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September 17, 2007 — 新研究認為，β-glucocerebrosidase(GBA)基因與巴金森氏症(Parkinson's disease，PD)有關，GBA突變增加了早發PD的風險。
研究發現有14%的PD病患有GBA突變，沒有此病者僅5%有此突變；再者，50歲之前發生PD的病患中，有此突變的有22%，50歲之後發生此病的人則有10%有此突變。
本研究的第一作者，哥倫比亞大學醫學中心Taub阿茲海默氏症與老化腦部研究中心的Lorraine Clark博士向Medscape表示，這些發現開啟了研究的新視野，可以引導出新的治療發展方向。
本研究登載於9月18日的神經學(Neurology)期刊。
Clark醫師表示，她的研究團隊決定探討GBA基因突變間的關係，是因為之前的研究顯示這些突變會導致高雪氏疾病(Gaucher disease)，這是常見於中歐猶太人的一種微脂體儲存異常疾病；成年人中，第一型為非神經病變型(non-neuronopathic) PD，有多種神經方面的表徵，包括巴金森氏症。
她表示，在這個研究中，主要進行的比較有二，我們比較了早發PD和遲發PD的病患，顯示GBA突變是早發的風險因素；此外，我們比較了猶太後裔和非猶太後裔的PD病患，顯示GBA突變是這兩組的共同風險因素，但是猶太族群的突變頻率比較高—超過兩倍。
本研究之贊助來自國家健康研究中心和巴金森氏症基金會，是第一個指出PD案例和控制對照組GBA基因序列的研究，共包括278位 PD案例和179位年紀與性別相仿之控制對照組，以及178位猶太案例和85位猶太控制組。
所有研究對象接受醫療史評估，「統一巴金森氏症分級量表（Unified Parkinson's Disease Rating Scale/UPDRS）」以及「簡易智能評估(Mini-Mental State Examination/MMSE)」。
研究者對278位案例和179位控制組的GBA基因進行所有表現序列之排序，整體而言，在PD案例辨識出9種突變，包括 84insGG、E326K、T369M、N370S、D409H、L444P、RecNcil，以及新發現的 P175P突變。
在90位50歲之前發生PD的病患中，GBA突變的頻率是22.2%，185個50歲之後發生PD的病患中，GBA突變的頻率是9.7%。
猶太後裔的PD案例中，16.9%有GBA基因突變，非猶太後裔者只有8%突變；校正評估時的年紀、性別、家族PD史、猶太血統等因素之後，作者報告指出，有GBA載體者的PD發生時間比沒有載體者提早1.7年。
雖然研究發現令人興奮，且最終可以引領PD的及早診斷和改進治療，但Clark醫師提醒，這仍是初步結果，她表示，我們需要在更大樣本的族群進一步研究，以便在任何臨床運用之前得以精準決定風險和發生率。
不過，她指出，GBA基因可以加入 parkin 和 LRRK2 基因作為PD病理學的主要角色，這兩個基因在一般族群皆有，特別是猶太人口。
作者之報告與研究無相關利益衝突。
GBA Mutations Linked to Early-Onset Parkinson's Disease
By Caroline Cassels
Medscape Medical News
September 17, 2007 — New research suggests that the ß-glucocerebrosidase (GBA) gene is a susceptibility gene for Parkinson's disease (PD) and that GBA mutations increase the risk of early-onset PD.
The study found that 14% of PD patients carry GBA mutations, compared with 5% of individuals without the disease. Furthermore, mutations were found in 22% of PD patients who developed the disease before the age of 50 years and in 10% of those who experienced disease onset after the age of 50.
"These findings open up a whole new avenue of research that could eventually lead to the development of new treatments," the study's first author Lorraine Clark, PhD, of Columbia University's Taub Institute for Research on Alzheimer's Disease and the Aging Brain, in New York, told Medscape.
The study is published in the September 18 issue of Neurology.
Dr. Clark said her team decided to investigate the link between GBA gene mutations because previous research has shown that they cause Gaucher disease, a liposomal storage disorder common among the Ashkenazi Jewish population. In adult-onset "nonneuronopathic", or type 1, PD, a range of neurologic manifestations can occur, including parkinsonism.
"In this study, we've essentially made 2 comparisons. We compared patients with early PD to those with late-onset PD, and showed that GBA mutations are a risk factor for early onset. In addition, we compared PD patients of Jewish ancestry with those not of Jewish ancestry and showed that such mutations are a risk factor in both groups, but that the frequency of mutations in the Jewish population is much higher — more than double," she said.
Funded by the National Institutes of Health, the study is the first to sequence the GBA gene in both PD cases and matched controls. It included 278 PD cases and 179 age- and sex-matched controls, including a subset of 178 Jewish cases and 85 Jewish controls.
All study participants underwent assessment, consisting of a medical history, Unified Parkinson's Disease Rating Scale (UPDRS), and Modified Mini-Mental State Examination (MMSE).
The investigators sequenced all exons of the GBA gene in 278 cases and 179 controls. Overall, 9 different mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, L444P, ReNcil, and a novel mutation P175P.
The frequency of GBA mutations was 22.2% in the 90 PD patients who developed the disease at age 50 years or younger and 9.7% among 185 individuals who developed PD after age 50.
Among those PD cases with Jewish ancestry, 16.9% had GBA gene mutations, compared with only 8% of non-Jewish controls. After adjustment for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, the authors report that PD onset was 1.7 years earlier in GBA carriers than non-carriers.
Although the study's findings are exciting and might ultimately lead to earlier diagnosis and improved treatment of PD, Dr. Clark cautioned that they are still preliminary.
"We need further studies in larger patient populations and in families to precisely determine the risk and penetrance before there would be any clinical applicability," she said.
Nevertheless, she added, the GBA gene will likely join the ranks of the parkin and LRRK2 genes as major players in PD etiology, both in the general population as a whole, and the Jewish population in particular.
The authors report no conflicts of interest related to the study.
Neurology. 2007;69:1270-1277.