recently it was demonstrated that the affected individuals in a large family with recessive myopathy and ophthalmoplegia linked to chromosome 17 p13.1-p12 were homozygous for a frame shift mutation in MYH2 because of a single-base deletion.…”

“…[5][6][7] These include autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles (OMIM #605637), which was first reported as inclusion body myopathy (IBM3), caused by a single point mutation in the fast IIa MyHC gene (MYH2); [8][9][10] recessive myopathy with ophthalmoplegia because of truncating MYH2 mutations; 11 Laing early-onset distal myopathy (OMIM #160500) 12,13 and myosin storage myopathy (OMIM #608358), 14 caused by different mutations in the slow/ b-cardiac MyHC gene (MYH7); Trismus-pseudocamptodactyly syndrome (OMIM #158300), caused by mutation in fetal MyHC (MYH8); 15 distal arthrogryposis (DA) type 1 (OMIM #108120), type 2A (OMIM # 193700; Freeman-Sheldon syndrome) and type 2B (OMIM # 601680; Sheldon-Hall syndrome), caused by mutations in embryonic MyHC (MYH3). 16,17 Here we describe for the first time the clinical findings, muscle morphology and molecular genetic characteristics in six patients from four unrelated families with recessive missense mutations in MYH2 and also a patient with a novel recessive truncating MYH2 mutation.…”

Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)

“…An "autosomal dominant myopathy with congenital contractures, ophtalmoplegia and rimmed vacuoles" linked to the MYH2 gene on chromosome 17p13.1 has been reported by Darin and co-workers (15). This missense mutation is in a highly conserved region of the motor domain of the type IIa MyHC isoform and gives rise to an amino acid shift from a negatively (Glu-706) to a positively charged (Lys) residue (14,17) and the progression and severity of the disease correlates with type IIa MyHC expression (18).…”

“…In previous studies on patients with the IIa MyHC missense mutation, morphological muscle biopsy analyses at the light and electron microscopic level have shown an irregular intermyofibrillar network and rimmed vacuoles in type 2A fibers, increased variability in size of muscle fibers, increased interstitial fat and connective tissue and internalized myonuclei (14,15,18). A short summary of the clinical picture and histopathological findings are listed in Materials & Methods.…”

“…However, pure skeletal muscle myosinopathies have not been reported until recently (10,11). These include different mutations in the distal region of the β/slow MyHC affecting primarily skeletal muscle and a mutation of the IIa MyHC (10,(12)(13)(14)(15)(16)). …”