eMedicine Specialties > Physical Medicine and Rehabilitation > Muscular Dystrophy

Limb-Girdle Muscular Dystrophy

Author: Vinod Sahgal, MD, MS, Chairman, Department of Physical Medicine and Rehabilitation Services, The Cleveland Clinic Foundation; Professor, Department of Physical Medicine and Rehabilitation, Ohio State University
Coauthor(s): Steven Reger, PhD, CP, Professor, Department of Industrial and Manufacturing Engineering, Cleveland State University; Director of Rehabilitation Technology, Department of Physical Medicine and Rehabilitation, Cleveland State University
Contributor Information and Disclosures

Updated: Apr 30, 2009

Introduction

Background

The earliest descriptions of limb-girdle weakness are ascribed to Leyden1 and Möbius2 in 1876 and 1879, respectively. They described adult patients with a pelvic and femoral distribution of weakness and atrophy with a benign course. In 1884, Erb characterized a juvenile form of proximal muscle weakness.3 Erb's patient had only shoulder-girdle weakness and atrophy, with sparing of other muscles of the body and a benign disease course compared with that described by Duchenne in the 1860s. Duchenne, a French physician, initially described a condition of progressive lethal wasting of degenerative skeletal muscle, which was later referred to as Duchenne muscular dystrophy. At that time, the differentiation between the spinal muscular atrophies and weakness associated with central nervous system disorders and primary muscle disease had not been established.

In 1891, Erb put forward the concept of muscular dystrophies as a primary degeneration of muscle and coined the term "dystrophia muscularis progressiva."4 Erb's description was followed by various attempts at classifying these dystrophic disorders. In 1909, Batten classified primary muscle disease into the following 7 categories, which are still used today5 :

  • Simple atrophy1,2
  • Duchenne pseudohypertrophic variety
  • Erb juvenile weakness
  • Fascioscapulohumeral dystrophy6
  • Distal myopathy7,8
  • Myotonic dystrophy
  • Mixed form

Between 1909 and 1954, many individual case reports of primary muscle disease with a limb-girdle distribution of weakness were published. In 1954, when Walton and Nattrass reported 105 cases of limb-girdle weakness associated with many other disorders, the nosologic entity of limb-girdle dystrophy was formally established.9 Walton and Nattrass described the disease as a progressive muscle weakness with atrophy involving predominantly proximal muscles (eg, pelvis, shoulder). They described the disease as having a variable age of onset in the late first, second, third, fourth, or fifth decade of life; a slow clinical progression; and an autosomal recessive or autosomal dominant form of inheritance. (See image below and Image 10.)

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.

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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 development of sophisticated diagnostic tools of histology, histochemistry, ultrastructure, electrodiagnosis, and genetic studies has since shown that the entity, as originally described, is composed of a variety of neuromuscular disorders (eg, spinal muscular atrophy, polymyositis, endocrine disorders, metabolic conditions, congenital myopathies). Since the original descriptions of the condition, reports of many sporadic cases have been published with this pattern of muscle weakness associated with many other disorders.

Thus, the concept of limb-girdle muscular dystrophy (LGMD) as a nosologic entity was challenged, and now it is fair to consider it a symptom complex that consists of at least 4 disorders with varied inheritance patterns and etiologies. Therefore, importantly, the clinical features, the inheritance pattern, and the exclusion of other entities should define the disorders of LGMD.

Pathophysiology

Molecular genetics of limb-girdle muscular dystrophy (LGMD)

Skeletal muscle consists of 2 major components: the sarcolemma and the sarcomeres. The sarcolemma is the sheath that covers the sarcomeres; it is composed of the plasma and basement membranes and the reticular lamina, which contains collagen. The sarcomeres represent the contractile element, which is composed of actin, myosin, and Z-band proteins (see image below and Image 8). These proteins, like all others, are genetically coded and have a specific structure and distribution. Advances in molecular genetics have help in the discovery of significant information on the relationship between muscle biology and clinical neuromuscular diseases. This is very well exemplified in the shift from descriptive classifications of neuromuscular diseases to molecular pathobiologic classifications of neuromuscular diseases.10,11

Electron micrograph showing streaming of band Z a...

Electron micrograph showing streaming of band Z and splitting of the muscle fiber. A central nucleus is surrounded by a collection of small mitochondria.

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Electron micrograph showing streaming of band Z a...

