NARCOLEPSY--MULTICENTER GENETIC AND FAMILY STUDY

嗜睡症，如目前所理解的，是一种中枢神经系统疾病，其特征在于睡眠和觉醒的失能性失调。 嗜睡症并不罕见，大约每1000到2000个北美人中就有一个患有嗜睡症。 虽然嗜睡症的遗传尚不清楚，但该疾病与HLA区域染色体6的亚型[HLA-DR 15（DRB 1 *1501）和HLA-DQ 6（DQB 1 *0602）]强烈相关，但并不总是如此。 因此，HLA相关和非HLA相关形式的存在表明发作性睡病是至少两种疾病。 此外，HLA相关（H+）和非HLA相关（H -）形式均作为散发性孤立病例（F-）和家族史阳性病例出现。这四种类型（H+F-）、（H+F+）、（H-F-）、（H-F+）中的每一种可能代表不同的病因。这项多中心临床研究拨款是基于几个关键发现：（a）在几个群体中与相同HLA等位基因的强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，并且他们往往没有受影响的亲属，（c）大多数具有多个受影响成员的家族不具有相关的HLA单倍型，（d）一对MZ双胞胎在临床症状方面不同，有/没有cataelia，和（e）先证者一级亲属的睡眠研究揭示了轻微的睡眠障碍。我们的总体目标是：（i）通过序贯抽样方案确定另外113名先证者及其家属，该方案要求所有被选为先证者的患者符合严格的嗜睡症临床标准（忽略HLA类型），并对先证者的所有一级亲属进行研究。 以这种方式进行严格的采样避免了由于选择“感兴趣的”家族而产生的偏倚，并允许准确评估具有相关HLA类型的发作性睡病患者的比例、发作性睡病和相关临床亚型的分离分析以及连锁分析。(ii)鉴别两种家族性发作性睡病的遗传方式。 确定相关睡眠障碍症状的家族聚集和遗传（例如，白天过度嗜睡）。(iii)利用先证者系列家系和选择的“高密度”家系，通过基因组DNA标记筛选和连锁分析，绘制非HLA相关家族形式的位置。(iv)通过共分离和关联研究来检验HLA相关等位基因在嗜睡症中的作用。

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.