Physical Medicine and Rehabilitation for Limb-Girdle Muscular Dystrophy Clinical Presentation

Updated: Apr 19, 2016
  • Author: Vinod Sahgal, MD; Chief Editor: Stephen Kishner, MD, MHA  more...
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Presentation

History

The history of limb-girdle muscular dystrophy varies by type. [15]

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Autosomal Dominant Limb-Girdle Muscular Dystrophy

The classification of these relatively uncommon disorders ranges from limb-girdle muscular dystrophy (LGMD) type 1A to LGMD type 1F.

LGMD type 1A

This is an adult-onset, slowly progressive muscle atrophy with weakness in a limb-girdle distribution, which, in addition, has pharyngeal involvement leading to nasal speech. These patients do not develop any contractures, muscle hypertrophy, or cardiac involvement. Creatine kinase (CK) levels are normal.

The inheritance pattern is autosomal dominant. The protein product has been identified as myotilin, which is related to the sarcomere. The gene site locus is 5q31. Even though the protein product has been identified, no direct relationship has been established between the amount of protein and the severity of the disease. The subcellular localization of this protein is on the Z-line. [16, 17, 18]

LGMD type 1B

This form is characterized by symmetrical, proximal lower limb weakness, followed by upper limb involvement. The disease begins in childhood. Contractures are rare and late. Cardiac involvement is common, manifesting as syncopal episodes and/or bradycardia and requiring pacemaker implantation. In late stages, these patients may develop dilated cardiomyopathy. Patients may die of sudden cardiac death. The CK level ranges from normal to moderately elevated. The clinical course is one of slow progression.

The locus of this myopathy has been mapped to 1q11-21. The protein product of this genetic variation is lamina A/C. The subcellular localization of this protein is unknown. [19]

LGMD type 1C

This type is a disorder of childhood-onset proximal muscle weakness, myalgia, and muscle cramps. Muscle rippling to percussion is a unique feature of this syndrome. The disease has slow progression and is not associated with contractures. The CK level is always elevated. The gene location is 3p25, and the gene product is caveolin-3. Caveolin-3 is a muscle-specific protein related to the caveolae, which are the invaginations of the plasma membrane. Mutation of the caveolin-3 gene (CAV3) causes this disorder. [20] See image below.

Dystrophin-glycoprotein complex bridges the inner Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, in dysferlin, and in caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan, can result in limb-girdle muscular dystrophy.

LGMD type 1D

This is adult-onset limb-girdle dystrophy is very rare. Features are proximal weakness with cardiac conduction defects and, later, dilated cardiomyopathy. The gene site for this rare disorder seems to be 6q23. The subcellular location and protein product are unknown. [21]

LGMD types 1E and 1F

These dominantly inherited LGMDs are of the adult-onset type and are not associated with contractures. The clinical course is one of slow progression, and the CK level is normal. The gene site is 7q, and the subcellular location and protein product are unknown. [22]

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Autosomal Recessive Limb-Girdle Muscular Dystrophy

These are generally childhood forms of LGMD that affect males and females in the same sibship. Onset is usually in the first decade of life. In general, the course of disease is one of gradual progression over years. Distribution of muscle weakness is typically in the pelvis (80-90% of cases), and later in life, involvement of the shoulder girdle is noted in approximately 30% of cases. Hypertrophy of the calves is absent, in contrast to other forms of muscular dystrophy. The various types of autosomal recessive LGMD range from type 2A to type 2J.

A review of published case reports showed that nearly 70% of involved patients were ambulatory when aged 25-40 years. In all the cases, contractures of the hips were present. Educational achievements, intellectual level, or vocational status of patients was not mentioned. The incidence of cardiac and respiratory involvement reportedly was rare, although it has been reported by Mascarenhas et al [23] and by Gigliotti et al. [24] Scoliosis occurred rarely, but lumbar lordosis was present in as many as 70-80% of patients. The inheritance pattern is strongly autosomal recessive with consanguinity, and thus, a positive family history often is reported.

