PDF(Pubmed)
Abstract：
The genetic bases of Alzheimer\'s disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.
摘要：
对阿尔茨海默病(AD)和额颞叶痴呆(FTD)的遗传基础进行了全面研究,对于未分类为这些诊断的非典型病例，情况并非如此。在本研究中,我们的目标是有助于对由尿素循环基因突变引起的高氨血症导致的非AD和非FTD痴呆的发展的分子理解.通过对90例患者进行合并的全外显子组测序（WES），并通过在常染色体基因中寻找尿素循环途径的酶或转运蛋白的罕见致病变异来进行分析。该调查返回了导致I型瓜氨酸血症的两种罕见致病性编码突变：rs148918985，p.Arg265Cys，C>T;rs121908641,p.Gly390Arg,精氨酸琥珀酸合酶1(ASS1)基因中的G>A。p.Arg265Cys变体导致酶缺乏，而p.Gly390Arg使酶失活。在简单或复合杂合性中发现的这些变体可导致I型瓜氨酸血症的迟发性形式，与高氨含量有关，这可能导致大脑功能障碍，从而导致痴呆症的发展。引起尿素循环障碍的突变的存在可用于早期开始抗高氨血症治疗，以防止神经毒性作用。
