Limb Girdle Muscular Dystrophies

The limb girdle muscular dystrophies (LGMDs) are being reclassified on a genetic basis as their underlying pathologies are unraveled. The genes and their products or actions identified thus far again point to disturbances in the structural support system of muscle, particularly of the sarcoglycan complex. It may be that a disturbance in the sarcolemma-extracellular matrix interaction is the molecular basis for muscle fiber necrosis ( Tab.le.3.6.:5. ). Emery estimates LGMD prevalence to be 1 in 100,000. As early as 1960, Morton proposed that homozygosity at either of two loci could produce LGMD and that about 1.6 percent of the normal population is heterozygous for an LGMD gene.y

With the exception of the severe childhood autosomal recessive muscular dystrophy (SCARMD) found primarily in northern Africa, the LGMDs all fall within a clinical spectrum that includes weakness of proximal lower extremities, which is usually symmetrical, appearing any time from the first decade until middle age, and generally followed by weakness in the shoulder girdle region. Occasionally, shoulder girdle weakness may precede the pelvic girdle weakness. Facial muscles are uninvolved. The progression is generally slow, with loss of ambulation occurring 10 to 30 years after onset. Cardiac involvement is not reported, except in the newly recognized autosomal dominant form reported from the Netherlands, known as LGMD-1B.

The features of SCARMD have been well described by Ben Hamida and associates. y Pelvic girdle weakness precedes pectoral girdle weakness, with onset occurring between ages 3 and 12. Abdominal, neck flexor, and intercostal muscles are often affected, whereas external ocular, facial, lingual, and pharyngeal muscles are spared. Seventyfive percent of patients are unable to walk by their 30s. Contractures form and reflexes are lost as the disease progresses. Cardiomegaly and EKG abnormalities are common by the intermediate stages of the illness. There is no cognitive impairment.

If sufficient informative family members are available, linkage analysis can provide a genetic diagnosis if the patient has one of the previously linked types of LGMD. SCARMD can be diagnosed by a negative sarcolemmal immunostain for adhalin. y

TABLE 36-5 -- LIMB GIRDLE MUSCULAR DYSTROPHY

Type

Inheritance

Gene Locus

Gene Product

Unusual Symptoms

1A

AD

5qS1-SS

?

Palatal weakness

1B

AD

?

?

?

2A

AR

15q

Calpain-S

2B

AR

2plS

?

Some Canadians had distal extremity weakness and wasting (Miyoshi myopathy)

2C

AR

13ql2

gamma-Sarcoglycan

Cardiac involvement, abdominal, neck flexor and intercostal muscles affected, malignant course

2D

AR

17q.SS

alpha-Sarcoglycan (adhalin)

2E

AR

4ql2

beta-Sarcoglycan

AD, Autosomal dominant; AR, autosomal recessive.

There are several nonspecific findings associated with the LGMDs. Serum CK is mildly to moderately elevated, except in SCARMD, in which the levels may rival those of DMD.y Creatinuria and hypocreatinuria are nonspecific indicators of muscle destruction that may be present. The EMG shows nonspecific myopathic changes, including short duration, low-amplitude motor unit potentials, increased proportion of polyphasic potentials, and rapid recruitment. Fibrillation and positive sharp waves may occur with denervation caused by muscle fiber necrosis. Muscle biopsy pathology also is nonspecific, with morphology like that of other myopathies. y

The LGMDs have relatively common and nonspecific clinical and laboratory findings that may be seen in other neuromuscular disorders. Therefore, care must be taken in evaluation. As an example, in a Japanese series, 17 percent of patients with clinically diagnosed LGMD actually had a dystrophinopathy when muscle dystrophin content was analyzed, which emphasizes the need for examination of dystrophin protein and gene studies for accurate diagnosis ( Ta,b|e.3.6:6 ) [19'

There are no specific treatments for any of the LGMDs. The physician's goal is to preserve as much function for as long as possible through the use of physical and occupational therapy and psychological support. Research into the pathogenesis of these disorders is proceeding rapidly. Recently, a missense mutation in the gene at 5q33 that encodes for delta-sarcoglycan, which is homologous to upsilon-sarcoglycan and has a striated muscle-specific expression of mRNA similar to that of delta-sarcoglycan and upsilon-sarcoglycan, has been associated with yet another mild autosomal-dominant myopathy. y As the relationships and workings of the dystroglycan and sarcoglycan complexes are better understood, it may be possible to offer a rational treatment for these disorders.

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