Supplementary Material for: Early-Onset Vascular Dementia in a 43-Year-Old Man with Accelerated Atherosclerotic Disease, Elevated Lipoprotein (a), and a Missense DNAJC5 Variant with Potential Association to Adult-Onset Ceroid Lipofuscinosis

Early-onset dementia is defined as dementia occurring prior to the age of 65. Given its impact on physical, mental, and socioeconomic well-being, it is crucial to identify modifiable risk factors. Here, we report a 43-year-old man with early-onset dementia associated with elevated lipoprotein (a) and a missense variant in the DNAJC5 gene. He presented to the hospital with memory loss and multiple cerebrovascular infarcts. Eight months prior, an MRI revealed small acute and subacute infarcts involving the left PCA for which he was treated with antiplatelet agents and a statin. Three months later, he was readmitted for progressive memory loss. CT imaging showed evolving and new infarcts compared to prior scans. A cardiac echocardiogram excluded thrombus and PFO, and he was diagnosed with early vascular dementia. He was readmitted again 5 months later with additional evaluation revealing multifocal moderate to severe stenosis and irregularities involving the bilateral ICA and bilateral PCAs. MRI showed more pronounced infarcts compared to a previous MRI as well as new infarcts. CSF studies, VDRL, RF, ANA, ANCA, homocysteine, and MMA levels were normal. Lipoprotein (a) was found to be markedly elevated, and genetic testing revealed a missense variant of the DNAJC5 gene, the mutation of which is associated with ceroid lipofuscinosis. In conclusion, in patients with early-onset dementia and evidence of accelerated atherosclerosis, it is reasonable to measure Lp(a) and consider testing for variants in genes such as DNAJC5 and others, particularly when disease severity appears unexplained by known risk factors or circumstances.

早发性痴呆（Early-onset dementia）被定义为发病年龄早于65岁的痴呆。鉴于其对躯体、精神及社会经济健康的多重影响，识别可干预的危险因素具有重要临床意义。本文报告1例43岁男性早发性痴呆患者，其发病与脂蛋白(a)（lipoprotein (a)）水平升高及DNAJC5基因错义变异相关。患者因记忆力减退及多发脑血管梗死首次就诊。8个月前，患者的磁共振成像（MRI）检查显示左侧大脑后动脉（PCA）供血区存在急性及亚急性小梗死灶，遂予抗血小板药物（antiplatelet agents）及他汀类药物（statin）治疗。3个月后，患者因进行性记忆力减退再次入院，计算机断层扫描（CT）显示相较于此前影像，梗死灶呈进展性改变且出现新发梗死灶。心脏超声心动图（cardiac echocardiogram）检查排除了血栓（thrombus）及卵圆孔未闭（PFO），患者被诊断为早发性血管性痴呆。5个月后患者第三次入院，完善额外检查后发现双侧颈内动脉（ICA）及双侧大脑后动脉（PCA）存在多灶性中至重度狭窄伴管壁不规则。本次磁共振成像显示，相较于此前检查，梗死灶范围更广泛，同时可见新发梗死灶。脑脊液（CSF）检查、性病研究实验室试验（VDRL）、类风湿因子（RF）、抗核抗体（ANA）、抗中性粒细胞胞浆抗体（ANCA）、同型半胱氨酸（homocysteine）及甲基丙二酸（MMA）水平均未见异常。实验室检测发现脂蛋白(a)水平显著升高，基因测序结果显示DNAJC5基因存在错义变异，该突变与蜡样脂褐质沉积症（ceroid lipofuscinosis）的发生相关。综上，对于存在早发性痴呆且伴加速性动脉粥样硬化证据的患者，检测脂蛋白(a)（Lp(a)）水平并考虑筛查DNAJC5等相关基因的变异具有临床合理性，尤其当疾病严重程度无法通过已知危险因素或临床背景解释时。