Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
J Neurol Sci. 2013 Mar 15;326(1-2):75-82. doi: 10.1016/j.jns.2013.01.017. Epub 2013 Feb 13.
Presenile dementia may be caused by a variety of different genetic conditions such as familial Alzheimer's disease, prion disease as well as several hereditary metabolic disorders including adult onset neuronal ceroid lipofuscinosis. We report a multigenerational family with autosomal dominant presenile dementia harboring a cerebellar phenotype. Longitudinal clinical work-up in affected family members revealed ataxia accompanied by progressive cognitive decline, rapid loss of global cognition, memory, visuospatial and frontal-executive functions accompanied by progressive motor deterioration and early death. Linkage analysis and exome sequencing identified the p.S170F mutation of Presenilin 1 in all affected individuals, which is known to be associated with very early onset Alzheimer's disease. Additional search for potentially modifying variants revealed in all affected individuals of the third generation a paternally inherited variant p.A58V (rs17571) of Cathepsin D which is considered an independent risk factor for Alzheimer's disease. Involvement of cerebellar and brainstem structures leading to functional decortication in addition to rapid progressive presenile dementia in this PSEN1 family may therefore indicate an epistatic effect of the p.A58V Cathepsin D variant on the deleterious course of this disease.
早老性痴呆症可能由多种不同的遗传条件引起，如家族性阿尔茨海默病、朊病毒病以及几种遗传性代谢紊乱，包括成年起病的神经元蜡样脂褐质沉积症。我们报告了一个具有常染色体显性遗传早老性痴呆症和小脑表型的多代家族。对受影响家族成员的纵向临床评估显示，出现共济失调，伴有进行性认知能力下降、全球认知能力、记忆力、视空间和额叶执行功能迅速丧失，伴有进行性运动恶化和早逝。连锁分析和外显子组测序在所有受影响的个体中发现了早老素 1 的 p.S170F 突变，该突变已知与早发性阿尔茨海默病有关。对潜在修饰变体的进一步搜索发现，第三代所有受影响的个体都携带一种父系遗传的组织蛋白酶 D 的 p.A58V 变体（rs17571），该变体被认为是阿尔茨海默病的一个独立危险因素。小脑和脑干结构的参与导致功能性皮质切除术，加上这种 PSEN1 家族中快速进行性早老性痴呆症，因此可能表明 p.A58V 组织蛋白酶 D 变体对这种疾病的有害病程具有上位效应。
