Division of Neurology and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada,
Acta Neuropathol. 2015 Mar;129(3):383-90. doi: 10.1007/s00401-015-1393-4. Epub 2015 Feb 3.
Autophagic vacuolar myopathies (AVMs) are a group of disorders united by shared histopathological features on muscle biopsy that include the aberrant accumulation of autophagic vacuoles. The classic conditions that compose the AVMs include Pompe Disease, Danon Disease and X-linked myopathy with excessive autophagy (XMEA). Other disorders, including acquired myopathies like chloroquine toxicity, also have features of an autophagic myopathy. This review is focused on XMEA, a myopathy with onset of slowly progressive proximal weakness and elevated serum creatine kinase (2× to 20× normal) typically in the first decade of life. However, both late-adult onset and severe, sometimes lethal, neonatal cases also occur. Skeletal muscle pathology is characterized by numerous cytoplasmic autophagic vacuoles, complex muscle fiber splitting with internalization of capillaries, and complement C5b-9 deposition within vacuoles and along the sarcolemma. The autophagic vacuoles have sarcolemmal features. Mutations in the VMA21 gene at Xq28 cause XMEA by reducing the activity of lysosomal hydrolases. The VMA21 protein regulates the assembly of the V-ATPase required to acidify the lysosome. Increased lysosomal pH and poor degradation of cellular debris may secondarily induce autophagy, the net effect being accumulation of autophagolysosomes. The relationship of XMEA to other lysosomal disorders of muscle and potential therapeutic interventions for XMEA are discussed.
自噬性空泡肌病（AVMs）是一组以肌肉活检的共同组织病理学特征为特征的疾病，包括自噬空泡的异常积累。组成 AVMs 的经典病症包括 Pompe 病、Danon 病和 X 连锁伴过度自噬的肌病（XMEA）。其他疾病，包括获得性肌病，如氯喹毒性，也具有自噬性肌病的特征。本综述重点介绍 XMEA，这是一种肌病，其特征是进行性近端无力，血清肌酸激酶升高（正常的 2 至 20 倍），通常在生命的第一个十年。然而，也有晚发性成人发病和严重的、有时致命的新生儿病例。骨骼肌病理学的特征是大量细胞质自噬空泡、伴有毛细血管内化的复杂肌纤维分裂，以及补体 C5b-9 沉积在空泡内和沿肌膜。自噬空泡具有肌膜特征。Xq28 上的 VMA21 基因突变通过降低溶酶体水解酶的活性导致 XMEA。VMA21 蛋白调节 V-ATP 酶的组装，V-ATP 酶是使溶酶体酸化所必需的。溶酶体 pH 升高和细胞碎片降解不良可能继发诱导自噬，其净效应是自噬溶酶体的积累。讨论了 XMEA 与肌肉其他溶酶体疾病的关系以及 XMEA 的潜在治疗干预措施。
