Clinical and Neuropsychological Investigations in Batten Disease

描述(申请人提供)：神经性蜡样脂褐素沉积症(NCLS，巴顿病)是一种遗传性、常染色体隐性遗传性溶酶体储存性疾病。虽然NCL相对罕见，但儿童变种是儿童最常见的神经退行性疾病，在美国约有1：25,000人患病，全球发病率高达1：12,500。NCL变种主要根据其不同的发病年龄和症状进展的速度来区分。少年型NCL(JNCL)是由CLN-3基因突变引起的一种较为常见的NCL。JNCL的症状出现在5至8岁之间，进展缓慢，直到生命的第二或第三个十年死亡。JNCL最常见的早期症状是视力丧失、癫痫发作、痴呆、行为障碍和运动技能受损。随着疾病的发展，孩子变得越来越残疾，照顾者的负担很大。关于JNCL自然历史的定量资料很少。众所周知，JNCL包括广泛的神经、神经心理和行为/精神症状。随着疾病的发展，会逐渐丧失言语、语言、运动技能和自我照顾技能。在一些人中，攻击性行为、焦虑、幻觉、痴迷或个性变化是突出的。然而，目前还不知道每种类型的症状对总体残疾和照顾者负担的贡献程度。也不知道癫痫发作和癫痫控制在多大程度上导致残疾。此外，还不知道基因对表型变异的影响有多大。我们提出了三个具体目标来定量确定JNCL的自然病史，表征JNCL的神经心理和行为表型，建立JNCL评定量表的效度和可靠性，以及确定JNCL个体表型和基因之间的相关性。该项目的成功完成将为推进这一毁灭性疾病的临床试验提供必要的框架。虽然JNCL是一种罕见的疾病，但我们的研究具有广泛的意义，可以推广到儿童其他退行性神经疾病的研究，并为这些疾病的翻译临床试验做准备。

DESCRIPTION (provided by applicant): The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited, autosomal recessive lysosomal storage diseases. Although the NCLs are relatively rare, the childhood variants represent the most common neurodegenerative disorders of childhood, affecting approximately 1:25,000 in the U.S. and with an incidence worldwide as high as 1:12,500. NCL variants are distinguished mainly by their different ages of onset and the rate at which symptoms progress. Juvenile NCL (JNCL), due to the CLN-3 mutation, is one of the more common forms of NCL. Symptom onset for JNCL is between ages 5 to 8, with slow progression until death in the 2nd or 3rd decade of life. The most common early symptoms of JNCL are vision loss, seizures dementia, behavioral difficulties, and impaired motor skills. As the disease progresses, the child becomes increasingly disabled and there is a substantial caregiver burden. There are few quantitative data on the natural history of JNCL. It is known that JNCL includes a broad range of neurological, neuropsychological, and behavioral/psychiatric symptoms. There is progressive loss of speech, language, motor skills, and self-care skills as the disease progresses. In some individuals, aggressive behavior, anxiety, hallucinations, obsessions, or personality changes are prominent. However, it is not known to what degree each type of symptoms contributes to the overall disability and caregiver burden. It is also not known to what degree the seizures and seizure control contributes to disability. Further, it is not known to what extent genotype influences phenotypic variability. We propose three specific aims to determine the natural history of JNCL quantitatively, to characterize the neuropsychological and behavioral phenotype of JNCL, to establish validity and reliability of a rating scale for JNCL, and to determine correlations between phenotype and genotype of individual JNCL subjects. Successful completion of this project will provide the necessary framework for moving forward with clinical trials in this devastating disease. Although JNCL is a rare disease, our research has implications that can be generalized to the study of other degenerative neurologic disorders in children and for preparing translational clinical trials in these diseases.