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Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy

From the Division of Neurology, Department of Paediatrics (Drs. Minassian and Banwell) and Department of Genetics (Dr. Minassian, R. Aiyar, and S. Alic), Hospital for Sick Children and University of Toronto, Ontario, Canada; Institute of Neurological Sciences (Dr. Villanova), University of Siena, Italy; Institut de Myologie (Dr. Fardeau), INSERM Unite 153, Paris, France; Departments of Pathology (Neuropathology) (Dr. Mandell) and Neurology (Dr. Juel), University of Virginia, Charlottesville; Department of Neuroscience (Dr. Rafii), Brown University, Providence, RI; Department of Molecular Medicine (Dr. Auranen), Biomedicum, National Public Health Institute, Helsinki, Finland; and Department of Pathology (Dr. Kalimo), Turku University Hospital, Finland.

Address correspondence and reprint requests to B.A. Minassian, MD, Division of Neurology, Departments of Paediatrics and Genetics, Hospital for Sick Children and University of Toronto, 555 University Ave., Toronto, Ontario, Canada M5G 1X8; e-mail: bminass{at}sickkids.ca

Background: X-Linked myopathy with excessive autophagy (XMEA) is a childhood-onset slowly progressive disease of skeletal muscle with no cardiac, nervous system, or other organ involvement. Pathology is distinctive: membrane-bound autophagic vacuoles, multifold reduplication of the basement membrane, and intense deposition of membrane attack complex and calcium at the myofiber surface. XMEA has been linked to the most telomeric 10.5 cM of Xq28. The authors now report identification of new families, refinement of the locus, mapping of genes to the region, and screening of candidate genes for mutations.

Methods and Results: Seven new families were ascertained, including an American family with XMEA. Using 11 new microsatellite genetic markers, the authors fine-mapped a recombination in this family and a common ancestral haplotype in two French families, which localized the gene in a 4.37-Mb region. Sequence data were assembled from public and private databases and a near-continuous sequence derived for the entire region. With this sequence, a gene map of 82 genes and 28 expressed sequence tag clusters was constructed; to date, 12 candidate genes have been screened for mutations.

Conclusions: This study doubles the number of reported families with XMEA and more firmly establishes its distinctive clinicopathologic features. It also advances the search for the XMEA causative defect by reducing the disease locus to approximately half its previous size, assembling an almost complete sequence of the refined region, identifying all known genes in this sequence, and excluding the presence of mutations in 10% of these genes.

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