Electron micrograph showing streaming of band Z and splitting of the muscle fiber. A central nucleus is surrounded by a collection of small mitochondria.


This concept is best observed in regard to our understanding of the very heterogeneous LGMD syndromes. These syndromes are now classified on the basis of at least 15 identified genes—5 autosomal dominant and 10 autosomal recessive. The 5 dominant genes are associated with the components of sarcomeres. The 10 recessive genes are associated with the plasma basement membrane and the adjacent reticular lamina, which contains the fibrillary collagen.12,13

See the descriptions of each type of LGMD in the History section.

Frequency

United States

Exact figures are not available. The frequency of limb-girdle muscular dystrophy in the general population cannot be estimated because of the heterogenous nature of this group of disorders (see Background).

Mortality/Morbidity

Limb-girdle muscular dystrophy is associated with low mortality and morbidity.

Race

No racial predilection is described for limb-girdle muscular dystrophy.

Sex

Limb-girdle muscular dystrophy may show an autosomal recessive or sporadic method of inheritance.

Age

Some forms of limb-girdle muscular dystrophy dramatically affect young adults, while other types progress so slowly that they are not detected until much later in life.

Clinical

History

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.14,15,16

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.17

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.18 (See image below and Image 10.)

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.

[ CLOSE WINDOW ]
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.19

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.20

Autosomal recessive LGMD

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 al21 and by Gigliotti et al.22 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-3.23,24

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 10). 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.25,26,27

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 10.)

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.26,28,29,30

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.31

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.32

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.33

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.34

Pelvifemoral atrophy (Leyden-Möbius)

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.

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.

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).35 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.36 De Coster et al reported 9 members of one family, all males, over 3 generations who also exhibited these symptoms.37 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.38 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,39 Shy and McEachren,38 and Walton9 described several additional sporadic cases. Van Wijngaarden et al40 and Espir and Matthews41 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.

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.

Causes

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

More on Limb-Girdle Muscular Dystrophy

Overview: Limb-Girdle Muscular Dystrophy
Differential Diagnoses & Workup: Limb-Girdle Muscular Dystrophy
Treatment & Medication: Limb-Girdle Muscular Dystrophy
Follow-up: Limb-Girdle Muscular Dystrophy
Multimedia: Limb-Girdle Muscular Dystrophy
References
Further Reading
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References

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Keywords

limb-girdle muscular dystrophy, muscular dystrophy, dystrophy, muscle disease, muscular disease, polymyositis, spinal muscular atrophy, muscular atrophy, muscular dystrophy symptoms, neuromuscular disease, muscle diseases, limb girdle muscular dystrophy, limb girdle dystrophy, muscular dystrophy causes, neuromuscular diseases, Leyden-Mobius muscular dystrophy, pelvofemoral muscular dystrophy, scapulohumeral muscular dystrophy, LGMD, limb-girdle dystrophy, dystrophia muscularis progressiva, sarcoglycanopathy, sarcoglycanopathies

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Contributor Information and Disclosures

Author

Vinod Sahgal, MD, MS, Chairman, Department of Physical Medicine and Rehabilitation Services, The Cleveland Clinic Foundation; Professor, Department of Physical Medicine and Rehabilitation, Ohio State University
Vinod Sahgal, MD, MS is a member of the following medical societies: American Academy of Neurology, American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Medical Association, and American Spinal Injury Association
Disclosure: Nothing to disclose.

Coauthor(s)

Steven Reger, PhD, CP, Professor, Department of Industrial and Manufacturing Engineering, Cleveland State University; Director of Rehabilitation Technology, Department of Physical Medicine and Rehabilitation, Cleveland State University
Steven Reger, PhD, CP is a member of the following medical societies: Association for Academic Psychiatry and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Elizabeth A Moberg-Wolff, MD, Associate Professor and Pediatric PM&R Fellowship Director, Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin; Program Director, Tone Management and Mobility, Department of Physical Medicine and Rehabilitation, Children's Hospital of Wisconsin
Elizabeth A Moberg-Wolff, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation
Disclosure: Medtronic Neurological Grant/research funds Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Kat Kolaski, MD, Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine
Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation
Disclosure: Nothing to disclose.

CME Editor

Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
Disclosure: Nothing to disclose.

Chief Editor

Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
Denise I Campagnolo, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, and Consortium of Multiple Sclerosis Centers
Disclosure: Teva Neuroscience Honoraria Speaking and teaching; Serono-Pfizer Honoraria Speaking and teaching

 
 
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