NARCOLEPSY--MULTICENTER GENETIC AND FAMILY STUDY

据目前所知，发作性睡病是一种中枢神经系统疾病，其特征是睡眠和觉醒功能失调。嗜睡症并不罕见，每1000到2000名北美人中就有一人患有嗜睡症。虽然发作性睡病的遗传尚不清楚，但这种疾病与HLA6号染色体区域的亚型[HLADR15(DRB1*1501)和HLADQ6(DQB1*0602)]密切相关，但并不总是如此。因此，人类白细胞抗原相关和非人类白细胞抗原相关形式的存在表明发作性睡病至少是两种疾病。此外，人类白细胞抗原相关(H+)和非人类白细胞抗原相关(H-)形式均为散发性孤立病例(F-)和家族史阳性病例。(H+F-)、(H+F+)、(H-F-)、(H-F+)四种类型可能代表不同的病因。这项多中心临床研究拨款基于几个主要发现：(A)在几个人群中与相同的HLA等位基因的强烈关联表明这些等位基因/单倍型可能起作用，(B)只有70%的发作性睡病先证者具有HLA相关等位基因，他们往往没有患病的亲属，(C)大多数有多个受影响成员的家庭没有相关的HLA单倍型，(D)一对MZ双胞胎在临床症状方面不同，有/没有猝倒，以及(E)先证者的一级亲属的睡眠研究显示出轻微的睡眠障碍。我们的总体目标是：(I)通过顺序抽样计划确定另外113名先证者及其家人，该计划要求所有被选为先证者的患者都符合发作性睡病的严格临床标准(忽略HLA型)，并对先证者的所有一级亲属进行研究。以这种方式进行的严格抽样避免了由于选择“有趣的”家系而产生的偏见，并允许准确地评估发作性睡病患者具有相关的HLA型的比例、发作性睡病及其相关临床亚型的分离分析以及连锁分析。(2)确定两种发作性睡病家族形式的遗传方式。确定相关睡眠障碍症状(例如，白天过度嗜睡)的家族聚集性和遗传性。(Iii)利用先证者系列家系和选定的“高密度”家系，通过基因组DNA标记筛选和连锁分析，确定非人类白细胞抗原相关的家系形式的位置。(4)通过共分离和关联研究，研究人类白细胞抗原相关等位基因在发作性睡病中的作用。

Narcolepsy, as presently understood, is a central nervous system disorder characterized by disabling dysregulation of sleep and wakefulness. Narcolepsy is not rare and afflicts about 1 of every 1000 to 2000 North Americans. While the inheritance of narcolepsy is not known, the disorder is strongly, but NOT always, associated with subtypes of the HLA region chromosome 6 [HLA-DR15(DRB1*1501) and HLA-DQ6(DQBl*0602)]. Thus, the presence of HLA-associated and non-HLA associated forms indicates that narcolepsy is at least two disorders. Further, both the HLA associated (H+) and the non-HLA associated ( H - ) form occur as sporadic isolated cases (F-) and family history positive cases. It is possible that each of the four types, (H+F-),(H+F+), (H-F-), (H-F+) represent different etiologies. This Multi-Center Clinical Study grant is based on several key findings: (a) the strong association with the same HLA alleles across several populations indicates a probable role for these alleles/haplotypes, ( b ) only 70 percent of the probands with narcolepsy have the HLA-associated alleles and they tend not to have affected relatives, (c) the majority of families with multiple affected members do not have the associated HLA haplotypes, (d) one pair of MZ twins differs with respect to clinical symptoms, with/without cataplexy, and (e) sleep studies of first degree relatives of probands reveal subtle sleep disturbances. Our overall goals are: (i) Ascertain an additional 113 probands and their families via a sequential sampling scheme which requires that all patients selected as probands meet the strict clinical criteria for narcolepsy (ignoring HLA type) and that all first degree relatives of probands be studied. Rigorous sampling in this manner avoids bias due to selecting "interesting" families and permits accurate evaluation of the proportion of narcoleptics patients with the associated HLA types, segregation analysis for narcolepsy and the related clinical subtypes, as well as linkage analyses. (ii) Identify the modes of inheritance for the two familial forms of narcolepsy. Determine the familial aggregation and inheritance of the related sleep disorder symptoms (e.g., excessive daytime sleepiness). (iii) Using both the proband series families and selected "high density" pedigrees, map the location of the non-HLA associated familial form via a genome DNA marker screen and linkage analyses. (iv) Examine the role of the HLA-associated alleles in narcolepsy through both co-segregation and association studies.