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Limb girdle muscular dystrophy


Clinical types

This is a group of diseases with similar clinical manifestations. The diseases are marked by progressive weakness of the muscles, mainly the pelvic and pectoral girdle muscles. This is not one disease, but rather a group of diseases involving two different inheritance patterns - autosomal recessive and autosomal dominant. In each inheritance pattern there are subtypes differentiated by the types of proteins affected in the muscle, and therefore by different genes. The abnormal proteins in LGMD are associated with a complicated protein complex built around the central protein called dystrophin, lack of which is responsible for Duchenne and Becker muscular dystrophy. Sometimes the muscles affected in LGMD are also affected in Duchenne and Becker muscular dystrophy, which can lead to confusion between LGMD and Becker muscular dystrophy.

There are two main types

Type 1 - this is transmitted by autosomal dominant inheritance. There are at least four subtypes differentiated according to the protein affected. These are:

A1 (a defect in a protein known as myotilin)
B1 (a defect in laminin)
C1 (a defect in caveolin 3)
D1 (the defect is not yet known)

Type 2 - this is transmitted by autosomal recessive inheritance. There are at least 9 subtypes differentiated according to the protein affected. These are:

A2 (a defect in a protein called calpain)
B2 (a defect in dysferlin, also associated with a specific condition known as Miyoshi myopathy)
C2-F2 (defects in four molecules known as sarcoglycans, in the following order: C2 - sarcoglycan gamma, D2 - sarcoglycan alpha, E2 - sarcoglycan beta, F2 - sarcoglycan delta)
G2 (a defect in telethonin)

At least two more types, H2 and I2, whose properties are not yet known.

Clinical signs

All types of LGMD manifest as muscle weakness beginning in the pelvic and pectoral girdle muscles. The weakness can be demonstrated especially when the patient is asked to get up from a supine position to standing without using his or her arms, or when the patient is asked to lift his or her arms up against resistance the examiner exerts on the shoulders. Sometimes there is muscle stiffness in the pectoral and pelvic girdles, in which case it is more likely that this is the autosomal recessive type, but this is not necessarily the case.
As in Duchenne and Becker muscular dystrophy, there may be swelling of the gastrocnemius muscles in the legs, although there is no increase in strength, but actually weakness in the enlarged muscle.
There is considerable variation among different patients in the same family regarding the muscle fiber.

Even though other muscles, including the muscles of facial expression and the eye muscles, may be involved later, these are not affected in the early stages of the illness, and if they are, then the diagnosis is not LGMD.

The disease can start at any age. In the autosomal recessive type, the onset is relatively early, before the age of 20.

In the autosomal dominant type, there is no specific age of onset. The rate of progression of the disease and the worsening of the muscle weakness varies from case to case. As a rule, in the autosomal recessive type, the disease is more severe and the progression more rapid.

A blood test reveals an increase in the level of an enzyme known as creatine phosphokinase (CPK). In the autosomal recessive type, the enzyme levels are usually higher than in the autosomal dominant type. Electromyography does not show a specific profile that allows a specific diagnosis of LGMD.

Muscle biopsy should be carried out in order to test for the specific staining of the muscle for dystrophin, and if this is present, Becker and Duchenne muscular dystrophy can be categorically ruled out. In a number of places in the world, special staining tests can be carried out to test for some of the specific proteins that are involved in the different types of LGMD, thus helping to focus the molecular genetic tests. In the case of these stains, if a protein does not stain properly, this indicates a lack of this protein, and if this is the case then the associated gene should be examined in order to identify any mutations and to define the exact genetic defect.

A precise diagnosis is important, and a diagnosis made in the past is not always accurate by today's standards. Because of this, the diagnosis must always be confirmed in a genetic institute by examining the patient, or at least by reviewing the results of neurological tests, laboratory and/or EMG results, and other data.

Even though we know a lot about the inheritance patterns, the risk of recurrence, pathogenesis, etc., most of these diseases have exceptions, and each case/family must be examined individually in a genetic institute. It must be remembered that the diagnosis of LGMD is very difficult to make, and even if the clinical criteria stated above are present, the diagnosis cannot necessarily be confirmed by the diagnostic methods and techniques available today.

