Anoctamin 5 Mutations Are a Frequent Cause of Limb Girdle Muscular Dystrophy and of the Miyoshi-Type Muscular Dystrophy in the Netherlands (S15.005)

Abstract

Objective: To perform Anoctamin 5 (ANO) mutation analysis, neurological and cardiological examination in the genetically undiagnosed remainder of the Dutch limb girdle muscular dystrophy (LGMD) cohort encompassing 105 patients from 68 families and in a proportion of a cohort of 22 patients from 16 families with a Miyoshi-type muscular dystrophy (MMD) in which no dysferlin mutations were found. Background ANO 5 mutations have recently been found to cause LGMD2L, MMD3 and asymptomatic hyperCKemia. Design/Methods: Neurological examination, cardiological investigations (i.e. electrocardiography, Holter monitoring, echocardiography), serum creatine kinase (sCK) activity assessments and ANO 5 mutation analysis were performed in LGMD and MMD patients. Results: 32 LGMD index patients and 12 MMD3 patients from 8 kindreds were examined. ANO 5 mutations were found in 13 sporadic LGMD cases (8 males). Age at onset ranged from 21-57 years, age at examination from 26-69. Symmetrical proximal leg muscle weakness had been the first manifestation. Rhabdomyolysis attacks were mentioned in one patient, and three had cardiological abnormalities, including intraventricular septum thickening (2) and hypertrophic cardiomyopathy (1). SCK was 10-25 times the upper limit of normal (ULN). In 8 patients (all male) from 6 MMD families mutations were identified. Age at onset ranged from 18-51 years and age at examination from 30-67. Uni- or bilateral calf muscle weakness had been the presenting symptom in 7 patients and one had been asymptomatic at time of diagnosis. SCK was 20-40 times ULN. None had associated symptoms and cardiological examination was normal. Exon 5 c.191dupA was the most frequently observed mutation and in addition novel mutations were identified. Conclusions: 1. LGMD 2L is found in 16% of the Dutch LGMD families and MMD3 in 40% of the MMD families.2. In three LGMD2L patients heart involvement was found and in none of the MMD3 patients. Disclosure: Dr. De Visser has received research support from Biogen Idec. Dr. van der Kooi has received research support from Biogen Idec. Dr. Linssen has nothing to disclose. Dr. Ginjaar has nothing to disclose. Dr. Wokke has received research support from Genzyme Corporation. Dr. van Doorn has received personal compensation for activities with Talecris, ZLB, Baxter, and Octapharma. Dr. van Doorn has received research support from Baxter.