尼曼匹克病C型诊疗新进展

尼曼匹克病C型(NPC)是一种常染色体隐性遗传的溶酶体脂质贮积病, 主要累及内脏器官和神经系统, 自婴幼儿至成人均可发病, 儿童期多见。新生儿期持续存在的胆汁淤积性黄疸、脾脏肿大、猝倒发作和垂直性核上性眼肌麻痹为该病的特征性表现, 因发病年龄不同, 首发的神经系统症状不一致, 临床有明显的异质性。NPC基因缺陷导致游离胆固醇转运障碍, 在细胞内大量沉积是疾病的始发因素, 细胞的自噬功能障碍、钙稳态失平衡、氧化应激等均参与疾病的病理生理过程。通过皮肤成纤维细胞培养发现异常沉积的游离胆固醇或行基因检查发现NPC的致病性突变可确诊该病。美格鲁特是唯一被批准上市的特效药物, 早期应用可以改善神经系统症状和延缓疾病的进展。

Research advances in diagnosis and therapy of Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disease associated with impaired intracellular cholesterol trafficking. A wide spectrum of clinical phenotype has been described, with a possible onset at all ages of life from the neonatal period to adulthood, more often in childhood. Typically, hepatosplenomegaly, dystaxia, dysphagia, dysarthria and dementia are presented in NPC patients. Neurologic symptoms vary according to the onset age, but prolonged neonatal cholestasis, splenomegaly, cataplexy and vertical supranuclear gaze palsy are more specific signs to the diagnosis of the disease. Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes. The definite diagnosis requires demonstration of unesterified cholesterol accumulated in fibroblasts cultured from skin biopsies or of pathogenic mutation of NPC1/NPC2 genes. Miglustat, the only available treatment approved to date, can alleviate neurological symptoms and slow disease progression when administered earlier.