eMedicine Specialties > Neurology > Neuromuscular Diseases

Limb-Girdle Muscular Dystrophy: Differential Diagnoses & Workup

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: Nov 28, 2007

Differential Diagnoses

Congenital Muscular Dystrophy
Inclusion Body Myositis
Congenital Myopathies
Metabolic Myopathies
Dermatomyositis/Polymyositis
Spinal Muscular Atrophy
Emery-Dreifuss Muscular Dystrophy
Thyroid Disease
Endocrine Myopathies
Facioscapulohumeral Dystrophy

Other Problems to Be Considered

Dystrophinopathies

Workup

Laboratory Studies

  • Autosomal recessive limb-girdle muscular dystrophies (LGMDs) often cause extremely high CK levels. The sarcoglycanopathies (LGMD2C-2F) and LGMD2B markedly elevate CK levels by 10-150 times normal. The other autosomal recessive LGMDs usually cause CK elevations that are 3-80 times normal.
  • Autosomal dominant LGMD1C can result in high CK elevations of 5-25 times normal. All other autosomal dominant LGMDs result in CK levels between normal and 15 times normal.
  • Myofibrillar myopathies have CK levels ranging from normal to 7 times normal.
  • Consider other myopathies that markedly elevate CK levels: dystrophinopathies, dermatomyositis and/or polymyositis, hypothyroid myopathy, rhabdomyolysis, and acid maltase deficiency.

Imaging Studies

  • Magnetic resonance imaging (MRI) can help differentiate forms of LGMD. Hyperintense signal change on T1 scans is seen in more severely affected muscles.
    • An MRI study of 20 patients with LGMD showed the following:
      • Patients with LGMD2I had the most severe MRI changes in posterior and adductor thigh muscles, with less severe changes in gluteal and calf muscles.
      • Patients with LGMD2A had similar severe involvement of posterior and adductor thigh muscles. However, these patients had more severe and selective involvement of the medial gastrocnemius and soleus muscles.
      • Patients with LGMD2B had a more variable MRI picture with severe involvement in either anterior or posterior thigh muscles.
      • Patients with LGMD2D and with Becker muscular dystrophy had more severe MRI changes in the anterior thigh compartment than in the posterior thigh.

Other Tests

  • Needle electromyography (EMG) and nerve conduction studies (NCSs)
    • Order EMG and NCSs in all patients with suspected LGMD to confirm the myopathic nature of the disease.
    • NCS results are normal in LGMD.
    • EMG shows early recruitment and the typical small-amplitude, narrow-duration, polyphasic motor-unit potentials that are seen in muscular diseases.
    • Abnormal spontaneous activity in the form of fibrillations and positive sharp waves is not prominent but has been described in a few cases of LGMD. When present, it should raise the clinician's suspicion for an inflammatory myopathy, such as polymyositis.
  • Electrocardiography
    • Cardiac involvement is common in the autosomal dominant syndromes of LGMD1A and 1B (50-65%). Cardiomyopathy of both and cardiac arrhythmias in LGMD1B may cause clinically significant morbidity. In patients with LGMD1E (dilated cardiomyopathy with conduction defect and muscular dystrophy), cardiomyopathy and arrhythmias are nearly always present.
    • In the autosomal recessive LGMD syndromes, cardiomyopathy is uncommon except in LGMD2G and 2I, where as many as 30-50% of patients can have mild-to-moderate cardiomyopathy. In the sarcoglycanopathies (most often LGMD2E and 2F), cardiomyopathy is occasionally problematic.
    • In myofibrillar myopathies, cardiac disease is common, occurring in more than 50% of cases. Presentation can be with cardiomyopathy or cardiac conduction disturbances. 
    • Annual screening with ECG (and possibly echocardiography if the patient is symptomatic) is important for quick diagnosis and follow-up in cases of LGMD and myofibrillar myopathy with cardiac disease.

