G.P.280

Limb-girdle muscular dystrophy type 2G (LGMD2G) is a disorder caused by mutations in the TCAP gene that encodes for the striated muscle specific protein telethonin. LGMD2G is extremely rare and was initially identified in the Brazilian population. Recently, a small number of LGMD2G patients have been diagnosed in populations with diverse genetic backgrounds indicating a wider geographical distribution of this disorder. Here we describe a 49year old male patient presenting a classical LGMD phenotype. He was born from non-consanguineous healthy parents of Indian descent. He had normal motor milestones but became noticeable slower in his early teens and presented scapular winging and Achilles tendon contractures. He eventually became wheelchair bound by age 47. There has been no cardiac involvement so far and the respiratory function is only mildly reduced with nocturnal hypoventilation. CK levels were 2541 iU/L. A muscle biopsy showed well preserved fascicular architecture with mild myopathic features. Immunohistochemistry with an antibody directed to the C-terminal portion of telethonin showed complete absence of labelling. However, an antibody directed against full-length telethonin showed some labelling on sections and a single band of ∼10kDa on Western blot. Sequence analysis of the TCAP gene revealed a novel homozygous non-sense c.244C>T (p.Gln82X) mutation in exon 2, predicted to generate a truncated protein of molecular mass consistent with the Western blot findings. Double labelling for telethonin and filamin C showed overlap in a cross-striated pattern, consistent with the Z-disc localization of both proteins, indicating that the mutant telethonin is retained at the Z-disc. Our results suggest that the mutant protein is correctly incorporated in the sarcomere allowing sufficient binding to titin such that functional rather than structural defects may be the mechanism that leads to LGMD2G.