Muscular limb girdle

Calpain Tissue specific calpains have been implicated in diabetes, cataracts, multiple sclerosis, and limb-girdle muscular dystrophy type 2A. More than 50 inhibitors of calpain have described which have a potential for therapeutic applications. 

LGMD, limb girdle muscular dystrophy DMD, Duchenne muscular dystrophies BMD, Becker muscular dystrophies... 

Duchenne muscular dystrophy. Mutations in the genes encoding some of the components of the sarcoglycan complex shown in Figure 49-12 are responsible for limb-girdle and certain other congenital forms of muscular dystrophy. 

The clinical picture in male children can closely resemble Duchenne-type muscular dystrophy in adults, it mimics limb-girdle dystrophy or polymyositis. The early and severe involvement of respiratory muscles in most patients with AMD is a distinctive clinical clue. Respiratory failure and pulmonary infection are the most common causes of death. 

Schematic model of the dystrophin-glycoprotein complex. Courtesy of Kevin P. Campbell. See Lim and Campbell1 Abbreviations LGMD, Limb Girdle muscular dystrophy CMD, congenital muscular dystrophy DMD / BMD, Duchenne / Becker muscular dystrophies.

Salmikangas, P., Mykkanen, O. M., Gronholm, M., Heiska, L., Kere, J., and Carpen, O. (1999). Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum. Mol. Genet. 8, 1329-1336. 

Anderson, L.V.B., Harrison, L.V.B., Pogue, R., Vafiadaki, E., Pollitt, C., Davison, K., Moss, J.A., Keers, S., Pyle, A., and Shaw, P J., et al., 2000, Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies)., Neuromuscul. Dis., 10, 553-559... 

Jia, Z., Petrounevitch, V., Wong, A., Moldoveanu, T., Davies, P.L., Elce, J.S., and Beckmann, J.S., 2001, Mutations in calpain 3 associated with limb girdle muscular dystrophy analysis by molecular modeling and by mutation in m-calpain., Biophys. J., 80, 2590-2596... 

Saito, K., Elce, J.S., Hamos, J.E., and Nixon, R.A., 1993, Widespread Activation of Calcium-Activated Neutral Proteinase (Calpain) in the Brain in Alzheimer Disease A Potential Molecular Basis for Neuronal Degeneration, Proc. Natl. Acad. Sci. U. S. A., 90, 2628-2632 Kawai, H., Akaike, M., Kunishige, M., Inui, T., Adachi, K., Kimura, C., Kawajiri, M., Nishida, Y., Endo, I., and Kashiwagi, S. et al., 1998, Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families, Muscle Nerve, 21, 1493-1501... 

Sorimachi, H., Ono, Y., Suzuki, K., 2000, Skeletal muscle-specific calpain, p94, and connectin/titin their physiological junctions and relationship to limb-girdle muscular dystrophy type 2A, Adv. Exp. Med. Biol., 481, 383-95... 

Volonte, D., Peoples, A.J., and Galbiati, F., 2003, Modulation of myoblast fusion by caveolin-3 in dystrophic skeletal muscle cells implications for Duchenne muscular dystrophy and limb-girdle muscular dystrophy-lC, Mol Biol Cell, 14, pp 4075-4088. 

Sorimachi, H., Kinbara, K., and Kimura, S. (1995). Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence./. Biol. Chem. 270, 31158-31162. 

Bittner, R. E., Anderson, L. V., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., et al. (1999) Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. Nat Genet 23, 141-142. 

Two phase I trials have been undertaken with rAAV-factor IX (FIX) vectors, one involving intramuscular administration (Kay et al., 2000), and the second involving direct delivery to the liver by way of a catheter in the hepatic artery. Early results from the muscle delivery trial were quite encouraging, but the switch to the intraphepatic route was made in an attempt to exploit the more efficient secretory ability of hepatocytes. One additional trial was initiated using a rAAV-alpha sarcoglycan vector in one patient with limb-girdle muscular dystrophy. This last trial was halted after one patient due to factors unrelated to the study results. 

Stedman, H., Wilson, J. M., Finke, R., Kleckner, A. L. and Mendell, J. (2000). Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy Alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular instillations of adeno-associated vectors. Hum. Gene Ther. 11, 777-790. 

Autosomal dominant 5q33 (5-Sarcoglycan (5-Sarcoglycan Limb girdle muscular dystrophy... 

Muchir, A., Bonne, G., van der Kooi, A.J., van Meegen, M., Baas, F., Bolhuis, P.A., de Visser, M. and Schwartz, K. (2000) Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMDIB). Hum. Mol. Genet. 9, 1453-1459. 

Thus in muscular dystrophy it is apparent that both the mean elevations of the serum enzyme values and the magnitudes of their variations upon physical activity are proportional to the mass of dystrophic muscle remaining and to the severity of the disease in it. Both are thus greater in early than in evident Duchenne-type dystrophy, less in limb-girdle dystrophy, and least in myotonia congenita. Further, though serum creatine kinase has been found to be an exceedingly delicate index of myopathy (A2, S14), for present purposes serum aldolase is suflBciently... 

Fig. 10. Effect of alternate rest and physical activity in advanced severe limb-girdle muscular dystrophy. A, first appearance as outpatient B, admission after 7 weeks of general exercise C, after 17 days of systematic hospital exercises. Periods R and S, successive intervals of 6 and 7 days of bed rest. J, discharged ambulant from hospital.

Figs. 11 and 12. Normal twin pregnancy during early mild limb-girdle muscular dystrophy. A, admission to bed for assessment B, brief active physiotherapy C, discharged home under observation D, admission to bed in early labor E, 8 hours, and F, 2 hours before first birth in strong labor G, during uterine relaxation between deliveries. 

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