Infantile muscular dystrophy in Canadian aboriginals is an αb-crystallinopathy

Marc R. Del Bigio, Albert E. Chudley, Harvey B. Sarnat, Craig Campbell, Sharan Goobie, Bernard N. Chodirker, Duygu Selcen

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Objective: A recessively transmitted fatal hypertonic infantile muscular dystrophy has been described in Canadian aboriginals. The affected infants present with progressive limb and axial muscle stiffness and develop severe respiratory insufficiency, and most die in the first year of life. We sought to determine the genetic basis of this disease. Methods: We performed histochemical, immunocytochemical, electron microscopy, and molecular genetic studies in a cohort of 12 patients affected by this disease. Results: Conventional histochemical and electron microscopy studies suggested myofibrillar myopathy (MFM). Therefore, we searched for ectopic expression of multiple proteins typical of MFM. Alpha B-crystallin (αBC) expression was absent from all fibers using a monoclonal antibody raised against the entire protein. However, a monoclonal antibody directed against the first 10 residues of αBC immunostained portions of abnormal fibers. Pursuing this clue, we searched for mutations in the gene for αBC (CRYAB) in available DNA samples of 8 patients. All harbored a homozygous deletion, c.60C, predicting a Ser to Ala change at codon 21 and a stop codon after 23 missense residues (p.Ser21AlafsX24). Clinically unaffected parents were heterozygous for this mutation. Interpretation: The homozygous c.60delC in CRYAB pinpoints the genetic basis of the fatal infantile hypertonic muscular dystrophy of Canadian aboriginals. MFMs are typically transmitted by dominant inheritance, but in this disease the parental phenotype is rescued by limited expression of the highly truncated nonfunctional mutant gene product. The severe patient phenotype is due to homozygosity for the markedly hypomorphic allele.

Original languageEnglish (US)
Pages (from-to)866-871
Number of pages6
JournalAnnals of neurology
Issue number5
StatePublished - May 2011

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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