Procedures

  • Muscle biopsy is the most important diagnostic evaluation of patients in whom LGMD is suspected.
    • In most cases of LGMD, routine histochemical studies show typical dystrophic features, including various degrees of muscle-fiber degeneration and regeneration, variation in fiber size with small round fibers, and endomysial fibrosis.
    • Details of routine muscle histochemistry include the following:
      • In LGMD1B the muscle biopsy shows only mild myopathic features.
      • In LGMD1D and 1E the muscle biopsy shows only mild dystrophic features.
      • In LGMD1F and 1G the muscle biopsy can show rimmed vacuoles.
      • In LGMD2A the muscle biopsy may show perimysial and perivascular T-cell infiltrates and may be mistaken for polymyositis.
      • In LGMD2C-2F and LGMD2I, biopsy often shows severely dystrophic features.
    • Immunohistochemical findings are as follows:
      • Dystrophin testing is usually the first step in dystrophic biopsy performed by using antibodies against the N-terminus, rod, and C-terminus. A minor reduction in dystrophin staining can be seen in sarcoglycanopathies. Conversely, a minor reduction in sarcoglycan staining may occur in dystrophinopathies.
      • All sarcoglycan antibodies should be tested next. In alpha-sarcoglycanopathy, alpha-sarcoglycan is most reduced, with relative preservation of gamma-sarcoglycan. In gamma-sarcoglycanopathy, gamma-sarcoglycan is most reduced, with variable preservation of other sarcoglycans. In beta- and delta-sarcoglycanopathy, all sarcoglycans are usually absent.
      • In sarcoglycanopathies beta-dystroglycan is normal, but alpha-dystroglycan is often markedly reduced.
      • Staining with laminin-alpha2 is reduced in congenital muscular dystrophy with laminin-alpha2 deficiency. (See Congenital Muscular Dystrophy).
      • Alpha-dystroglycan antibody staining is reduced in LGMD2I, LGMD2K and LGMD2L; laminin-alpha2 staining may also be deficient. This pattern is often present in congenital muscular dystrophies due to abnormal glycosylation of alpha-dystroglycan.
      • Calpain-3 deficiency can not be evaluated by immunohistochemistry. Western blotting can detect reduced levels of calpain-3, but some patients with calpain-3 gene mutations may have normal amounts of protein by Western blot. A recent study used a functional in vitro assay to detect calpain-3 autolytic activity.5  Of 148 biopsy specimens, 17 had lost normal autolytic activity and calpain-3 gene mutations were found in 15 of these 17 patients. This suggests that loss of calpain-3 activity is highly specific for calpain-3 gene mutations and would aid in the diagnosis of LGMD2A.
      • Calpain-3 deficiency can be seen not only in LGMD2A, but also in LGMD2B (dysferlin).
      • Dysferlin deficiency can be detected by immunohistochemistry or Western blot. Dysferlin deficiency can sometimes be seen in LGMD2A (by Western blots).
      • Other antibodies that can be tested include those against caveolin-3 (LGMD1C) and emerin. (See Emery-Dreifuss Muscular Dystrophy.)
      • Antibodies against desmin show abnormal staining in the myofibrillar myopathies.  There may also be ectopic expression of dystrophin and of the sarcoglycans.

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
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Further Reading

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Keywords

limb-girdle muscular dystrophy, sarcoglycanopathy, alpha-dystroglycanopathy, LGMD, LGMD1, LGMD2, LGMD2C, LGMD2D, LGMD2E, LGMD2F, myofibrillar myopathy, desmin-storage myopathy,  LGMD2A, calpainopathy, LGMD2B, dysferlinopathy, telethoninopathy, TRIM32 -related dystrophy, LGMD2J, titinopathy, myotilinopathy, laminopathy, caveolinopathy, desminopathy, alpha-β-crystallinopathy, myotilinopathy, filamin C myopathy, selenoprotein N myopathy, laminopathy, LGMD2J, titin protein

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Contributor Information and Disclosures

Author

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

Raj D Sheth, MD, Professor, Departments of Neurology and Pediatrics, Director of Comprehensive Epilepsy Program, Department of Neurology, University of Wisconsin at Madison
Raj D Sheth, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Neurological Association, and Child Neurology Society
Disclosure: Nothing to disclose.

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

Managing Editor

Agapito S Lorenzo, MD, Laboratory Director, Associate Professor, Departments of Neurology, Creighton University and University of Nebraska Medical Center
Agapito S Lorenzo, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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