ANO5-muscular dystrophy: clinical, pathological and molecular findings

Background and purpose: Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 cause primary skeletal muscle disorders (limb-girdle muscular dystrophy 2L and distal muscular dystrophy), which are phenotypically similar to dysferlinopathy, a muscular dystrophy due to dysferlin-encoding gene (DYSF) mutations. Methods: This study reports the phenotype and genotype of seven unrelated patients with ANO5-muscular dystrophy. Results: Three patients had amyloid deposition in muscle and two had cardiac involvement. An additional patient without skeletal muscle amyloidosis had cardiac involvement with septal hypokinesis and supraventricular tachycardia requiring ablation. Amyloid subtyping using laser capture microdissection and mass spectrometry-based proteomic analysis did not identify ANO5 or any fragment of ANO5 in the amyloid deposits, but detected other known amyloidogenic proteins. Three patients had myotonic discharges without clinical myotonia. Four ANO5 mutations are novel, including a heterozygous 0.4 Mb deletion involving the entire ANO5 gene. Conclusions: The results of the present study suggest that ANO5 mutations can be associated with amyloid deposition in muscle, but the nature of the amyloid deposits remains indeterminate, as does their relationship with cardiac involvement. ANO5 analysis should be considered in cases of muscle amyloid deposition of indeterminate etiology. Electrical myotonia can accompany ANO5-muscular dystrophy.