AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.14 Autophagic vacuolar myopathy with autophagic vacuoles with sarcolemmal features (AVSF myopathy) including Danon disease and XMEA: A new clinical entity

Abstract

A subgroup of autophagic vacuolar myopathies (AVMs) is characterized by unusual autophagic vacuoles with sarcolemmal features (AVSFs) and includes Danon disease and X-linked myopathy with excessive autophagy (XMEA). We suggest referring to this subgroup as ‘AVSF myopathy’ as a new clinical entity. However, the features of AVSF myopathy have not been well established. Therefore, to evaluate the clinical features, we reviewed the clinical histories, muscle specimens, and genetic analyses of Japanese patients with AVSF myopathy. In addition, to address the diagnostic importance of AVSFs, we studied AVSF myopathy and other AVMs (Pompe disease and rimmed vacuolar myopathies) pathologically. We identified 39 patients with Danon disease (17 males and 22 females) from 20 families with LAMP-2 mutations, 12 XMEA male patients from 4 families with VMA21 mutations, one male patient with adult-onset AVM with multiorgan involvement, and one asymptomatic female patient. Cardiomyopathy was evident in all patients with Danon disease. Among the 20 patients who died, 19 (95%) died of cardiac failure. Cardiomyopathy was not evident in all patients with XMEA. Among the 9 patients who died, all died of respiratory failure. Pathologically, AVSFs expressed virtually all sarcolemmal proteins in addition to AChE on their vacuolar membranes in all patients with AVSF myopathy. Multilayering of the basal lamina along vacuolar membranes was present in XMEA, adult type and asymptomatic type. This unique intracytoplasmic membrane structure was not found in other AVMs. AVSFs are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structures and delineate AVSF myopathy. In conclusion, AVSF myopathy is a very rare muscular disorder and may be primarily caused by lysosomal dysfunctions in consideration of both genetically diagnosable Danon disease and XMEA. Our findings suggest that AVSF myopathy may include more clinical phenotypes apart from Danon disease and XMEA.