Myopathy, Distal, 5

A number sign (#) is used with this entry because of evidence that distal myopathy-5 (MPD5) is caused by compound heterozygous mutation in the ADSSL1 gene (612498) on chromosome 14q32.

Description

Distal myopathy-5 is an autosomal recessive, slowly progressive muscle disorder characterized by adolescent onset of distal muscle weakness and atrophy predominantly affecting the lower limbs. Other features include facial weakness and hyporeflexia. Patients remain ambulatory even after long disease duration (summary by Park et al., 2016).

Clinical Features

Park et al. (2016) reported 3 brothers, born of unrelated Korean parents, with onset of distal myopathy between 13 and 15 years of age. They also reported a female from an unrelated Korean family with a similar disorder. All had normal early motor development, and presented in the teenage years with slowly progressive mild facial muscle weakness as well as muscle weakness and atrophy of the lower limbs, with less severe findings in the upper limbs. Deep tendon reflexes were diminished. Imaging showed initial involvement of the gastrocnemius muscles, which had fatty replacement, followed by involvement of the quadriceps muscle after long disease duration. All patients were able to walk and climb stairs 10 to 17 years after symptom onset. Laboratory studies showed mildly elevated serum creatine kinase. Muscle biopsy showed marked variation in fiber size, a predominance of type 1 fibers, increased internal nuclei, few rimmed vacuoles, fiber splitting, increased fibrosis, and disorganized myofibrillar networks. There was no sensory impairment, joint contractures, high-arched palate, bulbar symptoms, or cardiac involvement.

Inheritance

The transmission pattern of MPD5 in the families reported by Park et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated Korean families with MPD5, Park et al. (2016) identified compound heterozygous mutations in the ADSSL1 gene (D304N, 612498.0001; c.1048delA, 612498.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Haplotype analysis suggested a founder effect for both mutations. Patient muscle samples showed decreased expression of the mutant missense protein and no expression of the truncated protein, which was attributed to increased degradation of the mutant proteins. In vitro studies in cultured mouse muscle cells and zebrafish indicated that the mutations resulted in a loss of function.

Animal Model

Park et al. (2016) found that morpholino knockdown of the adssl1 ortholog in zebrafish embryos resulted in muscle damage characterized by abnormal birefringence that may have been due to detachment of fibers from the myotendinous junctions. Staining with myosin heavy chain antibodies showed that there were lesions in the muscle fibers, with loosely packed myofibers and disorganized fiber patterns due to abundant gaps.