Miyoshi muscular dystrophy is an autosomal recessive skeletal muscle disorder characterized by onset in young adulthood of distal muscle weakness affecting the upper and lower limbs but sparing the intrinsic hand muscles. Muscle weakness and atrophy particularly affects ... Miyoshi muscular dystrophy is an autosomal recessive skeletal muscle disorder characterized by onset in young adulthood of distal muscle weakness affecting the upper and lower limbs but sparing the intrinsic hand muscles. Muscle weakness and atrophy particularly affects the gastrocnemius and soleus muscles, and can later spread to involve the thigh and gluteal muscles. Patients showed impaired tip-toe standing, difficulty in climbing stairs, and difficulty walking, but usually remain ambulatory. Serum creatine kinase is increased and muscle biopsies show myopathic and dystrophic changes with necrosis (summary by Miyoshi et al., 1986). - Genetic Heterogeneity of Miyoshi Muscular Dystrophy Miyoshi muscular dystrophy is a genetically heterogeneous disorder: MMD2 (613318) has been mapped to chromosome 10p, and MMD3 (613319) is caused by mutation in the ANO5 gene (608662) on chromosome 11p14. See also Welander myopathy (604454), an autosomal dominant form of late-onset distal myopathy.
Miyoshi et al. (1967) reported 4 patients from 2 Japanese families with distal myopathy inherited in an autosomal recessive pattern. Sasaki et al. (1969) and Ideta et al. (1973) each reported 4 affected patients. Kuhn and Schroder (1981) ... Miyoshi et al. (1967) reported 4 patients from 2 Japanese families with distal myopathy inherited in an autosomal recessive pattern. Sasaki et al. (1969) and Ideta et al. (1973) each reported 4 affected patients. Kuhn and Schroder (1981) reported 2 affected Caucasian brothers born of consanguineous parents. They had early-adult onset in the distal leg muscles and elevated creatine kinase. Miyoshi et al. (1986) described in detail 17 cases from 8 families including an autopsy case. Consanguinity was found in 7 of the 8 families and in 2 families there was pseudodominance, i.e., affected father and children. Eighty percent of the cases had onset between 16 and 20 years with long survival. Serum CK activity was markedly elevated in all except 1 patient, aged 56 years; CK was mildly elevated in preclinical stages. The pattern of muscle involvement was distinctive; the muscles of the lower legs and forearms were involved, whereas the small muscles of the feet and hands were relatively spared. Skilled movements of the fingers were not disturbed, but grip strength was decreased early in the disease. No lesions were detected in the brain, spinal cord, or peripheral nerves. Miyoshi et al. (1986) noted that the disorder could be distinguished from Welander myopathy, which shows atrophy of small muscles of the hands and extensor muscles of the legs with inability to stand on the heels but ability to stand on tip-toes, whereas in Miyoshi myopathy, impaired toe-standing was an early symptom and heel-standing was normal. Isaacs et al. (1988) described 5 patients with autosomal recessive distal myopathy of late onset; 3 of the patients belonged to a single sibship. One of the cases resembled the Nonaka form (605820). The authors concluded that autosomal recessive distal myopathy can occur in different ethnic groups. Yamanouchi et al. (1994) examined 19 muscle biopsies from 14 patients with autosomal recessive distal muscular dystrophy. The histologic features were similar to those of Duchenne muscular dystrophy (DMD; 310200) with active muscle fiber necrosis and regeneration, as well as disorganization of the intermyofibrillar network. In half of the patients, small angular fibers and scattered rimmed vacuoles were found. However, dystrophin (300377) and utrophin (128240) were expressed normally, even in severely affected gastrocnemius muscles. In a large, inbred, aboriginal Canadian kindred with 9 muscular dystrophy patients, Weiler et al. (1996) found that the ancestry of all but 2 of the carrier parents could be traced to a founder couple 7 generations earlier. Seven patients presented with proximal myopathy consistent with limb-girdle muscular dystrophy, whereas 2 patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy. Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MD was consistent with autosomal recessive inheritance. Rowin et al. (1999) described 2 patients with a clinical diagnosis of Miyoshi myopathy who demonstrated marked inflammatory changes on muscle biopsy of clinically less affected muscles. The findings illustrated the importance of recognizing the marked variability in histopathology of Miyoshi myopathy, which may include an inflammatory infiltrate on muscle biopsy, mimicking the histopathologic picture of an inflammatory myopathy. One patient was a 25-year-old Pakistani man, born of consanguineous parents, with a 1.5-year history of progressive atrophy of both calves associated with 'limping.' He denied involvement of the upper extremities. The second patient was a 29-year-old woman who had had progressive difficulty in walking, particularly in high-heeled shoes, beginning at the age of 18 and progressing to include difficulty walking up stairs and stumbling over her feet. Ro et al. (2004) reported 4 Chinese patients from 2 unrelated families living in Taiwan with MM confirmed by molecular identification of mutations in the dysferlin gene. Three sibs in 1 family experienced difficulty in toe walking beginning at ages 17 to 18 years. In the following 2 to 5 years, all had difficulty in climbing stairs and rising from a squatting position accompanied by moderate to severe weakness in the gastrocnemius and soleus muscles and mild weakness in the hamstring and quadriceps muscles. The tibialis anterior muscle was relatively spared. Two patients had muscle wasting and weakness in the lower legs. Reflexes were decreased or absent in the ankles. CK was elevated and muscle biopsies showed dystrophic patterns with decreased or absent dysferlin staining. MRI showed a mild to moderate increase of signal intensity in the affected muscles of the lower legs, reflecting fatty infiltration. The 1 patient from the other family had a similar clinical course and MRI findings. Illa et al. (2007) reported 2 sibs with Miyoshi myopathy due to a homozygous mutation in the DYSF gene (G519R; 603009.0015). Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. Spuler et al. (2008) reported 2 sibs with Miyoshi myopathy caused by mutation in the DYSF gene (G299W; 603009.0018). Skeletal muscle biopsy of 1 showed amyloid fibrils on skeletal muscle biopsy. Amyloid was located in the sarcolemma of muscle cells as well as in blood vessel walls and interstitium. Spuler et al. (2008) postulated that the mutation destabilized the protein structure of dysferlin and increased the propensity to form amyloid fibrils.
In 9 families with either Miyoshi myopathy or LGMD2B, Liu et al. (1998) identified 9 mutations in the dysferlin gene (see, e.g., 603009.0001), indicating that they are allelic disorders.