Expanding the Spectrum of ANO5-Muscular Dystrophy: Skeletal Muscle Amyloidosis, Cardiac Arrhythmia and Novel Mutations (PD6.001)

Abstract

Objective: To investigate the clinical and pathological spectrum of ANO5-muscular dystrophy. Background Anoctamin-5 (ANO5) is a putative calcium-activated chloride channel and is highly expressed in skeletal and cardiac muscles and in bone. Dominant mutations in ANO5 cause gnathodiaphyseal dysplasia, while recessive mutations result in limb-girdle muscular dystrophy or distal myopathy. Design/Methods: Clinical examination, EMG, EKG, echocardiography, muscle histochemical studies, and mutational analysis in 4 unrelated patients. Results:Patient (Pt) 1: A 53-year-old woman with exercise-induced myalgia since childhood, rhabdomyolysis, adult-onset progressive limb-girdle weakness and asymmetric calf atrophy and weakness. Pt2: A 42-year-old man with progressive asymmetric distal and proximal weakness and paroxysmal atrial fibrillation since late 309s. Pt3: A 32-year-old woman with delayed motor milestones, myalgia, progressive limb-girdle weakness since mid 209s, and supraventricular tachyarrhythmia requiring ablation. Pt 4: A 68-year-old man with long standing history of asymptomatic hyper-CKemia followed by weakness of the calf muscles, subsequently extending to the limb-girdle muscles. All patients had elevated CK and myopathic EMG changes. Muscle biopsy revealed nonspecific myopathic changes in Pt1, Pt2, and Pt4; signs of reinnervation in Pt3; and amyloid deposits within the interstitium and blood vessel walls in Pt1 and Pt2. Echocardiogram revealed septal wall global hypokinesis in Pt3 and normal findings in the other patients. All 4 patients harbored two heterozygous ANO5 mutations; Pt2, Pt3 and Pt4 carry novel ANO5 mutations. Conclusions: The presence of cardiac arrhythmia in 2/4 patients suggest that cardiac involvement can occur in ANO5-muscular dystrophy and underlines the need for close cardiac monitoring. The presence of skeletal muscle amyloidosis in 2/4 patients increases the pathological similarity between ANO5-muscular dystrophy and dysferlinopathy and provides a clue to the diagnosis in the absence of dysferlin deficiency and/or dysferlin mutations. Supported by: The Neurology Department at Mayo Clinic, Rochester MN. Disclosure: Dr. Liewluck has nothing to disclose. Dr. Dimberg has nothing to disclose. Dr. Winder has received personal compensation for activities with PreventionGenetics. Dr. Milone has nothing to disclose.