Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
Neurology. 2010 Jun 1;74(22):1798-805. doi: 10.1212/WNL.0b013e3181e0f79c.
While homozygous mutations in the PINK1 gene cause recessively inherited early-onset Parkinson disease (PD), heterozygous mutations have been suggested as a susceptibility factor.
To evaluate this hypothesis, 4 homozygous PINK1 patients with PD and 10 asymptomatic carriers of a single heterozygous mutation from a large German family (family W) were included in this study. Clinical follow-up of the heterozygous mutation carriers 3 years after the initial visit included a detailed videotaped neurologic examination using the Unified Parkinson's Disease Rating Scale III protocol and smell and color discrimination testing. At follow-up, PET with 18-fluorodopa (FDOPA) of 13 family members was obtained in order to evaluate the clinical phenotype in light of nigostriatal dopaminergic functioning. The clinical and PET data were compared to those of healthy controls.
While there was mild worsening of clinical signs in previously affected heterozygous mutation carriers upon follow-up, 3 additional individuals had newly developed signs of possible PD. Hyposmia was found in 7 of the heterozygous mutation carriers, diminished color discrimination in 4. The homozygous mutation carriers who were all definitely affected with PD showed a severe, 60% decrease of caudate and putaminal FDOPA uptake; heterozygous offspring also had a significant 20% putaminal FDOPA uptake reduction compared to controls.
Our findings strengthen the hypothesis that heterozygous PINK1 mutations act as a susceptibility factor to develop at least subtle Parkinson disease motor and nonmotor signs, as supported by the finding of a reduced striatal dopaminergic FDOPA uptake not only in homozygous but also, albeit to a lesser extent, in heterozygous mutation carriers.
虽然 PINK1 基因突变纯合子可导致常染色体隐性遗传的早发性帕金森病（PD），但杂合子突变已被认为是一个易感因素。
为了验证这一假说，我们纳入了来自一个德国大家族（家族 W）的 4 名 PD 纯合 PINK1 患者和 10 名携带单个杂合突变的无症状携带者。在首次就诊后 3 年对杂合子突变携带者进行临床随访，包括使用统一帕金森病评定量表 III 协议进行详细的录像神经检查以及嗅觉和颜色辨别测试。在随访时，对 13 名家族成员进行了 18-氟多巴（FDOPA）PET，以根据黑质纹状体多巴胺能功能评估临床表型。将临床和 PET 数据与健康对照组进行比较。
虽然先前受影响的杂合子突变携带者在随访期间临床症状有轻微恶化，但另外 3 名个体出现了新的可能 PD 症状。7 名杂合子突变携带者存在嗅觉减退，4 名存在颜色辨别能力下降。所有明确患有 PD 的纯合子突变携带者的尾状核和壳核 FDOPA 摄取均出现严重的 60%下降；杂合子后代的壳核 FDOPA 摄取也与对照组相比显著减少 20%。
我们的研究结果进一步支持了杂合 PINK1 突变作为易感性因素导致至少轻微帕金森病运动和非运动症状的假说，这一假说得到了纹状体多巴胺 FDOPA 摄取不仅在纯合子，而且在杂合子突变携带者中均减少的发现的支持，尽管程度较轻。
