LGMD2A/1R

• Progressive weakness and wasting of hip or shoulder-girdle muscles
• Onset after two years of life
• Varying degrees of creatine kinase (CK) elevation, ranging from normal to markedly elevated
• Variable pathologic findings, ranging from nonspecific myopathic changes to dystrophic features
• May involve cardiac and/or muscles of respiration

LGMD2A/1R is an autosomal recessive subtype of LGMD caused by mutations of the Calpain-3 (CAPN3) gene, which codes a non lysosomal Ca2+ protease. LGMD2A/1R is one of the most common LGMD subtypes. CAPN3 belongs to a large family of proteases and is expressed specifically in skeletal muscle. Clinical presentation in LGMD2A/1R is most often associated with progressive, symmetrical, predominantly proximal muscle weakness, with age of onset between eight and 16 years. It typically begins in the pelvic girdle, with involvement of hip adductors and gluteus maximus, manifesting as problems running, climbing stairs, or standing up from a chair.

The lower limb girdle muscles are most severely affected, although some patients do have initial or simultaneous presentation in the shoulder girdle. Clinical complaints about shoulder girdle and upper limb weakness appear later in the disease course. Across the individual subtypes of LGMD, age of onset and progression varies widely as do patient symptoms and abilities, including the loss of mobility.
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Current diagnosis involves the combination of identification of the clinical signs and symptoms consistent with the known disease expression, in vitro diagnostic testing, physiologic testing, imaging, and genetic analysis.

Genetic testing can identify specific subtypes and confirm diagnoses in approximately 75% of LGMDs. Currently there are no drugs or biological products specifically indicated for use in LGMD, or LGMD2A/1R, with no disease-modifying treatments available.

Management of LGMD2A/1R is guided by well-defined clinical parameters and genetic diagnosis, with the objective of improving quality of life and, in the case of the uncommon cardiac and respiratory involvement, prolong life.