ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease
ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease
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DOI：
10.1212/01.wnl.0000260963.08711.08
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发表时间：
2007-05-08
期刊：
影响因子：
9.9
通讯作者：
Bonifati, V.
中科院分区：
文献类型：
--
作者：
Di Fonzo, A.;Chien, H. F.;Bonifati, V.
目的：评估青少年型帕金森综合征（发病年龄<21岁）或早发型（21 - 40岁）帕金森病（YOPD）患者中ATP13A2基因突变的患病率、性质及相关表型。方法：我们研究了46例患者，大多数来自意大利或巴西，其中包括11例青少年型帕金森综合征患者和35例YOPD患者。33例为散发性病例，13例有符合常染色体隐性遗传的阳性家族史。42例仅有帕金森症状，而4例（均为青少年发病）有多系统受累。从基因组DNA对ATP13A2基因的整个编码区（29个外显子）及外显子 - 内含子边界进行测序。结果：在一名来自巴西的青少年型帕金森综合征散发性病例中发现了一种新的纯合错义突变（Gly504Arg）。该患者12岁发病，对左旋多巴有反应的严重运动不能 - 强直型帕金森综合征，有左旋多巴诱导的运动波动和异动症，严重的视幻觉以及核上性垂直凝视麻痹，但无锥体束缺陷和痴呆。脑部CT扫描显示中度弥漫性萎缩。此外，两例无典型特征的意大利YOPD患者携带一种新的单杂合状态的错义突变（Thr12Met，Gly533Arg）。结论：我们证实ATP13A2纯合突变与人帕金森综合征相关，并通过描述该基因在一名表型比最初与ATP13A2突变相关的表型（库夫尔 - 拉克布综合征）更温和的患者中的纯合错义突变，扩展了相关的基因型和临床谱。我们的数据还表明，ATP13A2单杂合突变可能与YOPD患者的病因相关，有必要在帕金森病中对该基因进行进一步研究。
Objective: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset < 21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). Methods: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. Results: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. Conclusions: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.