OBJECTIVE:

Distal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent-onset distal myopathy.

METHODS:

Four patients from two unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis.

RESULTS:

Patients had an adolescent-onset distal myopathy phenotype which included distal dominant weakness, facial muscle weakness, rimmed vacuole, and mild elevation of serum creatine kinase. Exome sequencing identified completely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1 which encodes a muscle-specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the mutation sites were located in well conserved regions. Both the D304N and I350fs mutations in ADSSL1 led to decreased enzymatic activity. The knock-down of the adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knock-downed zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect.

INTERPRETATION:

We suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adolescent-onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics. This article is protected by copyright. All rights reserved.

© 2015 American Neurological Association.