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

我们对来自13个不同家族的38例经遗传证实的Danon病患者进行了临床病理鉴定。所有男性都有心肌病和肌病，但70%的男性存在智力低下。血清CK水平在所有男性中升高，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的心肌病，即使她们的症状较轻。我们发现了两种新的自噬性空泡性肌病（AVM），它们类似于Danon病，但在遗传上是不同的：成人发病的多器官累及AVM和类似于先天性肌病的x连锁AVM。后一种疾病定位于Xq28。LC3本应在自噬体与溶酶体融合后立即降解，但在x连锁AVM中未被降解，提示降解过程异常。我们发现编码UDP-GlcNAc 2- epimase /ManNAc激酶（GNE/MNK）的GNE基因与遗传性包涵体肌病一样，是边缘空泡远端肌病（DMRV）的致病基因。在患者中发现的重组蛋白突变表明，GNE结构域突变的患者GNE活性降低，而MNK突变的患者MNK活性降低。患者细胞中的唾液酰化降低，通过添加ManNAc或NeuAc恢复。我们的结果提示了DMRV治疗的可能性。

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.