G.P.152: Novel recessive mutations in MYH2 presenting with congenital facial weakness, ophthalmoparesis, severe progressive scoliosis, and mild muscle weakness

Abstract

Congenital myopathies are a heterogeneous group of non-dystrophic muscle disorders characterized by weakness/hypotonia presenting in infancy. Diagnoses are based on clinical and characteristic pathologic features confirmed with genetic testing. Ophthalmoparesis is a useful but non-specific clinical sign that can be diagnostically helpful if the clinical context is taken into careful consideration. Myosins are fiber-type specific, actin-binding proteins essential for muscle contraction. MYH2 encodes MyHC IIa, predominantly expressed in type 2A fibers. 2 confirmed AD missense mutations have been reported in MYH2 and are associated with a childhood/adult-onset, slowly-progressive inclusion body myopathy with ophthalmoparesis and congenital contractures. 10 recessive MYH2 mutations have been recognized and are characterized by childhood-onset marked external ophthalmoparesis and a mild myopathy. We describe siblings with previously unreported compound heterozygous truncating mutations in MYH2 presenting with decreased fetal movements, congenital onset facial weakness and myopathy without congenital contractures, normal acquisition of motor milestones, marked ophthalmoparesis, and notably rapidly progressive scoliosis requiring spinal fusion in the early teens. While spinal abnormalities are frequently reported in the dominant mutations, it has not been a significant finding in recessive mutations. Severe progressive scoliosis has not been reported in either type/form. Congenital joint contractures are a hallmark feature in patients with dominant MYH2 mutations, yet this is not observed with recessive mutations. These findings indicate that recessive MYH2 mutations should be considered in the differential diagnosis of early-onset ophthalmoparesis, mild myopathy with type I predominance, and progressive scoliosis in the absence of a positive family history or other distinctive biopsy findings.