A.P.11

Autophagy is a highly conserved cellular degradative pathway that includes several tightly regulated steps, evolving from the initial formation of phagophores to autophagosomes, whose fusion with lysosomes results in the final structures of degradation, autolysosomes. Ectopic P-Granules Autophagy Protein 5 Homolog encoded by EPG5 is a key autophagy regulator in multicellular organisms. Recessive EPG5 mutations cause severe abnormalities of autolysosome formation and have been implicated in Vici syndrome (VS), an extensive multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. Here we report post mortem ( n  = 4), muscle ( n  = 13), liver ( n  = 2), nerve and skin ( n  = 1 each) biopsy findings from 17 individuals with VS and related EPG5-associated disorders. Muscle biopsies featured variable combinations of increased variability in fibre size with predominance of often atrophic type 1 fibres, increase in internalized nuclei, fat and connective tissue, and abnormal glycogen content. Autophagic vacuoles were conspicuous on light microscopy, often associated with basophilic stippling and acid phosphatase positive inclusions, and confirmed on electron microscopy. Other variable EM features included abnormalities of mitochondrial structure and distribution. Few patients showed additional core-like structures. Nerve biopsy findings suggested an associated neuropathy. Post mortem examination demonstrated callosal agenesis, neuromigrational abnormalities and variable hypoplasia of cerebellum, pons and corticospinal tracts as the most striking CNS abnormalities. Abnormal vacuoles and increased glycogen content were found in multiple organs, including kidney, liver and heart. These findings indicate consistent neuromuscular and CNS involvement as part of the EPG5-related phenotypical spectrum, and suggest substantial overlap with other neuromuscular conditions, and the glycogen and lysosomal storage disorders.