Knowledge on rare diseases and orphan drugs

The estimated prevalence for all forms of LGMD ranges from 1/44,000 to 1/123,000.

LGMD ranges from severe forms with onset in the first decade and rapid progression (resembling Duchenne muscular dystrophy) to milder forms with late onset and slower progression (similar to Becker muscular dystrophy). LGMD is characterized by weakness and wasting predominantly of the limb musculature (proximal greater than distal). The initial presentations are usually weakness of the hip and proximal leg muscles. Affected individuals usually have normal early motor and intellectual milestones and show a positive Gowers' sign. Cardiac involvement in the form of dilated or hypertrophic cardiomyopathy and dysrhythmias are present in LGMD 2C-F, 2I, 2W, 2X, 1B, and 1E. At some stage, when upper arm muscles are involved, all subtypes may also have respiratory muscle weakness with nocturnal hypoventilation, in particular type 2I where it is noted from an earlier stage. Additional clinical features include a waddling gait, muscle pain during exercise, hypertrophy of the deltoids and quadriceps, and muscle wasting, affecting either the pelvis and/or shoulder girdle. The facial muscles are usually spared or involved only minimally.

LGMD is caused by mutations in more than 25 genes which encode numerous components of the myofiber, contractile apparatus, nuclear lamina, sarcolemma or the cytoplasm.

Diagnosis of LGMD involves physical examination and muscle biopsy, which reveals fiber size variation including (non specific) fiber hypertrophy, scattered degenerating and regenerating muscle fibers, and a mild increase in perimysial tissue. Serum creatine-kinase can be normal or mildly to grossly elevated. Diagnosis of a specific LGMD subtype can be achieved by biochemical protein testing performed on muscle biopsies, followed by confirmation with genetic testing. Genetic testing, using panels, is becoming more readily available and can confirm diagnosis.

The differential diagnosis of LGMD includes facioscapulohumeral muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, polymyositis, myotonic, myofibrillar, distal and metabolic myopathy, collagen 6-related disorders and dermatomyosistis.

Prenatal diagnosis is available when a causative gene in a family is known.

There are at least 30 different genetic forms of LGMD, among which the type 1 LGMDs (LGMD1) are inherited in an autosomal dominant manner and the type 2 LGMDs (LGMD2) are inherited in an autosomal recessive manner. Genetic counseling should be offered to families according to the mode of inheritance.

Treatment of LGMD remains palliative and supportive and includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social as well as emotional support and stimulation.

The clinical course of LGMD is typically progressive, although it is highly variable and is dependent on the severity of the individual genetic mutation. In most childhood onset forms of LGMD (in particular the rapidly progressive forms), ambulation is achieved but is invariably lost in later years. In other forms of LGMD, ambulation can be maintained and wheelchair assistance needed only later in life.

Last update: April 2017 - Expert reviewer(s): Dr A.J. [Anneke] VAN DER KOOI