LGMD type 2A (calpain 3 myopathy)

The onset of this childhood form of LGMD is in the first decade of life (9.7 ±3 y). The distribution of muscle weakness is predominantly proximal (pelvic and shoulder girdle). The disease progresses slowly, with loss of ambulation at age 38.5 ±2.1 years. Muscle atrophy is a prominent feature. Cardiac involvement is not described, and the CK level is only moderately elevated. The locus of the culprit gene is on 15q15, and the protein product is calpain-3. [25, 26]

LGMD type 2B (dysferlin myopathy)

This form has a variable clinical presentation. The onset is in the juvenile years, and developmental milestones are normal. The distribution of weakness is mostly in the lower extremities distally (ie, anterior compartment), with the Miyoshi form showing posterior distribution. The scapular musculature is relatively preserved early, but later, atrophy of the forearms occurs. CK levels are markedly elevated, and cardiac involvement has been reported. The mutation is found to lie across a large gene site. Immunohistochemical studies showed deficiency of dysferlin in the sarcolemma (see image below). The gene site is 2p13. The protein can be assayed in blood samples using commercially available monoclonal antibodies. The findings from blood studies complement the findings from muscle studies. [27, 28, 29, 30]

Dystrophin-glycoprotein complex bridges the inner Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, in dysferlin, and in caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan, can result in limb-girdle muscular dystrophy.

LGMD types 2C, 2D, 2E, and 2F (sarcoglycanopathies)

These 4 disorders have many clinical features in common. The first is age of onset, which varies from early childhood to adulthood. The clinical picture of these disorders varies from mild to severe. Persons with the severe forms tend to lose the ability to walk before age 10 years, while persons with the mild forms maintain the ability to walk late into adulthood. Considerable intergenerational and intragenerational variability exists in the clinical course. Among LGMD patients, 20-25% develop one of these types.

These patients develop severe lumbar lordosis and contractures of the Achilles tendons. Muscle hypertrophy is common, and CK levels are very high. The rate of cardiac conduction defects and dilated cardiomyopathy is 30%. Experimental work in animals suggests that disintegration of the smooth muscle sarcoglycan complex occurs, which results in coronary artery constriction and leads to myocardial ischemia. See image below.

Dystrophin-glycoprotein complex bridges the inner Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, in dysferlin, and in caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan, can result in limb-girdle muscular dystrophy.

The mutations are at 13q12 for type C, 17q21 for type D, 4q12 for type E, and 5q33-34 for type F. Sarcoglycanopathy has been reported. The subcellular localization is the sarcolemma. The gene product is 2, B & S sarcoglycan. Seventy-seven distinct pathogenic mutations have been found: 41 in LSG, 20 in BSG, 10 in 2SG, and 6 in 8SG. [28, 31, 32, 33]

LGMD type 2G

This form has a childhood and juvenile age of onset. It progresses slowly and is characterized by anterior tibial weakness with foot drop. The CK level is always elevated to moderate to high levels. Cardiac involvement may or may not occur. The mutation for this disorder is at 17q11-12, and the protein is telethonin, with a subcellular localization at the Z-disc product. [34]

LGMD type 2H

The onset for this disorder is in the juvenile and young-adult age group. It is characterized by fatigability without muscle weakness or hypertrophy. The CK level is almost always elevated. The locus of the mutation is 5q31-34, and the protein product is TRIM (tripartite motif) 32, which has cytosolic localization. [35]

LGMD type 2I

This type has a very variable age of onset (childhood, juvenile, adult). The upper extremities are preferentially involved, with upper arm weakness and atrophy. The prevalence of cardiac and respiratory involvement is high. The clinical course can vary from very fast (rarely) to slow (generally). The gene mutation locus is 19q13.3, and the protein product is FKRP (fukutin-related protein). The subcellular localization is the Golgi apparatus. [36, 37, 30]

LGMD type 2J

This is the last of the recessively inherited LGMDs, and it also has a variable age of onset and slow progression. The CK level is mildly to moderately elevated. The gene mutation locus is on 2q, and the protein product is titin, which is located on the sarcomere. [38]

