LIMB-GIRDLE MUSCULAR DYSTROPHY I: P.2ANO5 - Three different phenotypes and a new histological pattern

Abstract

Anoctamin 5 (ANO5) is a putative intracellular calcium- activated chloride channel. Recessive mutations in ANO5 cause primary muscle disease, and the clinical spectrum ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L). The objective of this work was to describe the clinical, pathological and molecular findings of three unrelated patients with ANO5 - related muscle dystrophy. To that end, we did a retrospective study, analyzing our database from October 2004 to February 2018 where 1,500 muscle biopsies for diagnostic purposes were performed. Patients were attended by two myology experts, who performed and analyzed muscle biopsies. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained and reacted routinely (minimum 16 stainings). A custom panel including 115 genes (Nextera Rapid Capture, Illumina) and TruSight One Panel (Clinical Exome, Illumina) was used for NGS sequencing in those cases without a definite pathological diagnosis. All samples were sequenced in a MiSeq (Illumina) platform. As a result, three patients were diagnosed of ANO5 -related muscle dystrophy, all of them presenting the common exon 5 mutation c.191dup plus a missense mutation in the other allele. They showed three different phenotypes (LGMD2L, distal myopathy and asymptomatic hyperCKemia). Curiously, all three muscle biopsies showed different patterns, but in one of them it was seen numerous ragged-red fibers with little endomysial inflammation and partial invasion cell by T lymphocytes. In conclusion, ANO5 - related muscle dystrophy is a heterogeneous disease with different clinical phenotypes as we already knew, but also different histological patterns, even mimicking a mitochondrial myopathy. This work widens clinical, histological and anatomo-pathological features related to ANO5 mutations.