LIMB-GIRDLE MUSCULAR DYSTROPHY I: P.3Phenotypic spectrum and muscle pathology in a Chinese cohort with ANO5 recessive mutations

Abstract

ANO5 encodes anoctamin-5, an endoplasmic reticulum-associated putative intracellular calcium-activated chloride channel that is highly expressed in skeletal and cardiac muscle and bone. ANO5 was found to be the causative gene of limb girdle muscular dystrophy type 2L, which was one of the most common forms of muscular dystrophy in Europe. The clinical manifestation ranged from mild symptoms such as asymptomatic hyperCKemia, myalgia, muscle cramps and stiffness, to severe symptoms such as muscle weakness and atrophy, recurrent rhabdomyolysis with the existence of cardiomyopathy. We collect the clinical manifestations, muscle MRI images and muscle pathology in 5 Chinese patients with recessive ANO5 mutations revealed by targeted next generation sequencing in the past 3 years. The ANO5 variants (NM_213599) include one reported missense mutation (c.1640G>A p.Arg547Gln) and 5 Novel mutations (c.1103C>T p.Thr368Met, c.1969C>T p.Gln657X, c.2423A>T p.D808V, c.2498T>G p.Met833Arg and c.2596_2597del p.K866fs). The clinical presentations of 5 patients manifested as asymptomatic hyperCkemia, isolated cardiomyopathy and limb-girdle muscle weakness. Muscle MRI revealed selective fatty infiltration in quadriceps femoris, adductor magnus and medial gastrocnemius. Muscle biopsy in three patients showed mild to moderate muscle fiber variation and increased internal nuclei. Subsarcolemmal deposits with PAS positive staining was demonstrated in one old male patient with cardiac involvement. Further western blotting with muscle samples showed mild to moderate reduction of anoctamin-5 protein expression. Taken together, we report a Chinese cohort with recessive ANO5 mutations, presenting diversified clinical phenotypes affecting the skeletal and cardiac muscles. PAS-positive deposits in skeletal muscles may offer a clue for further investigation on the pathogenesis of anoctamin-5 defect.