Description

The term limb-girdle muscular dystrophy (LGMD) refers to a group of rare, inherited disorders which predominantly affect the muscles around the shoulder girdle and hip girdle, causing progressive muscle weakness. Other muscles, including the heart, may be affected in some types of LGMD. The individual forms of LGMD vary widely in their genetics and clinical features.¹

See the table below (in 'Appendix') for details of the individual LGMD types.

Aetiology and classification¹

Several different aspects of muscle function seem to be involved.

Currently, limb-girdle muscular dystrophies (LGMDs) are classified into two main groups: autosomal dominant (group 1) or recessive (group 2). Within these groups, the subtypes are designated by letters (allocated in chronological order of gene identification).

The terminology of LGMDs may also relate to the protein involved in the pathology, e.g. LGMD 2C-F are termed sarcoglycanopathies. Other proteins involved include dystroglycan, fukutin-related protein, calpain, dysferlin and telethonin.²

Epidemiology¹

• The limb-girdle muscular dystrophies (LGMDs) individually are rare, with some forms reported in only a few families.
• The recessive forms are more common than the autosomal dominant forms.
• In the UK, LGMDs comprised 6.2% of the population of a specialist muscle clinic, giving a prevalence of 2.27/100,000.³

Presentation^1,4

By definition, all limb-girdle muscular dystrophies (LGMDs) involve the proximal muscles of the shoulder and pelvic girdles. However, the precise symptoms and signs will vary with the different forms of LGMD. In addition to proximal muscle weakness, there may or may not be:

• Distal muscle weakness.
• Muscle hypertrophy.
• Contractures.
• Involvement of heart, respiratory muscles or tongue. (Facial weakness is not usual.)
• Variation in the clinical expression of the condition, with clinical differences between individuals in one family.
• Age of onset and rates of progression vary. Also, note that the muscle weakness does not necessarily progress at a linear rate.
• Usually there is no intellectual impairment.

See the table below (in 'Appendix') for details of the individual LGMD types and their clinical features.

Assessment

LGMD is relatively rare: consider more likely diagnoses first. Reaching a diagnosis involves combining information from the clinical presentation and various investigations, mainly serum creatine kinase (CK), muscle biopsy and genetic testing.

History

• Ethnic and geographical origin - certain LGMDs have been found in specific regions or countries.
• Family history.
• Neonatal history.
• Childhood development and motor milestones.
• Sporting ability.

Examination

• Ability to rise from the floor.
• Is there a finding (or history) of Gower's sign? This is seen in patients with proximal muscle weakness of the lower limb: when rising to stand, they use the hands as support, such that the hands 'climb up the legs';⁵ this sign is common in Duchenne's muscular dystrophy).
• Spinal rigidity or scoliosis.
• Muscle weakness, hypertrophy or contractures (including calf and tongue hypertrophy).
• Note:
  • The mode of presentation and the pattern of muscle involvement.
  • Whether there any additional clinical features.

Interpretation of clinical patterns

The precise clinical pattern and course can help identify the specific LGMD cause. For example:

• Neonatal hypotonia occurs in LGMD 1B.
• Contractures are most common in LGMD 1B.
• LGMD 2A - there is relative preservation of hip abductors and striking involvement of the posterior thigh muscles seen on MRI.
• LGMD 2A and LGMD 2C-F - scapular winging is characteristic.
• LGMD 2B - often have normal sporting ability until there is abrupt onset of symptoms.
• LGMD 1C - may have rippling muscle disease, characterised by signs of increased muscle irritability, such as percussion-induced rapid contraction, percussion-induced muscle mounding and/or electrically silent muscle contractions (rippling muscle).⁶

Specialist centres

• In the UK, the Newcastle Muscle Centre is the national LGMD diagnostic and advisory service.⁷
• The Dubowitz Neuromuscular Centre in London provides a diagnostic and advisory service for congenital muscular dystrophies and congenital myopathies.⁸

Investigations^1,4

Key investigations are:

1. Serum CK:
   • This is often raised in limb-girdle muscular dystrophy (LGMD), but can be normal in some types.
   • Exclude non-muscle conditions first.
   • The degree of CK elevation helps distinguish between different types.
2. Muscle imaging with CT or MRI - can show patterns of muscle involvement.⁹
3. Muscle biopsy:
   • Most useful on muscle which is affected clinically but is not 'end stage'.
   • Analysed by immunohistochemistry and immunoblotting in an expert laboratory.
   • All LGMDs show dystrophic features with variations in fibre size, greater numbers of central nuclei and endomysial fibrosis.
   • Muscle biopsy immuno-analysis can suggest the diagnosis in many of the genetically defined types of LGMD.
4. DNA analysis:
   • This is the 'gold standard' test, but its feasibility varies for different types of LGMD.
   • Requires a specialist laboratory.
   • For the rarer types of LGMD, this may only be available on a research basis.

