Adult-onset Niemann-pick type C disease - Clinical, biochemical, and genetic study
Adult-onset Niemann-pick type C disease - Clinical, biochemical, and genetic study
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DOI：
10.1001/archneur.1997.00550240084016
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发表时间：
1997-12-01
影响因子：
--
通讯作者：
Zeigler, M
中科院分区：
文献类型：
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作者：
Lossos, A;Schlesinger, I;Zeigler, M
背景：Niemann-Pick型C病是一种常染色体隐性遗传的神经代谢疾病，其起源未知，在大多数研究家族中定位于18q11 -12染色体。与鞘磷脂脂质病相反，在Niemann-Pick C型疾病中，成纤维细胞对外源性低密度脂蛋白（LDL）胆固醇的细胞内稳态反应受损。与异常LDL加工相关的疾病的生化异质性与各种临床表现有关，但成人发病的Niemann-Pick型C病很少见，尚未全面表征。目的：描述3例兄弟姐妹成人发病的尼曼-皮克C型病的临床、生化和遗传特征。设计和环境：三级保健中心的病例系列。患者：3例兄弟姐妹表现为垂直核上眼麻痹、共济失调和脾肿大的可变组合。脑磁共振成像显示小脑萎缩；脑干听觉诱发反应未见，骨髓检查显示典型泡沫细胞。患者年龄分别为20岁、26岁和28岁，属于由近亲健康父母所生的13名兄弟姐妹。方法：体外培养皮肤成纤维细胞进行外源性LDL胆固醇的酯化反应，并用filipin染色检测细胞内游离胆固醇。利用AC微卫星标记D18S40、D18S44、D18S480和D18S66进行基于聚合酶链反应的DNA连锁研究。结果：在4个半小时后，3例患者的成纤维细胞对诱导的胆固醇酯化反应有2396 ~ 58%的阻滞，游离胆固醇轻度~中度积累。DNA研究证实与主要的18q11-12 Niemann-Pick C型位点有关联，并鉴定出未受影响的携带者。结论：这些结果证实了该家族中生化影响最小的尼曼-匹克C型表型与成人发病疾病的诊断，并支持该年龄组轻度实验室和临床表现之间的相关性。
Background: Niemann-Pick type C disease is an autosomal recessive neurometabolic disorder of unknown origin mapped to chromosome 18q 11-12 in most of the studied families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C disease, fibroblasts are impaired in intracellular homeostatic responses to exogenous low-density lipoprotein (LDL) cholesterol. Biochemical heterogeneity of the disorder in relation to abnormal LDL processing is associated with various clinical presentations, but adult-onset Niemann-Pick type C disease is rare and has not been comprehensively characterized.Objective: To describe clinical, biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3 siblings.Design and Setting: Case series in a tertiary care center.Patients: The 3 siblings manifested a variable combination of vertical supranuclear ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable: and bone marrow examination disclosed typical foam cells. The patients were 20, 26, and 28 years old and belonged to a sibship of 13 born of consanguineous healthy parents.Methods: Esterification of exogenous LDL cholesterol in cultured skin fibroblasts and filipin staining for Free intracellular cholesterol. Polymerase chain reaction-based DNA linkage study using AC microsatellite markers D18S40, D18S44, D18S480, and D18S66.Results: Fibroblasts of the 3 patients showed a 2396 to 58% block in the induced cholesterol esterification after 4 1/2 hours and a mild to moderate accumulation of free choleslerol. DNA study demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and identified unaffected carriers.Conclusions: These results confirm the diagnosis of the least biochemically affected Niemann-Pick type C phenotype in this family with adult-onset disease and support a correlation between the mild laboratory and clinical findings in this age group.