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Pelvifemoral Atrophy (Leyden-Mobius)

The Leyden-Möbius variant of LGMD is the most heterogeneous of all limb-girdle dystrophies. Roughly 60-70% of cases are described as sporadic, while only a few cases are reported as familial. This syndrome is characterized by symmetrical or asymmetrical involvement of the pelvic girdle. The age of onset is later in life, during the second to sixth decades. The progression of the disease is variable, but most reports indicate that the progress is slow. In a significant number of cases, the progression is so slow that it gives the appearance of clinical arrest. The disability experienced by the patients is mild, with several patients continuing to ambulate well into their 70s. Intellectual deterioration or significant cardiac or respiratory involvement does not seem to occur. The survival rate associated with this disease is well into the seventh decade of life. CK values vary from normal to significantly elevated. Genetic studies have not revealed an associated abnormal gene.

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Scapulohumeral Dystrophy (Erb)

As the name indicates, this form mainly involves the upper extremities. It appears in some cases to have an autosomal recessive inheritance pattern. This disorder starts later in life (second to the fifth decades), and the disease is often so benign that years may elapse before it is diagnosed. Weakness is generally asymmetrical and may spare the deltoid, supraspinatus, and infraspinatus muscles. Not until very late in life may the lower extremities show signs of involvement. The progression of the disease is very slow, and patients have a normal life expectancy. The disability experienced by patients is fairly minimal, although frozen shoulder syndrome may significantly alter function if it is bilateral. Intellectual deterioration and cardiac involvement are rare.

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Late-onset Autosomal Dominant Limb Myopathy

This syndrome is documented in several families; the onset of weakness begins between the third and fifth decade of life. The course of the disease is benign, with upper and lower extremity weakness causing little functional impairment. Patients with this type of dystrophy maintain their ability to ambulate well into their sixth and seventh decades of life. This syndrome affects males and females.

Neither intellectual deterioration nor significant cardiac involvement is noted. Schneiderman et al reported a family with 16 members in 3 generations who also had the Pelger-Huët nuclear anomaly (ie, the bilobed nucleus of the neutrophils). [39] Bacon and Smith described another family with 6 affected members in 2 generations, all of whom had the late-onset type (third decade of life) with a benign course. [40] De Coster et al reported 9 members of one family, all males, over 3 generations who also exhibited these symptoms. [41] In 1951, Shy and McEachren described 12 cases of late-onset myopathy with a benign course and age of onset in the sixth and seventh decades of life, and they called it menopausal myopathy. [42] A collection of sporadic cases manifesting with the same clinical picture has been reported. The CK levels in these cases generally ranged from normal to mildly elevated, and, again, no cardiac involvement was described.

The disability experienced by these patients was minimal. In the familial cases, the abnormal gene was linked to band 5q22.3-31.3 and the linkage to chromosome 15 was excluded. This finding suggests that this entity is clinically and genetically different from the autosomal recessive varieties. Even though the above categories account for most patients, a minority of patients first described by Bramwell in 1922 exhibited weakness involving only the quadriceps muscle. Denny-Brown, [43] Shy and McEachren, [42] and Walton [9] described several additional sporadic cases. Van Wijngaarden et al [44] and Espir and Matthews [45] described a group of familial cases of quadriceps myopathy in which both sexes were affected. The weakness started in the third decade of life, and patients continued to ambulate well into their 60s. These authors considered such cases to be a limited presentation of LGMD.

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Physical

The clinical features of this group of disorders are described in the specific subsections listed in History. Limb-girdle muscular dystrophy is suggested in patients who are toe-walkers and who have increased lumbar lordosis, forward pelvic tilt, and flexion and abduction of the hips. However, in the upper extremities, no typical features (eg, winging of the scapula) are present. Muscle hypertrophy is not a characteristic of the affected muscles.

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Causes

Limb-girdle muscular dystrophy is an inherited disorder, with autosomal recessive and autosomal dominant forms reported.

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