Jih Kang-Yang, Hsu Ting-Rong, Fuh Jong-Ling, Lee Tse-Hao, Lin Yung-Shuan, Fang Shih-Yu, Liao Yi-Chu, Lee Yi-Chung
Department of Neurology, Taipei Veterans General Hospital, #201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112201, Taiwan.
Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
Alzheimers Res Ther. 2025 Apr 30;17(1):96. doi: 10.1186/s13195-025-01744-4.
Mutations in the presenilin 1 gene (PSEN1) are well-known causes of early-onset familial Alzheimer's disease, but they can also present with atypical phenotypes such as pure spastic paraparesis. This study aims to investigate the clinical and genetic features of PSEN1 variants in patients mainly manifested with hereditary spastic paraparesis (HSP)-like phenotypes.
Mutational analysis was performed in 242 unrelated Taiwanese patients with clinically suspected HSP using a targeted resequencing panel covering the entire coding regions of PSEN1, along with 76 genes associated with HSP and 55 genes linked to HSP-like phenotypes.
Two of the 242 patients (0.8%) were found to carry the pathogenic PSEN1 variants (p.P284S and p.F386S). In addition to the two probands, six affected family members were further identified to have the pathogenic PSEN1 variants. Six of these eight patients (75%) presented with spastic paraparesis as their initial symptom, one suffered from cognitive decline, and another manifested with personality change. The average age of symptom onset was 40.1 ± 4.8 years. Except for one patient, cognitive decline developed in all subjects before the last follow-up. For the patient carrying the PSEN1 p.P284S variant, amyloid deposition in bilateral lateral temporal, frontal, precuneus, and parietal regions was evident by amyloid PET, but no hippocampus atrophy was found on brain MRI. For the three patients carrying the PSEN1 p.F386S variant, brain atrophy with dilated ventricles were noted in the patient initially presented with personality changes, but normal MRI findings in the other two patients manifested with spastic paraparesis.
Spastic paraparesis can be the initial and isolated clinical presentation of PSEN1 mutations. We identified eight patients from two families carrying a pathogenic PSEN1 variant, all but one carriers have developed cognitive symptoms. PSEN1 related spastic paraparesis usually has a later age of onset compared to other common hereditary spastic paraparesis subtypes, and the family history of early onset dementia might be obscure. Our findings suggested that PSEN1 variants are a rare cause of spastic paraparesis but should be considered especially in those with a later age of onset.
早老素1基因（PSEN1）突变是早发型家族性阿尔茨海默病的常见病因，但也可表现为非典型表型，如单纯性痉挛性截瘫。本研究旨在调查主要表现为遗传性痉挛性截瘫（HSP）样表型的患者中PSEN1变异体的临床和遗传特征。
对242名临床疑似HSP的非相关台湾患者进行突变分析，使用靶向重测序面板覆盖PSEN1的整个编码区，以及76个与HSP相关的基因和55个与HSP样表型相关的基因。
242名患者中有2名（0.8%）被发现携带致病性PSEN1变异体（p.P284S和p.F386S）。除两名先证者外，另外六名受影响的家庭成员也被鉴定携带致病性PSEN1变异体。这八名患者中有六名（75%）以痉挛性截瘫为首发症状，一名患有认知功能下降，另一名表现为性格改变。症状首发的平均年龄为40.1±4.8岁。除一名患者外，所有受试者在最后一次随访前均出现认知功能下降。对于携带PSEN1 p.P284S变异体的患者，淀粉样蛋白PET显示双侧颞叶外侧、额叶、楔前叶和顶叶区域有淀粉样蛋白沉积，但脑MRI未发现海马萎缩。对于三名携带PSEN1 p.F386S变异体的患者，最初表现为性格改变的患者脑萎缩伴脑室扩张，而另外两名表现为痉挛性截瘫的患者MRI结果正常。
痉挛性截瘫可能是PSEN1突变的首发和孤立临床表现。我们从两个家族中鉴定出八名携带致病性PSEN1变异体的患者，除一名携带者外，所有患者均出现认知症状。与其他常见的遗传性痉挛性截瘫亚型相比，PSEN1相关的痉挛性截瘫通常发病年龄较晚，且早发性痴呆的家族史可能不明显。我们的研究结果表明，PSEN1变异体是痉挛性截瘫的罕见病因，但在发病年龄较晚的患者中应特别考虑。
