Hedrich Katja, Hagenah Johann, Djarmati Ana, Hiller Anja, Lohnau Thora, Lasek Kathrin, Grünewald Anne, Hilker Rüdiger, Steinlechner Susanne, Boston Heather, Kock Norman, Schneider-Gold Christiane, Kress Wolfram, Siebner Hartwig, Binkofski Ferdinand, Lencer Rebekka, Münchau Alexander, Klein Christine
Department of Neurology, University of Lübeck, Germany.
Arch Neurol. 2006 Jun;63(6):833-8. doi: 10.1001/archneur.63.6.833.
Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear.
To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W).
Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating.
University of Lübeck.
Twenty family members.
The PINK1 genotype and PD status of all family members.
The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers.
Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.
尽管PTEN诱导的假定激酶1（PINK1）基因的纯合突变已明确与早发性帕金森病（PD）相关，但单个杂合PINK1突变的作用尚不清楚。
在一个大型德国家系（W家族）中研究纯合和杂合PINK1突变的作用。
PINK1突变分析以及由3名独立的运动障碍专家进行的标准化神经学和运动检查结果，包括盲法视频评分。
吕贝克大学。
20名家庭成员。
所有家庭成员的PINK1基因型和PD状态。
W家族的索引患者携带纯合无义突变（c.1366C>T；p.Q456X），其表现出的表型与特发性PD非常相似，但发病年龄为39岁。该家族共有4名受影响的纯合成员（年龄60 - 71岁；发病年龄39 - 61岁），6名有轻微或中度PD体征（受影响）且携带杂合突变的成员（年龄31 - 49岁），以及5名未受影响的杂合突变携带者（年龄34 - 44岁）。尽管没有杂合受影响的家庭成员意识到自己的体征（无症状），但临床发现明确，主要或仅出现在其优势右手侧，例如单侧手臂摆动减少或消失以及单侧僵硬。杂合成员都比受影响的纯合突变携带者年轻得多。
杂合PINK1突变可能易患PD，正如无症状突变携带者中多巴胺代谢减退的存在所暗示的那样。对我们的大型W家族进行长期随访提供了一个绝佳机会，可在以后的生活中进一步评估单个杂合PINK1突变的作用，这将对遗传咨询产生重大影响。
