A.P.12: A novel, EPG5-related vacuolar myopathy

Abstract

Autophagy is a fundamental cellular degradative pathway and involves several tightly regulated steps conserved throughout evolution. We have recently identified recessive null mutations in EPG5, encoding a protein with a crucial role in autolysosome formation, as the cause of Vici syndrome (VS), a severe multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. The consistently associated myopathy shares prominent vacuoles as the most striking histopathological feature with the primary autophagic vacuolar myopathies (AVMs), Danon disease and X-linked myopathy with excessive autophagy (MEAX). Here we report 2 sisters presenting from childhood with generalized weakness, elevated CK levels (5–10× normal) and a characteristic pattern of selective involvement on muscle MRI. Progression was relentless in the index case, resulting in almost complete paralysis requiring a gastrostomy and continuous invasive ventilation within a decade. Muscle biopsies showed increased variability in fibre size, multiple internal nuclei, fat and endomysial connective tissue increase, and abnormal glycogen content. Autophagic vacuoles with sarcolemmal features were prominent and confirmed on EM. Whole exome sequencing revealed a paternally inherited heterozygous EPG5 frame shift mutation (g.43534647G>A, c.721C>T, p.R241^∗). Investigation of the EPG5 transcript by RT-PCR of mRNA from fibroblasts revealed a rearrangement in the other transcribed allele, with non-coding X-chromosomal material inserted into EPG5 exon 23. Further functional studies in patient-derived fibroblasts suggested a moderate disturbance of autophagic flux. We speculate that the inserted sequence partially disrupts epg5 function, resulting in a "milder" phenotype compared to typical VS. Our findings define a novel EPG5-related vacuolar myopathy and indicate that EPG5 mutations ought to be considered in unresolved patients with suggestive features.