What is the pathophysiology of limb-girdle muscular dystrophy (LGMD)

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

LGMD is caused by mutations in genes encoding for proteins constituting the sarcolemma, cytosolic contents, or nucleus of muscle cells (myocytes). Given the heterogenous nature of mutations, mechanism of myocyte damage and muscle fiber degeneration may variably include errors in protein complex formation, functional or structural errors in the contractile apparatus, sarcolemmal instability, enzymatic abnormalities, or errors in repair mechanisms. With accumulating damage, there is eventual deposition and replacement of muscle by fibrotic and adipose tissue. Although the primary defect in many LGMDs is known, the precise mechanism leading to the dystrophic phenotype has not always been elucidated. Specific protein function and abnormalities are discussed below with each LGMD.

Dystrophin-glycoprotein complex bridges the inner Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, dysferlin, and caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan can result in limb-girdle muscular dystrophy syndrome. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
Schematic of the sarcomere with labeled molecular Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.

There is considerable overlap of the LGMD phenotype with other hereditary myopathies. Often, mutations in the same gene lead to phenotypes variably characterized as LGMD or as congenital muscular dystrophy, myofibrillar myopathy, or less commonly as Emery-Dreifuss muscular dystrophy, congenital myasthenic syndrome, congential myopathy, or metabolic myopathy. Most of these are discussed in separate chapters, but mutations causing myofibrillar myopathy are discussed in this article. Of interest, several mutations that result in myofibrillar myopathy are in genes that code for Z-disk proteins.

LGMD subtypes based on pathophysiological mechanism: [4]

  • Dystrophin-glycoprotein complex (Sarcoglycanopathy): LGMD2C-F 
  • Sarcomeric proteins: LGMD1A, LGMD1D, LGMD1E, LGMD2A, LGMD2G, LGMD2J, LGMD2Q, LGMD2R
  • Defects in glycosylation/α-dystroglycan (α-dystroglycanopathy): LGMD2I, LGMD2K, LGMD2M, LGMD2N, LGMD2O, LGMD2P, LGMD2S, LGMD2T, LGMD2U, LGMD2Z
  • Proteins of nuclear envelope/function: LGMD1B, LGMD1F, LGMD1G, LGMD2X, LGMD2Y
  • Defects in signal transduction: LGMD1C, LGMD2P, LGMD2W 
  • Defects in trafficking/repair: LGMD1C, LGMD1F, LGMD2B, LGMD2L

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