Limb–girdle muscular dystrophy: Diagnostic evaluation, frequency and clues to pathogenesis
Received 23 July 2007; received in revised form 23 July 2007; accepted 17 August 2007.
Abstract
We characterized the frequency of limb–girdle muscular dystrophy (LGMD) subtypes in a cohort of 76 Australian muscular dystrophy patients using protein and DNA sequence analysis. Calpainopathies (8%) and dysferlinopathies (5%) are the most common causes of LGMD in Australia. In contrast to European populations, cases of LGMD2I (due to mutations in FKRP) are rare in Australasia (3%). We have identified a cohort of patients in whom all common disease candidates have been excluded, providing a valuable resource for identification of new disease genes. Cytoplasmic localization of dysferlin correlates with fiber regeneration in a subset of muscular dystrophy patients. In addition, we have identified a group of patients with unidentified forms of LGMD and with markedly abnormal dysferlin localization that does not correlate with fiber regeneration. This pattern is mimicked in primary caveolinopathy, suggesting a subset of these patients may also possess mutations within proteins required for membrane targeting of dysferlin.
aInstitute for Neuromuscular Research, The Children’s Hospital at Westmead, Sydney, Australia
bDiscipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Sydney, Australia
cCentre for Clinical Neurosciences and Neurological Research, St. Vincent’s Hospital, Melbourne, Australia
dConcord Repatriation General Hospital, Sydney, Australia
Corresponding author. Address: Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Sydney, Australia. Tel.: +61 2 98451906; fax: +61 2 98453389.
ABSTRACT