All limb-girdle muscular dystrophies (LGMD) show a similar distribution of muscle weakness, affecting both upper arms and legs. Frequently, the first reported symptoms are difficulty climbing stairs, standing from a squatting position, or raising arms above the head.
The limb-girdle muscular dystrophies are known to be genetically heterogeneous, with both dominant and recessive forms reported.
Autosomal Dominant LGMD
The dominant LGMDs usually show adult onset. In addition to muscle weakness, the creatine kinase (CK) values are elevated in affected individuals usually 4 - 10 times the normal laboratory values. Currently, neither presymptomatic nor prenatal testing is available for any form of dominantly inherited limb-girdle muscular dystrophy.
This disease was linked to a 7cM region on 5q22.3-313. Several years ago, our laboratory identified a mutation in the myotilin gene that is responsible for causing this disease in a single large family living on the east coast. More than 50% of affected family members have a nasal quality to their speech and this particular speech pattern has not been seen in any other autosomal dominant families studied to date. The average age of onset is 27 years. More recently, we have identified a second family living in Argentina that has LGMD1A caused by a different mutation in the myotilin gene. These mutations cause changes in the amino acid sequence, thus producing an abnormal form of the protein.
We have now begun the next phase of our research, which is to understand why abnormalities in myotilin lead to LGMD. One approach has been to cause abnormal myotilin protein to be produced in the muscles of laboratory mice. These mice show many signs of disease that are quite similar to that seen in human patients. We are currently examining the physical properties of these mouse muscles, and determining the effect of exercise on the progress of the disease.
The gene for LGMD 1B has been linked to chromosome 1q11-q21. This form of LGMD was linked in several families in 1997. The clinical characteristics of this form of LGMD are the age of onset is less than 20 with slow progression, beginning in the lower extremities and progressing to involve the upper extremities by age 20-30. Individuals with this form of LGMD do not develop significant contractures. The feature that separates LGMD 1B from the other forms is the association of cardiac involvement in a high percentage of individuals in the families studied. The cardiac abnormalities reported have been atrioventricular (AV) conduction disturbances and abnormal cardiac rhythms with individuals developing symptoms of abnormally slow heart rates, fainting, and sometimes death. Presymptomatic treatment has necessitated the placement of a cardiac pacemaker in some individuals. The mutation for LGMD 1B has been identified in the Lamin A/C gene on chromsome 1q. Two other syndromes which also have mutations in this gene are familial partial lipodystrophy (Köbberling-Dunnigan Syndrome) and Emery Dreifuss muscular dystrophy, type 2.
The gene for this form of LGMD has been localized to chromosome 3p25 and is known as the Caveolin-3 gene. This is a childhood onset disorder (mean 5 years) which results in moderate weakness of the hip and shoulder girdle muscles. Often there is enlargement (hypertrophy) of the calf muscles which may cause confusion with another myopathy which commonly causes calf hypertrophy, Duchenne muscular dystrophy. A common feature is the development of muscle cramps after exercise. The creatine kinase (CK) level in individuals with this disorder may be elevated from 4-25 times normal, a much higher CK range than in any of the other dominantly inherited LGMD forms.
In 1999 our lab reported the identification of a new locus for autosomal dominant LGMD which maps to 7q in two families. The clinical characteristics in these families are similar to other dominantly inherited LGMD forms, namely, the hip girdle muscles more involved than shoulder girdle, slow progression, but no associated findings such as unusual speech patterns, contractures, or cardiac effects. About 20% of patients have swallowing difficulties. The mean age of onset is 38 in these 2 families. Currently, we are trying to narrow the region of disease gene location.
Familial Dilated Cardiomyopathy with Conduction Defect & Muscular Dystrophy
Only 1 family of French Canadian ethnicity has been described with these clinical features and linkage to chromosome 6q23. The age of onset is teens and later. A few individuals have been reported to have calf hypertrophy. The progression is quite slow with no one yet reported to become wheelchair dependent. The cardiac manifestations which begin in the early to mid-twenties are the development of abnormal heart rhythms. From the twenties to the forties family members have been reported to develop congestive heart failure including the enlargement of all four chambers of the heart. Sudden death has occurred in some individuals who had no previous history of cardiac symptoms.
Other LGMD 1 forms
Thus, there are now 5 genes which can lead to autosomal dominant LGMD, but there are still a large number of other families with autosomal dominant transmission which do not link to any of the above mentioned loci. Given the number of unlinked families, one must assume there are chromosomal loci that are yet to be determined. This once again underscores the significant heterogeneity within the LGMD1 diagnostic classification.
Autosomal Recessive LGMD
The recessive LGMDs are more frequent than the dominant forms, and usually have childhood or teen-age onset. Currently, genes for nine different forms of recessive LGMD have been localized and/or identified. Additional loci have yet to be identified as there are families which are unlinked to any of the known loci. Genes responsible for LGMD2B, LGMD2C, LGMD2D, LGMD2E, and LGMD 2F have been shown to be a part of the sarcoglycan complex, intimately related to the dystroglycan complex and important for muscle integrity. You will note that the clinical descriptions of many of the recessive LGMD families are very similar. What distinguishes one form from the other, besides the genetic location, are the ethnic differences, the involvement of other body systems, and the rates of progression.
