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Symptomatic dysferlin gene mutation carriers: Characterization of two cases

From Servei de Neurologia i Laboratori de Neurologia Experimental (I.I., N.D.L., R.D.-P., R.R.-G., E.G.), Servei de Radiologia (J.P.), Servei de Genètica (P.G.), Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma, Barcelona, Spain; and Servicio de Neurología (C.P., C.M.), Hospital Universitario Valme, Sevilla, Spain.

Address correspondence and reprint requests to Dr. Isabel Illa, Department of Neurology, Hospital de Sant Pau, Av. Pare Claret 167, 08025 Barcelona, Spain; e-mail: iilla{at}santpau.es

Objective: To describe two symptomatic dysferlin gene mutation carriers.

Methods: One patient had limb girdle weakness. His brother was diagnosed with limb girdle muscular dystrophy 2B with two mutations in the dysferlin gene (D625Y and E1734G). The second patient had distal weakness. He had two sons with Miyoshi myopathy with a homozygous mutation (G519R). We performed immunofluorescence (dystrophin, DAG proteins, dysferlin, caveolin-3), Western blot (dysferlin, caveolin-3, calpain-3), and real-time PCR (dysferlin) using skeletal muscle samples. We also studied dysferlin in peripheral blood monocytes (PBMs) by Western blot.

Results: In addition to the muscle weakness, both patients showed elevated creatine kinase and abnormal muscle MRI. They presented a mutation in only one allele after screening of the whole gene (skeletal muscle and monocyte mRNA and genomic DNA). A muscle biopsy specimen showed moderate dystrophic changes and patchy dysferlin expression in the sarcolemma. Western blot of both PBMs and skeletal muscle demonstrated a significant reduction in dysferlin. All the other proteins including caveolin-3 and calpain-3 were normal. Real-time PCR showed normal levels of dysferlin mRNA vs the patients' affected relatives.

Conclusions: The diagnosis of symptomatic carriers of dysferlin mutations should be considered when a pathologic pattern of dysferlin protein is observed.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 17 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on February 7, 2007, at www.neurology.org.

Supported by research grants (PI020388 and PI03/1387) from the Fondo Investigación Sanitaria Instituto Carlos III and from the Ministerio de Ciencia y Tecnologia (SAF 03/9240).

Disclosure: The authors report no conflicts of interest.

Received March 28, 2006. Accepted in final form December 11, 2006.

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