Hereditary myosin myopathies

Abstract

Hereditary myosin myopathies have emerged as a new group of muscle diseases with highly variable clinical features and onset during fetal development, childhood or adulthood. They are caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. Mutations have been reported in two of the three MyHC isoforms expressed in adult limb skeletal muscle: type I (slow/β-cardiac MyHC; MYH7) and type IIa ( MYH2). The majority of more than 200 dominant missense mutations in MYH7 are associated with hypertrophic/dilated cardiomyopathy without signs or symptoms of skeletal myopathy. Several mutations in two different parts of the slow/β-cardiac MyHC rod region are associated with two distinct skeletal myopathies without cardiomyopathy: Laing early onset distal myopathy and myosin storage myopathy (MSM). However, early onset distal myopathy and MSM caused by MYH7 mutations may also occur together with cardiomyopathy. MSM affects proximal or scapuloperoneal muscles whereas Laing distal myopathy primarily affects the dorsiflexor muscles of the toes and ankles. MSM is morphologically characterized by subsarcolemmal accumulation of myosin in type 1 fibers, whereas Laing distal myopathy is associated with variable and unspecific muscle pathology, frequently with hypotrophic type 1 muscle fibers. A myopathy associated with a specific mutation in MYH2 is associated with congenital joint contractures and external ophthalmoplegia. The disease is mild in childhood but may be progressive in adulthood, with proximal muscle weakness affecting ambulation. Mutations in embryonic MyHC ( MYH3) and perinatal MyHC ( MYH8), which are myosin isoforms expressed during muscle development, are associated with distal arthrogryposis syndromes with no or minor muscle weakness. Clinical findings, muscle morphology and molecular genetics in hereditary myosin myopathies are summarized in this review.