Published online before print December 26, 2007, doi:10.1212/01.wnl.0000284605.27654.5a)

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NEUROLOGY 2008;71:312-321
© 2008 American Academy of Neurology

Diagnosis and etiology of congenital muscular dystrophy

R. A. Peat, PhD, J. M. Smith, MBChB, A. G. Compton, PhD, N. L. Baker, PhD, R. A. Pace, BSc(Hons), D. J. Burkin, PhD, S. J. Kaufman, PhD, S. R. Lamandé, PhD and K. N. North, MBBS, MD

From The Institute for Neuromuscular Research (R.A. Peat, J.M.S., K.N.N.), The Children's Hospital at Westmead; The Discipline of Pediatrics and Child Health (R.A. Peat, J.M.S., A.G.C., K.N.N.), Faculty of Medicine, University of Sydney; Murdoch Childrens Research Institute and University of Melbourne (N.L.B., R.A. Pace, S.R.L.), Australia; Department of Pharmacology (D.J.B.), University of Nevada School of Medicine, Reno; and Department of Cell and Developmental Biology (S.J.K.), University of Illinois, Chicago.

Address correspondence and reprint requests to Dr. Kathryn North, Douglas Burrows Professor of Pediatrics and Child Health, Faculty of Medicine, University of Sydney, Institute for Neuromuscular Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, 2145 Sydney, NSW, Australia kathryn{at}chw.edu.au.

Objective: We aimed to determine the frequency of all known forms of congenital muscular dystrophy (CMD) in a large Australasian cohort.

Methods: We screened 101 patients with CMD with a combination of immunofluorescence, Western blotting, and DNA sequencing to identify disease-associated abnormalities in glycosylated -dystroglycan, collagen VI, laminin 2, 7-integrin, and selenoprotein.

Results: A total of 45% of the CMD cohort were assigned to an immunofluorescent subgroup based on their abnormal staining pattern. Abnormal staining for glycosylated -dystroglycan was present in 25% of patients, and approximately half of these had reduced glycosylated -dystroglycan by Western blot. Sequencing of the FKRP, fukutin, POMGnT1, and POMT1 genes in all patients with abnormal -dystroglycan immunofluorescence identified mutations in one patient for each of these genes and two patients had mutations in POMT2. Twelve percent of patients had abnormalities in collagen VI immunofluorescence, and we identified disease-causing COL6 mutations in eight of nine patients in whom the genes were sequenced. Laminin 2 deficiency accounted for only 8% of CMD. 7-Integrin staining was absent in 12 of 45 patients studied, and ITGA7 gene mutations were excluded in all of these patients.

Conclusions: We define the distribution of different forms of congenital muscular dystrophy in a large cohort of mixed ethnicity and demonstrate the utility and limitations of current diagnostic techniques.

Abbreviations: CK = creatine kinase; CMD = congenital muscular dystrophy; EMG = electromyogram; FKRP = fukutin related protein; LGMD2I = limb-girdle muscular dystrophy type 2I; MDC1C = congenital muscular dystrophy type 1C; MEB = muscle-eye-brain disease; PVDF = polyvinylidene fluoride; SSCP = single strand conformational polymorphism; UCMD = Ullrich congenital muscular dystrophy; WWS = Walker-Warburg syndrome.

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Supplemental data at www.neurology.org

Editorial, page 308.

e-Pub ahead of print on December 26, 2007, at www.neurology.org.

*These authors contributed equally to this work.

Supported by the NH&MRC (K.N.N. and S.R.L.), NIH and MDA (S.J.K), an MDA development grant (D.J.B.), an NH&MRC Dora Lush Biomedical Research Scholarship (R.A. Peat), a University of Sydney Postgraduate Award and an NH&MRC Medical Postgraduate Research Scholarship (J.M.S.), and an Australian Postgraduate Award (R.A. Pace).

Disclosure: The authors report no conflicts of interest.

Received March 17, 2007. Accepted in final form July 13, 2007.

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