In addition:

• Myoglobinuria can occur in LGMD2I¹⁰ and has been reported recently in a patient with sarcoglycanopathy.¹¹
• Cardiac and respiratory investigations are often appropriate, to monitor for complications (see 'Complications and their management', below).

It is possible to reach a precise diagnosis in around 75% of the LGMD patients.

Differential diagnosis¹²

• Other types of muscular dystrophy (many of which are more common).⁴
• Congenital myopathies.
• Dermatomyositis or polymyositis.
• Endocrine or metabolic myopathies, including Cushing's syndrome and thyrotoxicosis.
• Spinal muscular atrophy.

Management¹

There is no specific therapy for limb-girdle muscular dystrophy (LGMD).

Nondrug treatment

• Physiotherapy to prevent contractures, using passive stretching, exercise therapy, ± orthoses.¹³
• Exercise - the role of exercise in LGMD is controversial, but guidelines for other types of muscular dystrophy suggest gentle exercise within limits of comfort, and avoidance of prolonged immobility.
• Occupational therapy and aids such as a wheelchair, with careful attention to seating so as to minimise the development of scoliosis.
• Genetic counselling.
• Advice on benefits.
• Support groups (e.g. Muscular Dystrophy Campaign).
• Monitoring for complications (see 'Complications and their Management', below).

Possible drug treatment

• Corticosteroids have been used in some patients with LGMD 2C-F, giving improvement in some reported cases.^1,14
• One small, short-term trial using creatine monohydrate in sarcoglycan-deficient LGMD patients was reported to give modest improvement.¹⁵
• A study involving two patients with dysferlin-deficient muscular dystrophy reported an improvement in muscle strength after treatment with rituximab.¹⁶

Complications and their management^1,4

Complications vary, depending on the specific limb-girdle muscular dystrophy (LGMD) and on individual variations in the clinical picture. Cardiac and respiratory surveillance are particularly important in LGMD 1B, LGMD 2C-F and LGMD 2I. Where the type of LGMD carries a high risk of cardiac or respiratory involvement, management should involve cardiac and respiratory physicians. This also applies in cases where the precise diagnosis is unknown.

Respiratory muscle weakness

This is most common in LGMD 2I and the sarcoglycanopathies. It leads to hypoventilation, which is often worse at night. Symptoms include frequent chest infections, morning headaches and daytime sleepiness. Management involves:

• Monitoring of FVC (sitting and supine) and overnight pulse oximetry, which is helpful.
• Influenza and pneumococcal vaccines; prompt treatment of infections.
• Nocturnal home ventilation if required.
• Other respiratory support if required - for details, see the section on 'Management of respiratory and cardiac complications' in the separate Duchenne's muscular dystrophy article.

Cardiac complications

Cardiomyopathy and/or conduction defects can occur in some forms of LGMD; they are common in LGMD 1B. Monitoring of cardiac function (under a cardiologist) is advised for LGMD 1B, LGMD 2C-F and LGMD 2I; or for where the LGMD type is unknown. Management involves:

• ECG and echocardiography as initial investigations.
• Standard management of heart failure.
• Management of arrhythmias, e.g. anticoagulation, pacemaker, implantable defibrillator.
• If there is severe cardiac impairment with good respiratory function, cardiac transplantation may be appropriate.

Anaesthesia¹⁷

• Rarely, a malignant hyperthermic reaction to general anaesthesia can occur.
• Caution is needed regarding possible cardiac complications.
• As in any muscle disease, succinylcholine administration could cause life-threatening hyperkalaemia, and should be avoided.

Musculoskeletal complications

• Contractures, e.g. of the Achilles tendon, may require surgical release.
• Scoliosis - occurs mainly after wheelchair dependence. Careful attention to seating is important.
• Chronic pain can occur, and pain management should be part of care.¹⁸

Prognosis

This depends on the type of limb-girdle muscular dystrophy (LGMD) and whether there is cardiac or respiratory involvement. In general, all types of LGMD progress with time, but this is highly variable between the different LGMD types, and also between individuals with the same specific type or within a family.¹⁹ Also, the rate of progression is not necessarily linear.¹

Prevention

Genetic counselling should be offered. If the specific subtype of limb-girdle muscular dystrophy (LGMD) can be identified, prenatal diagnosis or carrier testing for other family members may be possible.¹⁹

Research

Possible future treatments include:

• Antisense-mediated exon skipping - this is a promising therapeutic approach for Duchenne's muscular dystrophy. It may be applicable to conditions caused by mutations in the dysferlin gene, e.g. LGMD 2B and Miyoshi myopathy.²⁰
• Gene therapy is a potential form of treatment.²¹

Appendix - summary of limb-girdle muscular dystrophy (LGMD) types and their clinical features

