G.P.50 A nationwide survey of autophagic vacuolar myopathies characterized by autophagic vacuoles with sarcolemmal features (AVSF) in Japan

Abstract

Danon disease (DD), X-linked myopathy with excessive autophagy (XMEA), and related autophagic vacuolar myopathies (AVMs) are pathologically characterized by autophagic vacuoles with sarcolemmal features (AVSF). AVSF delineates a group of at least five clinically different myopathies, including DD and XMEA. However, the clinical features and the prevalences of these AVMs have not been well established. We sent questionnaires on these AVMs to 2617 hospitals in Japan that have departments of neurology, cardiology, or pediatrics. We reviewed clinical histories and muscle specimens provided by hospitals with AVM patients. In addition, we performed genetic analyses of the LAMP-2 and VMA21 genes. We identified 27 DD patients from 12 families, 3 XMEA patients from 1 family, 7 X-linked congenital AVM patients from 1 family, 2 infantile AVM patients, and 1 patient with adult-onset AVM with multiorgan involvement. All DD patients had LAMP-2 gene mutations. Lethal cardiomyopathy was evident in all DD patients. Hypertrophic cardiomyopathy (HCM) was documented in most men, while dilated cardiomyopathy was more common among women. All XMEA patients had VMA21 gene mutations. XMEA, infantile AVM, and congenital AVM patients had no cardiomyopathy. HCM developed in the adult with AVM. Pathologically, AVSF in all AVMs expressed virtually all sarcolemmal proteins on their vacuolar membranes. Multilayering of the basal lamina along vacuolar membranes was present in XMEA, infantile AVM, congenital AVM, and adult AVM. In addition, the locus for infantile AVM and congenital AVM was suggested to be the same region as that in XMEA. These AVMs are very rare muscular disorders and may be primarily caused by lysosomal dysfunctions in consideration of both genetically diagnosable DD and XMEA. Because infantile AVM and congenital AVM are pathologically and genetically similar to XMEA, these three diseases might be allelic.