Inserm U1127, CNRS UMR 7225, UPMC université Paris 06 UMR S1127, Sorbonne université, institut du cerveau et de la moelle épinière, ICM, 75013 Paris, France.
Inserm U1127, CNRS UMR 7225, UPMC université Paris 06 UMR S1127, Sorbonne université, institut du cerveau et de la moelle épinière, ICM, 75013 Paris, France; Département de génétique, hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France.
Rev Neurol (Paris). 2018 Nov;174(9):628-643. doi: 10.1016/j.neurol.2018.08.004. Epub 2018 Sep 21.
The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets.
帕金森病（PD）的病因在大多数患者中仍然未知。自 1997 年以来，随着第一个已知的导致 PD 的遗传突变在 SNCA 基因中被描述，许多其他具有孟德尔遗传的基因已经被确定。我们总结了自 1997 年以来文献中报道的与 27 个基因相关的遗传、临床和神经病理学发现，这些基因要么与常染色体显性（AD）遗传相关：LRRK2、SNCA、VPS35、GCH1、ATXN2、DNAJC13、TMEM230、GIGYF2、HTRA2、RIC3、EIF4G1、UCHL1、CHCHD2 和 GBA；要么与常染色体隐性（AR）遗传相关：PRKN、PINK1、DJ1、ATP13A2、PLA2G6、FBXO7、DNAJC6、SYNJ1、SPG11、VPS13C、PODXL 和 PTRHD1；要么与 X 连锁遗传相关：RAB39B。基因之间的临床和神经病理学变异性很大。LRRK2 突变携带者的表型与特发性 PD 相似，而根据 SNCA 突变的不同，表型范围从早发性典型 PD 到路易体痴呆，包括许多其他非典型形式。DNAJC6 无义突变导致非常严重的表型，而 DNAJC6 错义突变导致更典型的表型。PRKN、PINK1 和 DJ1 病例表现为典型的早发性 PD，进展缓慢，而其他 AR 基因则表现为严重的非典型帕金森病。RAB39B 导致女性的典型表型和男性的可变表型。GBA 是 PD 的一个主要危险因素，常与痴呆有关。越来越多的报告基因被描述为因果基因（DNAJC13、TMEM230、GIGYF2、HTRA2、RIC3、EIF4G1、UCHL1 和 CHCHD2），仍在等待复制或实际上尚未复制，因此对其致病性提出了质疑。需要对大量病例和对照进行表型数据收集和下一代测序，以区分不完全外显的致病性显性突变与罕见的非致病性变体。尽管已知的基因导致少数 PD 病例，但它们的鉴定将有助于更好地了解其病理机制，并可能有助于患者护理、遗传咨询、预后确定和寻找新的治疗靶点。
