From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
Neurology. 2020 Apr 21;94(16):e1702-e1715. doi: 10.1212/WNL.0000000000009290. Epub 2020 Mar 31.
To characterize subclinical abnormalities in asymptomatic heterozygote mutation carriers as markers of neurodegeneration.
Motor function, cognition, mood, sleep, and smell function were assessed in 20 first-degree heterozygous relatives of patients with Niemann-Pick disease type C (NPC) (13 male, age 52.7 ± 9.9 years). Video-oculography and abdominal ultrasound with volumetry were performed to assess oculomotor function and size of liver and spleen. NPC biomarkers in blood were analyzed. F-fluorodesoxyglucose PET was performed (n = 16) to detect patterns of brain hypometabolism.
NPC heterozygotes recapitulated characteristic features of symptomatic NPC disease and demonstrated the oculomotor abnormalities typical of NPC. Hepatosplenomegaly (71%) and increased cholestantriol (33%) and plasma chitotriosidase (17%) levels were present. The patients also showed signs seen in other neurodegenerative diseases, including hyposmia (20%) or pathologic screening for REM sleep behavior disorder (24%). Cognitive function was frequently impaired, especially affecting visuoconstructive function, verbal fluency, and executive function. PET imaging revealed significantly decreased glucose metabolic rates in 50% of participants, affecting cerebellar, anterior cingulate, parieto-occipital, and temporal regions, including 1 with bilateral abnormalities.
NPC heterozygosity, which has a carrier frequency of 1:200 in the general population, is associated with abnormal brain metabolism and functional consequences. Clinically silent heterozygous gene variations in may be a risk factor for late-onset neurodegeneration, similar to the concept of heterozygous mutations underlying Parkinson disease.
以亚临床异常作为无症状杂合突变携带者神经退行性变的标志物。
对 20 名尼曼-匹克病 C 型（NPC）患者的一级杂合亲属（13 名男性，年龄 52.7±9.9 岁）进行运动功能、认知、情绪、睡眠和嗅觉功能评估。进行视频眼动描记术和腹部超声检查以评估眼动功能和肝脾大小。分析血液中的 NPC 生物标志物。对 16 名患者进行 F-氟代脱氧葡萄糖 PET 以检测脑代谢低下的模式。
NPC 杂合子再现了 NPC 症状性疾病的特征性表现，并表现出 NPC 典型的眼动异常。存在肝脾肿大（71%）和胆甾三醇（33%）和血浆壳聚糖酶（17%）水平升高。患者还出现了其他神经退行性疾病的迹象，包括嗅觉减退（20%）或 REM 睡眠行为障碍的病理性筛查（24%）。认知功能经常受损，尤其是影响视觉构建功能、语言流畅性和执行功能。PET 成像显示 50%的参与者的葡萄糖代谢率明显降低，影响小脑、前扣带回、顶枕和颞叶区域，包括 1 例双侧异常。
在一般人群中杂合率为 1:200 的 NPC 杂合性与异常脑代谢和功能后果相关。可能是迟发性神经退行性变的风险因素，类似于帕金森病中杂合突变的概念。
