Limb-girdle muscular dystrophies

Limb-girdle muscular dystrophies (LGMDs):
The limb-girdle pattern of muscular weakness is the most common dystrophic phenotype in adults. This syndrome affects perhaps 1/100,000 of the population. However, this clinical picture can result from several pathologies including spinal muscular atrophy and inflammatory and mitochondrial myopathies, in addition to limb-girdle dystrophies, so full investigation is mandatory

Limb-girdle muscular dystrophies are a complex, genetically heterogeneous group of disorders, but can be divided into two broad clinical groups.
Milder forms usually present in the second to third decade, with progressive difficulty walking followed by proximal arm weakness and loss of ambulation after 20–30 years; however, age of onset and progression vary considerably, even within families. Cranial and bulbar musculature is unaffected. The neck muscles become weak. The muscles of the shoulder and pelvic girdles, and the proximal arm and leg muscles become weak and wasted. Distal involvement and calf hypertrophy is vari- able. Bilateral scapular winging is a typical and often early fea- ture. Family history may reveal either dominant or recessive inheritance, but many cases are sporadic.
Severe forms present in childhood. Severe childhood autosomal recessive muscular dystrophy (SCARMD) is clinically similar to DMD and is the most common cause of a DMD-like phenotype in girls. However, cardiac and mental functions are unaffected. Five  gene  loci  for  autosomal  dominant  LGMD  and  eight genes for autosomal recessive disease have been discovered (LGMD1A–E  and  LGMD2A–H,  respectively).  SCARMD  has been shown to result from absence of dystrophin-associated glycoproteins  (sarcoglycans),  which  anchor  one  end  of  the dystrophin molecule to the sarcolemma. LGMD2A results from deficiency of an enzyme (calpain 3) rather than a structural protein. LGMD2B results from deficiency of dysferlin (dysferlin deficiency is also the cause of Miyoshi myopathy, a form of distal myopathy both phenotypes have been reported within single families). Diagnosis by immunohistochemistry and immunoblotting is now available for some of these diseases. Creatinine kinase levels are increased by tenfold to more than 100-fold, and biopsy findings may range from mild, nonspecific dystrophic changes in milder forms to severe, often very focal fiber necrosis in SCARMD.

Management
There is no specific treatment, but gene therapy trials are planned for sarcoglycanopathies. The genes involved are smaller than the dystrophin gene and should pose less problems with regard to gene vectors.

Emery–Dreifuss  muscular  dystrophy  (EDMD)  presents  in childhood  with  progressive  weakness  and  wasting  of  the scapulohumeral  and  anterior  tibial  and  peroneal  muscle groups.  It  probably  accounts  for  most  forms  of  ‘scapuloperoneal muscular dystrophy’. Muscle contractures develop at an early stage, leading to a pathognomonic posture with elbow  flexion,  equinovarus  ankle  deformities  and  fixed  neck flexion. Cardiac involvement is prominent, leading to serious conduction disorders and sometimes sudden death. Prophylactic pacemaker insertion can be life-saving. In X-linked forms, muscle immunohistochemistry demonstrates deficiency of a nuclear membrane protein (emerin). An autosomal dominant form of EDMD caused by deficiency of lamin A/C, another nuclear membrane protein, has been described. The precise function of these proteins is unknown.

Bethlem myopathy is a relatively benign, autosomal dominant condition that progresses insidiously from infancy, causing increasing difficulty with running, then walking and standing. Significant disability develops in old age. Characteristic flexion contractures of the fingers but not thumbs (‘prayer sign’) are diagnostic,  and  are  associated  with  contractures  of  the  elbows, equinovarus ankle deformities and other joint contractures in most patients. Increases in CK are modest, and electromyography (EMG) and biopsy findings are of nonspecific myopathic type. The disease is caused by a deficiency of type VI collagen in the extracellular matrix of muscle fibers, and mutations of several collagen VI subunit genes have been identified.

Congenital muscular dystrophies present at birth or in the first few weeks of life, with proximal weakness and delayed milestones. Contractures are common and biopsy shows marked dystrophic features. The main differential diagnosis is spinal muscular atrophy. CNS involvement with mental retardation occurs in some forms. The genetic abnormalities and specific protein deficiencies have been defined for several of these diseases.