Inheritance pattern

As noted, there are 2 types: autosomal dominant and autosomal recessive.

Penetrance

This is usually complete in the autosomal recessive types. However, the type transmitted by autosomal dominant inheritance may be mild and sometimes may not manifest at all.

Associated features that can be demonstrated in tests performed during pregnancy

In families in which the mutation has been identified, a reliable genetic test can be performed in the fetus if there is a high risk that he or she may be affected. The disease cannot be detected by ultrasound examination in pregnancy or by regular amniocentesis.

What is the risk of recurrence in a subsequent pregnancy?

In the autosomal recessive type

A couple that has an affected child has a 25% risk of recurrence in every pregnancy. For other members of the family, the risk is not high (usually less than 1%). The exact risk is ascertained according to the pedigree within genetic counseling.

In the autosomal dominant type

Each patient has a 50% risk of having a child with the same condition. In families with this type of LGMD, even asymptomatic individuals may develop signs of the disease at a later age. This means that healthy family members are also at some risk of having affected children. The exact risk for more distant relatives depends on the number of affected individuals in the family, the relationship of each to the patients, consanguinity between the parents, if any, etc. The risk is ascertained within genetic counseling.

Molecular genetic information

The genes for the disease and the location of the genes

In the autosomal recessive type

  • In type A2, where the defect is in the protein called calpain, the gene is situated on chromosome 15q; a mutation in this gene causes a relatively severe illness. Such a mutation has already been shown to cause severe disease in certain ethnic groups including the Amish in North America, some groups in Brazil, etc. The blood CPK level in these patients is elevated. The age of onset is about 4 years. Difficulty in walking unaided commences at about the age of 30.

  • In type B2, the gene, dysferlin, is also associated with a specific condition called Miyoshi myopathy. Type B2 is moderately severe. This type is especially important in Israel because in Jews of North African (especially Libyan) origin, a unique mutation has been found that is common to all patients. This is 1624delG - a deletion of the base G (guanine) in position 1624 of the sequence of the gene. The frequency of carriers of this mutation in people of Libyan origin in Israel has been found to be relatively high - about 1 in 10 of the normal healthy population. There is variation in the manifestation of this disease in people of Libyan origin in Israel. In some, the muscle weakness starts in the distal limb muscles rather than in the pectoral and pelvic girdles. The age of onset of the muscle weakness is between 12 and 28 years. The progression of the disease is relatively slow.

  • In types C2-F2, the defects are in 4 molecules known as sarcoglycans, in the following order: C2 - sarcoglycan gamma, D2 - sarcoglycan alpha, E2 - sarcoglycan beta, F2 - sarcoglycan delta.

  • Type G2 results from a defect in telethonin.

  • There are another two types, H2 and I2, whose properties are not yet known.

In the autosomal dominant type

  • A1 - the defect is in a protein known as myotilin

  • B1 - the defect is in laminin

  • C1 - the defect is in caveolin 3

  • D1 - the defect is not known

Genetic testing

Diagnostic testing

This is a complex test in which a number of genes must be examined. See: indirect testing for genetic markers in a family with one or more patients in the family - when there are a number of different genes that can each cause the disease - all genes have having been located / identified / mapped - autosomal dominant disease. In the special case of LGMD in Jews of Libyan origin, it is possible to perform a direct test to look for the common, characteristic mutation present in most patients of this ethnic group. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal dominant diseases.

Carrier testing

In families in which the mutation in the gene responsible for the disease has been found, other carriers or patients in the family can be examined. It is currently not recommended to perform carrier testing in the general, healthy population, but in people of Libyan origin in Israel this is possible with relative ease. According to studies that have been published, the frequency of carriers of this mutation in people of Libyan origin is relatively high - up to 1 in every 10 healthy individuals.

Fetal testing

As for diagnostic testing.
 
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Comments (1)


Tuesday, June 15, 2010 3:09 PM
(1) Debbie  says:


limb girdle md/pregnancy

HELP! My daughter is 25, pregnant with her 2nd child. She is only about 6-8wks along, but says her muscles/bones are very sore and tired. Is she going to have a problem carrying this baby? Is it going to speed up the progression of her disease?





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