Limb Girdle Muscular Dystrophy Type 2L (Anoctamin 5 Deficiency): Cardiac Involvement and Characterization of the Skeletal Muscle Phenotype (S15.006)

Abstract

Objective: To test the prevalence of the newly discovered limb girdle muscular dystrophy type 2L (LGMD2L) in Denmark, and further characterize the phenotype. Background Mutations in the anoctamin 5 gene causes LGMD2L, which was first described in 2010. Two existing reports on small LGMD2L cohorts, suggest that LGMD2L may be a relatively common cause of LGMD2. Less than 30 patients have been reported so far. It appears that the disease, like LGMD2B (dysferlinopathy) may present as either classical LGMD2 or as a distal myopathy (MMD3), primarily involving the posterior calf musculature. In this study, we determined the prevalence of anoctamin 5 deficiency in a cohort of patients with unclassified LGMD2, hyperCKemia or distal myopathy. Design/Methods: All unclassified LGMD2 patients (26 out of 161), unexplained hyperCKemia (15 patients) and distal myopathies (5 patients) were tested for mutations in ANO5. All mutation-positive patients underwent a clinical exam, echocardiography and 48-h Holter monitoring. Results: Ten of 26 unclassified LGMD2 patients, 2 of the 15 hyperCKemia patients and 4 of 5 distal myopathy patients had LGMD2L. All patients carried the common c.191dupA mutation on at least one allele. Echocardiograhies were unremarkable, but Holter monitoring showed a 2.5-fold increase in premature ventricular contractions, which predicts an increased risk of cardiovascular disease. Only 2 of the 16 patients were women. In distal forms, the medial gastrocnemius muscle was the preferentially affected muscle, but the phenotype converges into a LGMD2 phenotype in all patients with time. Calpain 3 expression on Western blots was decreased in about half the patients. Conclusions: This study suggests that LGMD2L (16 patients) is the third commonest LGMD2 type in Denmark, only surpassed by LGMD2I (64 patients) and LGMD2A (22 patients). The study demonstrates for the first time that cardiac involvement may occur in this disease, and suggests a regular electrocardiographic follow-up of these patients. Disclosure: Dr. Vissing has received personal compensation for activities with Genzyme Corporation. Dr. Witting has nothing to disclose. Dr. Lauritsen has nothing to disclose. Dr. Duno has nothing to disclose.