The elucidation of pathomechanism and the development of therapy of myopathies with autophagic abnormalities

我们对来自13个不同家系的38名患者进行了临床病理特征分析，这些患者都患有基因确诊的达农病。所有男性都有心肌病和肌病，但70%的男性存在智力低下。所有男性的血清CK水平都升高，但只有63%的女性升高。男性死亡年龄为19±6岁，女性死亡年龄为40±7岁，均为心力衰竭。所有女性都患上了致命性心肌病，尽管她们的症状较轻。我们发现了两种新的自噬空泡肌病(AVM)，它类似于Danon病，但在遗传上是不同的：成人起病的多器官受累和X连锁AVM类似先天性肌病。后一种疾病被定位于Xq28。Lc3本应在自噬小体和溶酶体融合后立即降解，但在X连锁的AVM中没有被降解，这表明降解过程中存在异常。我们确认编码UDP-GlcNAc 2-差向异构酶/ManNAc激酶(GNE/MNK)的GNE基因与遗传性包涵体肌病一样，是远端伴有边沿空泡的肌病(DMRV)的致病基因。在患者中发现的突变重组蛋白显示，Gne结构域突变的重组蛋白GNE活性降低，MNK突变的重组蛋白MNK活性降低，患者细胞内唾液酸化减少，加入ManNAc或NeuAc后恢复。我们的结果提示了治疗DMRV的可能性。

We clinicopathologically characterized 38 patients from 13 distinct families with genetically confirmed Danon disease. Cardiomyopathy and myopathy were seen in all men but mental retardation was present in 70% of men. Serum CK level is elevated in all men but only in 63% of women. Men died at age 19±6 years while women died at age 40±7 years, both due to cardiac failure. All women developed lethal cardiomyopathy even though they had milder symptoms. We identified two new forms of autophagic vacuolar myopathy (AVM) which resembles Danon disease but are genetically distinct : adult-onset AVM with multi-organ involvement and X-linked AVM resembling congenital myopathy. The latter disease was mapped to Xq28. LC3,which is supposed to be degraded immediately after the fusion between autophagosomes and lysosomes, was not degraded in the X-linked AVM, suggesting an abnormality in the degradation process.We identified that the GNE gene encoding UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK) is the causative gene for distal myopathy with rimmed vacuoles (DMRV) just as in hereditary inclusion body myopathy. Recombinant proteins with mutations found in patients showed that those with mutations in GNE domain had decreased GNE activity while those with MNK mutations had decreased MNK activity.Sialylation was decreased in patients' cells, which was recovered by adding ManNAc or NeuAc. Our results suggest a possibility of curative therapy for DMRV.