Limb girdle muscular dystrophy (LGDMD) is a group of disorders affecting voluntary muscles, mainly those around the hips and shoulders (hence, “limb girdle”). There are more than 20 different types of LGMD, each due to mutation in a different gene. Some forms of LGMD are rapidly progressive, while others worsen only over many years.
Some forms of LGMD are caused by mutations in genes for proteins that are located in the muscle cell membrane, which surrounds the muscle cell. These include the sarcoglycan proteins, which link the interior of the muscle cell to the exterior. One function of the sarcoglycans is to transmit the force of contraction from the interior, where it is generated, to the exterior, ultimately to the bones of the skeleton that move in response to that contraction. Loss of function of these proteins leads to membrane disruption and muscle cell injury.
In LGMD, the muscle membrane also may be “leaky,” letting substances in or out that are supposed to stay on one side of the membrane or the other. Membrane proteins, when they’re made correctly and are in their normal positions, may also perform other essential functions in the cell; these functions may be defective when one or more of the proteins are absent.
Other LGMD proteins, including myotilin and telethonin, work with the contraction apparatus itself, while another, called lamin A/C, has a role at the cell nucleus. Dysferlin plays a role in muscle cell repair.
Despite the variety of causative genes, the consequences of LGMD are similar among many of the diseases, and so the therapeutic strategies are also similar. These include replacing the defective gene, correcting the defective gene, replacing the defective protein, replacing injured muscle cells, increasing muscle growth, and mitigating the effects of the mutant gene.