Limb-girdle Muscular Dystrophy

The term limb-girdle muscular dystrophy (LGMD) includes at least 15 different variations of inherited disorders.¹ An OMIM search for "limb girdle muscular dystrophy" finds 97 entries.² LGMD encompasses a group of progressive conditions which affect the muscles around the shoulder girdle and hip girdle and subsequently may involve other muscles, including cardiac muscle, over a period of time.

The earliest descriptions are attributed to Leyden in 1876 and Möbius in 1879.³ The term limb girdle muscular dystrophy was proposed by Walton and Natrass in 1954⁴ but more recently classification tends to be based on genetic and molecular defects. The classification is broadly divided into:⁵

• The autosomal recessive LGMDs - accounting for about 90% of LGMDs - which include:
  • Calpain-deficient LGMD (calpainopathy), LGMD 2A
  • Dysferlin-deficient LGMD (dysferlinopathy), LGMD 2B
  • Sarcoglycanopathies (the subtypes are denoted as LGMD 2C, LGMD 2D, LGMD 2E, LGMD2F)
  • LGMD G - LGMD J
• The autosomal dominant LGMDs which include:
  • LGMD1A
  • LGMD1B
  • LGMD1C (caveolin 3 deficiency)
  • LGMD with secondary protein deficiencies

Each has a specific genetic characteristic associated with it as well as subtly distinct clinical pictures. Other forms of LGMD include:

• Pelvifemoral atrophy (Leyden-Möbius)
• Scapulohumeral dystrophy (Erb)

• The overall frequency of all LGMD syndromes is between 5 and 70 per 1,000,000.⁶
• It affects both sexes equally.
• It is usually an autosomal recessive⁷ but a minority (about 10%) are dominant.⁸
• Of the autosomal-recessive syndromes, LGMD 2A (Calpain) is the most common, representing about 30% of cases generally (although there is a geographic variation and in the Basque region of Spain, for example, may account for up to 80% of cases).⁶
• The sarcoglycanopathies account for 20-25% of LGMDs.³ They account for a high percentage of more severe cases.⁶
• All forms are much rarer than Duchenne muscular dystrophy.

The precise symptoms and signs will vary according to the condition and even within a family there can be significant variation, particularly with regard to rate of progression:^3,6

There is a final form of LGMD known as late-onset autosomal dominant limb myopathy. This is a rather more benign condition characterised by onset of upper and lower weakness later on in life (third to fifth decades) that is mild with little functional adverse effects. There is no cardiac involvement and life expectancy is almost normal (usually until the seventh decade of life at least).

• Congenital myopathies
• Dermatomyositis or polymyositis
• Endocrine myopathies including Cushing's syndrome and thyrotoxicosis
• Facio-scapula-humeral muscular dystrophy
• Spinal muscular atrophy
• Metabolic myopathies including diabetes
• Becker muscular dystrophy
• Duchenne muscular dystrophy

• There are elevated blood creatine kinase levels in almost all types (see notes above).
• Electromyography shows a pattern of myopathy with fibrillation.
• In some less common forms there may be cardiomyopathy showing arrhythmias or heart block on ECG and heart failure on echocardiogram.⁹
• MRI may be used to distinguish between different types of LGMD (hyperintense signal change on T1 scans is seen in more severely affected muscles).⁶

Muscle biopsy

A muscle biopsy is performed: it shows degenerating muscle with splitting of muscle fibres and presence of phagocytes. Histochemical stains may be helpful in elucidating the exact form of the disease. By DNA and muscle protein analysis it is possible to identify 5 autosomal dominant and 10 autosomal recessive forms.¹⁰ Testing for dystrophin, the defective protein in Duchenne muscular dystrophy is negative. Other tests on a muscle biopsy may include light microscopy, electron microscopy and immunochemical staining.

Non-drug

Non-drug therapies are very important in this group of conditions. They may include:³

• Physical therapy including physiotherapy to help avoid contractures through passive stretching, exercise therapy¹¹ and appropriate wheelchair description (a teenager will have very different lifestyle needs to a thirty year old).
• Occupational therapy in individuals of all ages.
• Play therapy may play an important role in children.
• Depending on the degree of disability, there may be allowances available to the patient (see further reading: Muscular Dystrophy Campaign).

Drugs

Two small double-blind trials have suggested that co-enzyme Q10 (vitamin Q10) might be beneficial in this and other dystrophies but larger trials are needed.¹²

Surgical

Surgical treatment may be required for contractures (tendon-lengthening surgery or placement of orthoses to help maintain mobility) or scoliosis. A pacemaker be needed for arrhythmias.

• Progressive weakness leading to dependence on a wheelchair
• Difficulties with activities of daily living due to shoulder weakness
• Contractures due to decreased muscle movements and joint use
• Scoliosis
• Cardiac arrhythmias
• Respiratory complications

This depends upon the type. In general slow progression of weakness is to be expected. The affected muscles get worse and it spreads to more muscles. Morbidity and mortality varies between the various types but generally an early onset is associated with a more rapid decline and early mortality.⁶ In the slow types the patient may still be ambulatory 30 years later. The autosomal dominant forms tend to be less severe than the recessive.¹³

Cardiomyopathy with arrhythmias increases the risk of palpitations, syncope and sudden death. Most patients with this group of diseases live into adulthood but do not reach old age. Death is usually due to cardiac or respiratory failure.

Genetic counselling should be offered if there is a family history. Lung function will have to be monitored in anticipation of potential respiratory failure.