Sidransky Ellen
Section on Molecular Neurogenetics, NIMH 35 Convent Drive MSC 3708, 1A-213, Bethesda, MD 20892-3708, USA.
Mol Genet Metab. 2004 Sep-Oct;83(1-2):6-15. doi: 10.1016/j.ymgme.2004.08.015.
Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype-phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed alpha-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.
戈谢病是一种由葡糖脑苷脂酶隐性遗传缺陷引起的疾病，也是最常见的鞘脂贮积症，有非神经病变型和神经病变型两种类型，临床表现多种多样。基因型与表型相关性研究表明，临床症状相似的患者之间存在显著的基因型异质性，而具有相同突变的患者之间表型差异很大。位于1号染色体长臂上的葡糖脑苷脂酶基因（GBA）周围区域基因特别丰富，其下游16 kb处有一个高度同源的假基因序列。GBA基因座内的重组事件促成了戈谢病某些突变的病因。对有非典型表现（包括帕金森症、肌阵挛性癫痫、心脏受累和胶样皮肤）的戈谢病患者进行研究，旨在确定导致这些表型的其他遗传或环境因素。最近的报告表明戈谢病与帕金森症之间存在关联，这为孟德尔疾病的杂合性作为复杂疾病的危险因素提供了一个例子。有少数基因型不同的戈谢病患者会出现早发性、难治性帕金森症。一组这类患者的神经病理学检查显示，在与戈谢病特别相关的脑区有α-突触核蛋白反应性路易小体。对这些先证者的家族研究表明，帕金森症在必然杂合子中的发病率可能更高。作为一项补充发现，对散发性帕金森病患者尸检样本中的GBA进行检测，发现14%的队列中GBA序列存在改变。这些研究提供了证据，表明葡糖脑苷脂酶改变可能导致患帕金森症的易感性。此外，这项研究还展示了像戈谢病这样的罕见单基因疾病的研究成果如何能够为更常见的多因素遗传病的病因提供一个窗口。
