Molecular Genetics of Kleine-Levin Syndrome

描述（由申请人提供）：Kleine-Levin综合征（KLS）是一种孤儿神经精神疾病，通常始于儿童或青春期。其主要表现是中枢神经系统起源的周期性嗜睡（睡眠量急剧增加）。这些嗜睡症的发作也与认知障碍和行为异常有关，如食欲过盛、易怒和性欲亢进。对这种疾病的病因缺乏系统的研究，由于这种疾病的致残性和缺乏有效的治疗方法，迫切需要进行系统的研究。KLS传统上被认为是一种非常罕见的疾病，在过去的50年里，全球报告的病例不到200例。它现在似乎比以前预期的更普遍。我们已经通过在美国、欧洲和以色列的积极招募确定并描述了另外100多个病例。这种疾病的原因尚不清楚，但可能涉及一个主要基因。KLS在犹太人群中可能不成比例地频繁发生，因为该国报告了最大的病例系列，占全球报告的所有患者的近六分之一。我们最近来自美国的数据也表明，在德系犹太人中KLS的确定性增加，这表明遗传创始人效应。我们的招募结果进一步支持遗传因素的作用，因为我们在104名先证者中确定了5个家族性病例（4.8%），扩展了过去40年文献中发表的多重家族病例报告。基于上述情况，并由于事实上，这将是很难收集足够的多重家庭进行传统的连锁研究，我们建议进行全基因组关联研究，在200 trios，以确定一个主要的KLS遗传易感性位点。将对40个犹太三人组进行亚组分析，以利用潜在的创始人效应。我们将通过精细作图和基因内容的计算机分析来研究相关区域。最后，我们将确定和表征关键区域内的候选基因，并确定KLS患者的变异。Kleine-Levin综合征易感基因的鉴定将有助于揭示这种有趣疾病的病理生理学。这也可能导致对睡眠，食欲和其他本能行为控制的新见解，并在其他周期性神经精神疾病中具有潜在的应用。

DESCRIPTION (provided by applicant): Kleine-Levin Syndrome (KLS) is an orphan neuropsychiatric disorder, typically starting in childhood or adolescence. Its primary manifestation is a periodic hypersomnia (dramatic increases in sleep amounts) of central nervous system origin. These bouts of hypersomnia are also associated with cognitive disturbances and behavioral abnormalities such as hyperphagia, irritability and hypersexuality. Systematic research on the cause of this disease is inexistent, and is urgently needed due to the disabling nature of the disease and the lack of effective treatments. KLS has traditionally been considered an exceptionally rare disease, with fewer than 200 cases reported worldwide over the past 50 years. It now appears to be more common than previously expected. We have identified and characterized over 100 additional cases by active recruitment in the United States, Europe and Israel. The cause of this disease is unknown, but likely involves a major gene. KLS may be disproportionately frequent in the Jewish population, as the largest case series has been reported in this country, accounting for nearly one sixth of all patients reported worldwide. Our recent data from the United States also indicates increased ascertainment of KLS in Ashkenazi Jews, suggesting a genetic founder effect. Results of our recruitment further support the action of genetic factors, as we identified 5 familial cases among our 104 probands (4.8%), extending on case reports of multiplex families published in the literature over the last 40 years. Based on the above and due to the fact that it would be difficult to gather enough multiplex families to conduct traditional linkage studies, we propose to conduct a genome wide association study in 200 trios to identify a major KLS genetic susceptibility locus. A sub-analysis will be performed on 40 Jewish trios to take advantage of the potential founder effect. We will pursue regions of association through fine mapping and in silico analysis of gene content. Finally, we will identify and characterize candidate genes within the critical regions and identify variants in KLS patients. Identification of a Kleine-Levin Syndrome susceptibility locus will help to unravel the pathophysiology of this intriguing disease. This may also lead to novel insights in the control of sleep, appetite and other instinctual behaviors, with potential applications in other periodic neuropsychiatric disorders.