Individuals with this form have been shown to have a defect in the calpain-3 gene on chromosome 15q. To date, at least 100 different mutations have been identified including single base pair deletions, small insertions and deletions, and a large genomic deletion. The gene for LGMD2A was originally identified in families of French descent on LaRéunion Island and subsequently in the Northern Indiana Amish families, Basque country, Spain, and in Russia. The age of onset is between 2 and 40 years, with the mean being14 years. The weakness pattern involves the hip girdle and abdominal muscles more than upper extremities with loss of ambulation occuring at a mean age of 17. There is no cardiac involvement but some individuals with mild mental retardation. CK elevations range from 7-80 times normal.
The second recessive LGMD locus to be identified was on 2p12-14. The gene for this form of LGMD produces the protein dysferlin, which is found primarily in skeletal muscle but also the heart. Mutations including missense, deletions, and insertions have been identified. Attempts at correlating the type of mutation with the clinical presentation have not been successful. Interestingly, a different form of muscular dystrophy called Myoshi myopathy, which affects distal muscles (lower leg and forearm) instead of proximal (upper arm, hip girdle, shoulder) muscles has also been shown to be localized to this area. It is anticipated that different changes in the identical gene may lead to these different forms of muscular dystrophy. The onset age for LGMD 2B is 12 to 39 years, beginning with leg weakness. It is more slowly progressive than 2A as individuals do not become wheelchair dependent until at least their mid-30s. CKs are very high, like 2A, 10-72 times normal.
Patients affected with this form of recessive LGMD are usually more severely affected than patients with the other types of LGMD with onset in childhood. Formerly called Duchenne-like muscular dystrophy or severe childhood autosomal recessive muscular dystrophy (SCARMD), the gene responsible for this disorder was localized to chromosome 13 and the gene later identified as a defect in γ-sarcoglycan. Only a small proportion of American recessive LGMD families are felt to be LGMD2C, although this type of muscular dystrophy is more common in different parts of the world such as northern Africa. The mean age of onset is 5 years with loss of ambulation from 10-13 years. Both calf and tongue hypertrophy have been reported. Respiratory failure occurs in the 20s and cardiac involvement in the late stages of the disease.
The gene responsible for LGMD2D, also called primary adhalinopathy, has been localized to 17q21 and found to be a defect in a-sarcoglycan. The age of onset is 2 to 15 years. This form of the disorder has been associated with a variable severity: earlier onset with rapidly progressive weakness and the later onset with ambulation preserved throughout life. The original description of this disorder was in Algerian families, with subsequent identification in Brazilian families. The thigh muscles (quadriceps) are severe affected and are the muscles of the shoulder blades, especially in the early onset form. Only rare reports of cardiac involvement. CK is often >5000.
Defects in the ß-sarcoglycan gene on chromosome 4q12 are responsible for LGMD2E. This mutation was originally described in the Southern Indiana Amish families, where all families segregating for this mutation have been found to be homozygous for the same mutation. Other populations now known to have this mutation are the Northern Indiana Amish and Bern, Switzerland. The age of onset is <3 years to teens. Calf hypertrophy and winging of the shoulder blades is common. Wheelchair dependency occurs by age 25, but may occur as early as age 10-15. CK is >5000.
This gene, d-sarcoglycan, is located on chromosome 5q33-34, interestingly very close to the gene for LGMD 1A. It was identified in families with African-Brazilian ancestry. The mutations identified are frameshift, missense, and nonsense. The clinical course is quite severe with onset at 2-10 years and death at 9-19 years. Almost all patients are wheelchair bound by age 16. Calf hypertrophy and muscle cramps are frequent. Only rare cardiac abnormalities have been reported with no affect on intelligence. The CK range is 10-50 times normal.
This gene, known as Telethonin, like LGMD 2F was identified in Brazilian families. It is located on chromosome 17q11-12. Point mutations and small deletions in the gene have been reported as the cause of the disorder. The mean age of onset is 12 years with a range of 9-15 years. This disorder not only affects hip and shoulder girdle but causes foot drop as well. About 2 in 5 individuals will not be ambulatory by their 20s-30s. More than half have cardiac involvement. CK range is 3-30 times normal.
This recessively inherited LGMD is also known as the Manitoba (Canada) Hutterite Dystrophy and is located on chromosome 9q31-33. The Hutterites are a religious group which originated in 1530, reside in primarily rural areas in North America, and generally do not marry outside their religion. The age of onset is 8 to 27. In addition to weakness of the hip and shoulder girdles and back pain, weakness of the facial muscles is also a feature. This is unusual among the LGMD types since facial weakness is found is a number of the non-LGMDs; (e.g., facioscapulohumeral dystrophy and myotonic dystrophy). Progression is slow as many affected individuals are still ambulatory in their 50s. The CK range is 250-4500.
This form of LGMD has been identified in a Tunisian family and is located on chromosome 19q13.3. The age of onset is from 2-27 years. Again, lower extremities are affected before and more severely than upper extremities. More than three quarters of the affected individuals have calf hypertrophy. No cardiac or intellectual involvement has been reported. The progression is slow with only one quarter of the individuals being wheelchair dependent in their 50s. CKs range up to 5700.
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As CHG researchers continue to define the genetic causes of LGMD, they publish their findings in leading academic journals and share their knowledge with colleagues at meetings and conferences.
LGMD Research Publications
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For information on study participation, please contact:
LGMD Support Groups and Information Sources
Jeffrey M. Stajich, MA, PA-C
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3300 E. Sunrise Drive
Tucson, AZ. 85718-3208
Fax: (602) 529-5300
To schedule an appointment at Duke University Medical Center
for medical care and/or genetic counseling for Limb-Girdle
Muscular Dystrophy, please contact:
Muscular Dystrophy Association Clinic
Duke University Medical Center
Durham, NC 27710
Phone: (919) 681-5176
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