There are at least 19 forms of LGMD, and they’re classified by the genetic flaws that appear to cause them. Some 15 specific genes that lead to production of muscle proteins have been implicated as definite causes of LGMD when they’re flawed. MDA research was behind much of the work that identified these LGMD genes.
Genes, located on chromosomes in each cell in the body, are the codes, or recipes, for production of the body’s various proteins. The genes associated with LGMD normally make proteins necessary for muscle function.
When protein problems arise because one of these genes is faulty, fibers in the muscles don’t work properly. Gradually, the muscles become weak enough that people experience the symptoms of limb-girdle muscular dystrophy. Because LGMD is progressive, the muscles continue to get weaker throughout the person’s lifetime.
Six of the genes that, when flawed, cause LGMD lead to production of proteins that are normally located in the muscle cell membrane, a thin sheath that surrounds each muscle cell, helping to protect it from injury during muscle contraction. If any of these proteins is missing, the membrane probably loses some of its “shock absorber” qualities and has a harder time protecting the muscle cell from injury during normal contraction and relaxation cycles.
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.
Not all of the muscle proteins associated with LGMD are in the membrane, however. For instance, calpain-3 is probably located in the main part of the muscle cell, and myotilin and telethonin are located in the part of the muscle cell that allows it to contract and relax.
The types of LGMD are generally classified by letters and numbers that indicate which gene is known or suspected to be involved and whether the disorder is inherited as a dominant or recessive condition, meaning whether one or two flawed genes are needed to cause it.
Some physicians classify LGMD according to which protein is missing or deficient, if this is known. For example, one form may be called alpha-sarcoglycan deficiency, and another is known as beta-sarcoglycan deficiency. In the future, the term limb-girdle muscular dystrophy may become obsolete and be replaced by more specific terms.
The muscles most affected in limb-girdle muscular dystrophy (LGMD) are those surrounding the shoulders and hips, with nearby muscles in the upper legs and arms sometimes also weakening with time. These muscles are shown in red.
Inside each muscle cell, many proteins, some of which are shown here in blue and yellow-orange, help the cell contract and protect it from the stress of contractions.
When any of the proteins shown here in yellow-orange are missing or nonfunctional, LGMD is the result. At least six of these proteins are normally found in the muscle cell membrane, a sheath surrounding each cell. They form part of the structure of the membrane.
Determining which proteins are missing in LGMD and what their normal functions are in the muscle cell are crucial steps in developing treatments.
Bewildered patients often ask, “But it doesn’t run in the family, so how could it be genetic?”
LGMD can run in a family, even if only one person in the biological family has it. This is because of the ways in which genetic diseases are inherited.
LGMD can be inherited in one of two basic ways, known as the autosomal dominant pattern and the autosomal recessive pattern. The word autosomal means that the genes involved aren’t on the X or Y chromosome and, therefore, don’t have a preference for either men or women.
In diseases with dominant inheritance patterns, a person who inherits a flawed gene from one parent will have disease symptoms. That parent would also have the disease. In diseases with recessive inheritance, a person must inherit two flawed genes — one from each parent — to have disease symptoms. The parents don’t have symptoms.
A recessive form of LGMD can show up in one person when there’s no family history. Other family members may have been carriers, having no disease symptoms. Carriers have the genetic flaw (mutation) on a chromosome and can have a child with the disease, but only if the child’s other parent is also a carrier. So it isn’t unusual for carriers of a rare recessive disease not to know they’re carriers until someone in the family develops the disease.
Just to make things a little more complicated, a person with LGMD may have a brand new genetic mutation (after all, they have to start somewhere), so there may really be no family history or even carriers of the disorder in the family. However, once someone develops a genetic disease, even if the mutation is spontaneous (new) with that person, he or she can then pass on the mutation to any offspring, thereby introducing the gene for the disease into the family.
The details of inheritance risks for any particular form of LGMD depend on many circumstances, including exactly which type of LGMD has been diagnosed. A good way to find out more is to talk to your MDA clinic physician or ask to see the genetic counselor at the MDA clinic. More information can be found in MDA’s booklet Facts About Genetics and Neuromuscular Diseases.
To learn more, read In Focus: Limb-Girdle Muscular Dystrophy (October 2013 special report).