Document references

1. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies, European Federation of Neurological Societies (2007)
2. Guglieri M, Straub V, Bushby K, et al; Limb-girdle muscular dystrophies. Curr Opin Neurol. 2008 Oct;21(5):576-84. [abstract]
3. Norwood FL, Harling C, Chinnery PF, et al; Prevalence of genetic muscle disease in Northern England: in-depth analysis of a Brain. 2009 Nov;132(Pt 11):3175-86. Epub 2009 Sep 18. [abstract]
4. Bushby K; Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol. 2009 Dec;9(6):314-23. [abstract]
5. Medclip; Video clip showing child with Gower's sign
6. Bruno C, Sotgia F, Gazzerro E, et al; Caveolinopathies [abstract]
7. Newcastle Muscle Centre, Specialist service providing specific UK diagnostic and advisory facility for limb girdle muscular dystrophy. Accessed March 2011
8. Dubowitz Neuromuscular Centre
9. Wattjes MP, Kley RA, Fischer D; Neuromuscular imaging in inherited muscle diseases. Eur Radiol. 2010 Oct;20(10):2447-60. Epub 2010 Apr 27. [abstract]
10. Guglieri M, Bushby K; How to go about diagnosing and managing the limb-girdle muscular dystrophies. Neurol India. 2008 Jul-Sep;56(3):271-80. [abstract]
11. Pena L, Kim K, Charrow J; Episodic myoglobinuria in a primary gamma-sarcoglycanopathy. Neuromuscul Disord. 2010 May;20(5):337-9. Epub 2010 Mar 30. [abstract]
12. Lopate G; Limb-Girdle Muscular Dystrophy (Neurology perspective), Medscape, Feb 2010
13. Yeldan I, Gurses HN, Yuksel H; Comparison study of chest physiotherapy home training programmes on respiratory functions in patients with muscular dystrophy. Clin Rehabil. 2008 Aug;22(8):741-8. [abstract]
14. Wong-Kisiel LC, Kuntz NL; Two siblings with limb-girdle muscular dystrophy type 2E responsive to Neuromuscul Disord. 2010 Feb;20(2):122-4. Epub 2010 Jan 13. [abstract]
15. Walter MC, Lochmuller H, Reilich P, et al; Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled Neurology. 2000 May 9;54(9):1848-50. [abstract]
16. Lerario A, Cogiamanian F, Marchesi C, et al; Effects of rituximab in two patients with dysferlin-deficient muscular dystrophy. BMC Musculoskelet Disord. 2010 Jul 11;11:157. [abstract]
17. Richa FC; Anaesthetic management of a patient with limb-girdle muscular dystrophy for Eur J Anaesthesiol. 2011 Jan;28(1):72-3.
18. Engel JM, Kartin D, Carter GT, et al; Pain in youths with neuromuscular disease. Am J Hosp Palliat Care. 2009 Oct-Nov;26(5):405-12. [abstract]
19. Muscular Dystrophy campaign, LGMD link; Excellent general information
20. Aartsma-Rus A, Singh KH, Fokkema IF, et al; Therapeutic exon skipping for dysferlinopathies? Eur J Hum Genet. 2010 Aug;18(8):889-94. Epub 2010 Feb 10. [abstract]
21. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, et al; Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan Ann Neurol. 2009 Sep;66(3):290-7. [abstract]
22. Filosto M, Tonin P, Vattemi G, et al; Chronic ophthalmoparesis in limb girdle muscular dystrophy 1C. J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):448-9.
23. Burke G, Hillier C, Cole J, et al; Calpainopathy presenting as foot drop in a 41 year old. Neuromuscul Disord. 2010 Jun;20(6):407-10. [abstract]
24. Klinge L, Aboumousa A, Eagle M, et al; New aspects on patients affected by dysferlin deficient muscular dystrophy. J Neurol Neurosurg Psychiatry. 2010 Sep;81(9):946-53. Epub 2009 Jun 14. [abstract]
25. Margeta M, Connolly AM, Winder TL, et al; Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle Muscle Nerve. 2009 Nov;40(5):883-9. [abstract]

Internet and further reading

• Broglio L, Tentorio M, Cotelli MS, et al; Limb-girdle muscular dystrophy-associated protein diseases. Neurologist. 2010 Nov;16(6):340-52. [abstract]
• Finsterer J, Ramaciotti C, Wang CH, et al; Cardiac findings in congenital muscular dystrophies. Pediatrics. 2010 Sep;126(3):538-45. Epub 2010 Aug 2. [abstract]
• Rocha CT, Hoffman EP; Limb-girdle and congenital muscular dystrophies: current diagnostics, management, Curr Neurol Neurosci Rep. 2010 Jul;10(4):267-76. [abstract]
• Angelini C, Nardetto L, Borsato C, et al; The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B). Neurol Res. 2010 Feb;32(1):41-6. [abstract]

Acknowledgements