FP.31 ANXA11 related adult-onset muscular dystrophy in Greek families

Abstract

Pathogenic mutations in the low complexity domain of many RNA binding proteins have been reported in both neurogenic and myopathic disorders. Frequent involvement of multiple organs in patients often leads to associated diseases classified as multisystem proteinopathies (MSP) because of the shared aggregate pathology in the affected tissues. These mutations and associated molecular pathomechanisms are part of the dysfunctional cellular clearance of protein aggregates and stress responses. Interestingly, the same causative variant has often been observed in patients with ALS and large families with primary myopathies with or without ALS. Recently, we identified the c.118G>T; p.D40Y variant in <i>ANXA11</i> (NM_0145869.1) segregating with an autosomal dominant myopathy phenotype in five large Greek families from the relatively isolated island of Aegean Sea. However, this variant has been reported in French ALS patients and Brazilian MSP families with ALS patients. In our cohort, none of the patients have an ALS phenotype or family history of ALS. The age of onset in our patients was in the 3^rd-5^th decade of life. Muscle MRI shows myopathic fatty degeneration-replacement of adductors, semitendinosus, semimembranosus, and gastrocnemius muscles. However, none of our patients report any axial involvement with head drop described in the Brazilian MSP families with the same mutation. We present strong genetic evidence that <i>ANXA11</i> p.D40Y causes the observed phenotype in the Greek families. Further studies will unravel the additional molecular factors that can explain the involvement of different target organs causing either ALS or the primary myopathy phenotype.