About LGMD2I/R9
LGMD is progressive and variable
Limb-girdle muscular dystrophy (LGMD) comprises a genetically and clinically heterogeneous group of progressive myopathies primarily affecting the pelvic and shoulder girdle muscles. The presentation often includes proximal muscle weakness; however, the onset, progression, and systemic involvement can vary significantly between subtypes. More than 30 genes have been identified as causing LGMD.1-3
LGMD2I/R9 is rare and aggressive
LGMD2I/R9 is a rare autosomal recessive disorder characterized by a progressive disease burden (eg, muscle weakness and mobility loss) and increased risk of cardiac and respiratory involvement compared with other LGMDs.1,2,4 There are approximately 7000 individuals with LGMD2I/R9 or other addressable α-dystroglycanopathies in the United States and Europe.5,*
*Includes all patients with potentially treatable mutations in FKRP, FKTN, and ISPD.
LGMD2I/R9 is commonly caused by mutations in the FKRP gene. Patients with LGMD2I/R9 inherit 2 copies of the mutated FKRP gene, one from each parent.2
LGMD2I/R9 typically occurs between childhood and early adulthood, with most patients exhibiting symptoms by the age of 18.6
LGMD2I/R9 weakens the foundation of muscle
In LGMD2I/R9, the mutated FKRP gene, which codes for FKRP, an essential enzyme involved in the glycosylation of αlpha-dystroglycan (αDG), results in defective glycosylation of αDG, leading to weakened muscle fibers and progressive degeneration.2,7,8
αDG plays a critical role in stabilizing muscle cells, a key component of the body’s biochemical shock absorbers that allows muscles to stretch, contract, and recover. This shock absorption system only works if αDG is glycosylated, and in patients with FKRP mutations, the ability to glycosylate is impaired. Over time, this leads to inflammation and fibrosis of the muscle tissue, as well as muscle loss and failure. Eventually, individuals affected by LGMD2I/R9 will lose the ability to perform routine activities, such as walking or standing, without assistance.9-12
Healthy muscle tissue
LGMD2I/R9 muscle tissue
LGMD2I/R9 has an established genotype/phenotype association
Many FKRP mutations are associated with LGMD2I/R9, but homozygosity at c.826C>A (L276I) is common and always associated with LGMD2I/R9. Compared with individuals with other FKRP mutations, patients with L2761 homozygous tend to have relatively less severe disease, with a later onset of symptoms, lower rates of ambulation loss and wheelchair dependency, and a delayed need for respiratory support.13,14
