Limb-Girdle Muscular Dystrophy (LGMD)

Limb-Girdle Muscular Dystrophy (LGMD)

What is limb-girdle muscular dystrophy?

Limb-girdle muscular dystrophy (LGMD) is a diverse group of disorders with many subtypes categorized by disease gene and inheritance. LGMD usually manifests in the proximal muscles around the hips and shoulders. (The proximal muscles are those closest to the center of the body; distal muscles are farther away from the center — for example, in the hands and feet).

The shoulder girdle is the bony structure that surrounds the shoulder area, and the pelvic girdle is the bony structure surrounding the hips. Collectively, these are called the limb girdles, and it is the observed weakness and atrophy (wasting) of the muscles connected to the limb girdles that has given this group of disorders its name.

Together, the group of disorders that constitute LGMD is the fourth most common genetic cause of muscle weakness with an estimated prevalence in about 2 in every 100,000 individuals.^1,2,3

What are the symptoms of LGMD?

The unifying features of the LGMDs are the weakness and atrophy of the limb-girdle muscles. However, the age at which symptoms appear, and the speed and severity of disease progression, can vary.

Individuals may first notice a problem when they begin to walk with a “waddling” gait because of weakness of the hip and leg muscles. They may have trouble getting out of chairs, rising from a toilet seat, or climbing stairs. As this weakness progresses, the person may require the use of assistive mobility devices.³

Weakness in the shoulder area may make reaching over the head, holding the arms outstretched, or carrying heavy objects difficult. It may become increasingly hard to keep the arms above the head for such activities as combing one’s hair or arranging things on a high shelf. Some people find it harder to type on a computer or other keyboard and may even have trouble feeding themselves.

Some of the LGMD subtypes also are characterized by additional symptoms. For example, the heart can be affected in some types of LGMD, with weakness of the heart muscle (cardiomyopathy) and/or abnormal transmission of signals that regulate the heartbeat (conduction abnormalities or arrhythmias).^3,4,5

Some disease subtypes also involve the muscles used for breathing, and for that reason, respiratory function, along with cardiac function, should be monitored regularly.²

Other symptoms may be present in some of the different subtypes of LGMD, including but not limited to joint stiffness, muscle cramps, enlargement of calf muscles, and involvement of distal muscles of the body such as those controlling the hands and feet.^6,7

What causes LGMD?

Genes are the codes, or recipes, that cells use to manufacture the various proteins needed by the body. The genes associated with LGMD normally encode proteins that play vital roles in muscle function, regulation, and repair. When one of these genes contains a mutation (a flaw, such as missing or incorrect information), cells cannot produce the proteins needed for healthy muscles.

There are two major groups of LGMDs. Called LGMD1 and LGMD2, these two groups are classified by the respective inheritance patterns: autosomal dominant and autosomal recessive. If one copy of the abnormal gene is sufficient to cause the disease, it is said to be autosomal dominant; if two copies are needed, then the inheritance pattern is autosomal recessive. In some families, the inheritance pattern cannot be determined. For more details on the various inheritance patterns, see the NIH Genetics Home Reference.

Dozens of different genes, when mutated, have been shown to cause specific LGMD1 and LGMD2 subtypes. In these cases, the proteins associated with these genes are nonfunctional or deficient, and muscles are unable to function normally. Gradually, the muscles become weak enough that people experience the symptoms of LGMD.

In addition to the known LGMD1 and LGMD2 subtypes linked to specific genes, there are many cases of LGMD for which the causative gene is not yet known (and people with these cases are not identified as having a subtype-specific form of LGMD). Scientists are actively working to understand the causes of these unidentified subtypes of LGMD, because the more we understand about all the different causes of LGMD and the diverse ways that muscle can be compromised, the better chance we have of finding effective therapies to intervene in the pathological process.

What is the progression of LGMD?

At this time, progression in each type of LGMD cannot be predicted with certainty, although knowing the underlying genetic mutation can be helpful. Some forms of the disorder progress to loss of walking ability within a few years and cause serious disability, while others progress very slowly over many years and cause minimal disability.

LGMD can begin in childhood, adolescence, young adulthood, or even later. Both genders are affected equally.

When LGMD begins in childhood, some physicians say, the progression is usually faster and the disease more disabling. When the disorder begins in adolescence or adulthood, they say, it is generally not as severe and progresses more slowly. The course is usually one of slowly progressive, mostly symmetric weakness, with the exception of a few types with rapid progression or asymmetric weakness. ²

What is the status of research on LGMD?

MDA-supported scientists are pursuing several exciting strategies in muscular dystrophy research that have implications for LGMD. These strategies include gene therapy, exon skipping, stop codon read through, and myostatin blocking.

To learn more, read The Changing Landscape of LGMD Research.

Subtypes of LGMD

Below is a list of LGMD subtypes. Type 1 LGMDs are dominantly inherited, requiring only one mutation for symptoms to result. Type 2 LGMDs are recessively inherited, requiring two mutations, one from each parent for symptoms to appear. Sometimes, LGMDs are referred to by their names, not their numbers, and some types have not been assigned numbers. The discovery of genetically distinct subtypes has redefined the classification of LGMD and has led to nomenclature designating the autosomal dominant forms as LGMD1A, 1B, 1C, etc., and the autosomal recessive forms as LGMD2A, 2B, 2C, etc.

Dominant LGMD subtype numbers:

LGMD Subtype	Gene	Comment
LGMD1A	MYOT 8
LGMD1B	LMNA9, 10	Most common autosomal dominant type, accounts for 5-10% of all cases
LGMD1C	CAV37, 11
LGMD1D	DNAJB612, 13
LGMD1E	DES14
LGMD1F	TNP0315
LGMD1G	HNRNPDL16, 17
LGMD1H	Unknown18

Recessive LGMD subtype numbers:

LGMD Subtype	Gene	Comment
LGMD2A	CAPN319	Most common type world-wide, accounts for 15-40% of all LGMD cases
LGMD2B	DYSF 20	The second most common type, accounts for 5-35% of LGMD cases21
LGMD2C	SGCG22
LGMD2D	SGCA22
LGMD2E	SGCB22
LGMD2F	SGCD22
LGMD2G	TCAP23, 24
LGMD2H	TRIM3225
LGMD2I	FKRP15
LGMD2J	TTN26, 27, 42
LGMD2K	POMT128
LGMD2L	ANO529
LGMD2M	FKTN30
LGMD2N	POMT231, 32
LGMD2O	POMGnT133
LGMD2P	DAG134
LGMD2Q	PLEC135
LGMD2R	DES36
LGMD2S	TRAPPC1137
LGMD2T	GMPPB38
LGMD2U	ISPD39
LGMD2V	GAA40
LGMD2W	LIMS241
LGMD2X	BVES
LGMD2Y	TOR1A1P1

Download our Limb-Girdle Muscular Dystrophy (LGMD) Fact Sheet

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