G.P.51 Structural changes in X-linked myopathy with excessive autophagy: What do they look like?

Abstract

X-linked myopathy with excessive autophagy (XMEA) is an X-recessive linked myopathy due to mutations in the VMA 21 gene. This gene encodes a chaperone molecule necessary for the binding of V-ATPase to the lysosomic membrane. The disease is therefore characterized by the absence of normal acid pH within the lysosomes. Lysosomal pH raising reduces lysosomal degradative ability. It is responsible for neuropathological abnormalities which include autophagic vacuoles resulting from the fusion between lysosomes and autophagosomes. Similar or close neuropathological patterns can be observed in quite distinct disorders such as lysosome-associated membrane protein 2 (LAMP-2) myopathy (Danon’s disease) or colchicine induced myopathy. We studied muscle biopsies from three adult patients presenting with XMEA confirmed by genetic testing and compared them to muscles biopsies from one patient with Danon’s disease and one patient with a myopathy related to colchicine treatment. In XMEA, pathological features associate a “mild” myopathic aspect with an increased number of abnormal giant autophagic vacuoles. These vacuoles displace the normal structures of the myocytes with neither significant cytosolic abnormalities nor glycogene increase. They seems to be expulsed in the immediate surrounding of the cell within abnormal folding of the basal lamina. Presumably, this abnormal content is the primary event inducing a membrane attack complex deposit. This aspect is quite different from the one observed in the patient with LAMP2 negative Danon’s disease where the autophagic vacuoles are associated with glycogene storage and are not expulsed outside. On the other hand, the colchicine myopathy offers a very close ultrastructural aspect and is thought to be the consequence of impaired migration and fusion of autophagosomes and lysosomes. In conclusion, separate pathophysiological mechanisms can lead to similar vacuolation patterns.