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Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy or Erb's muscular dystrophy is a type of muscular dystrophy that includes Duchenne muscular dystrophy, Becker's muscular dystrophy, and a large number of rarer disorders. more...

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The term "limb-girdle" is used to describe these disorders because the muscles most severely affected are generally those of the hips and shoulders -- the limb girdle muscles.

Common symptoms of limb-girdle muscular distrophy are muscle weakness, myoglobinuria, pain, myotonia, cardiomyopathy, elevated serum CK, and rippling muscles.

The muscle weakness is generally symmetric, proximal, and slowly progressive.

Generally pain is not present with LGMD, and mental function is not affected.

LGMD can begin in childhood, adolescence, young adulthood or even later. The age of onset is usually between 10 and 30. Both genders are affected equally. When limb-girdle muscular dystrophy begins in childhood the progression appears to be faster and the disease more disabling. When the disorder begins in adolescence or adulthood the disease is generally not as severe and progresses more slowly.

The distal muscles are affected late in LGMD, if at all. Over time (usually many years), the person with LGMD loses muscle bulk and strength. Eventually, he may need a power wheelchair or scooter, especially for long distances.

While LGMD isn't a fatal disease, it may eventually weaken the heart and lung muscles, leading to illness or death due to secondary disorders.

LGMD is typically an inherited disorder, though it may be inherited as a dominant, recessive, or X-linked genetic defect. The result of the defect is that the muscles cannot properly form the proteins needed for normal muscle function. Several different proteins can be affected, and the specific protein that is absent or defective identifies the specific type of muscular distrophy.

Treatment for LGMD is primarily supportive. Exercise and physical therapy are advised to maintain as much muscle strength and joint flexibility as possible. Assistive devices may be used to maintain mobility and quality of life. Careful attention to lung and heart health is also required.

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Mutations in calpain 3 associated with limb girdle muscular dystrophy: Analysis by molecular modeling and by mutation in m-calpain
From Biophysical Journal, 6/1/01 by Jia, Zongchao

ABSTRACT Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by selective atrophy of the proximal limb muscles. Its occurrence is correlated, in a large number of patients, with defects in the human CAPN3 gene, a gene that encodes the skeletal muscle-specific member of the calpain family, calpain 3 (or p94). Because calpain 3 is difficult to study due to its rapid autolysis, we have developed a molecular model of calpain 3 based on the recently reported crystal structures of m-calpain and on the high-sequence homology between p94 and m-calpain (47% sequence identity). On the basis of this model, it was possible to explain many LGMD2A point mutations in terms of calpain 3 inactivation, supporting the idea that loss of calpain 3 activity is responsible for the disease. The majority of the LGMD2A mutations appear to affect domain/domain interaction, which may be critical in the assembly and the activation of the multi-domain calpain 3. In particular, we suggest that the flexibility of protease domain I in calpain 3 may play a critical role in the functionality of calpain 3. In support of the model, some clinically observed calpain 3 mutations were generated and analyzed in recombinant m-calpain. Mutations of residues forming intramolecular domain contacts caused the expected loss of activity, but mutations of some surface residues had no effect on activity, implying that these residues in calpain 3 may interact in vivo with other target molecules. These results contribute to an understanding of structure-function relationships and of pathogenesis in calpain 3.

INTRODUCTION

This work is supported by the Protein Engineering Network of Centres of Excellence. Excellent technical assistance from Sherry Gauthier and Yvonne Lam is fully appreciated. We would also like to thank Chris Hosfield for insightful discussions and help in analyzing the crystal structure of rat m-calpain. Zongchao Jia holds a Canada Research Chair.

Received for publication 3 January 2001 and in final form 21 March 2001.

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Zongchao Jia,* Vitali Petrounevitch,* Andrew Wong,* Tudor Moldoveanu,* Peter L. Davies,* John S. Elce,* and Jacques S. Beckmannt

*Department of Biochemistry, Queen's University and The Protein Engineering Network of Centres of Excellence, Kingston, Ontario K7L 3N6, Canada; and tDepartment of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel

Address reprint requests to Dr. Zongchao Jia, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6. Tel: 613-5336277; Fax: 613-533-2497; E-mail: jia@post.queensu.ca.

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