BACKGROUND AND PURPOSE Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 (PSEN1). METHODS Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing. RESULTS Four patients, aged 25-45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in PSEN1 (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing. CONCLUSION Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.

中文翻译：

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Presenilin-1 突变是原发性侧索硬化样综合征的原因。

背景和目的原发性侧索硬化症 (PLS) 是一种进行性上运动神经元 (UMN) 疾病。PLS 是肌萎缩侧索硬化 (ALS) 谱系的一部分，还是包含不同神经退行性疾病的综合征，尚有争议。最近，有人提出了新的 PLS 诊断标准。我们描述了两个谱系的四名患者，符合明确的 PLS 标准并在早老素 1 (PSEN1) 中具有两种不同的突变。方法 患者接受神经学和神经心理学检查、MRI、18F-氟脱氧葡萄糖正电子发射断层扫描 (FDG-PET)、淀粉样蛋白相关生物标志物和下一代测序 (NGS) 测试。结果 4 名年龄在 25-45 岁的患者出现进行性 UMN 综合征，符合明确 PLS 的临床标准。在疾病的第一年认知症状和体征轻微或不存在，但在病程后期出现或进展。脑部 MRI 显示两个兄弟姐妹有微出血，但运动皮层中没有与铁相关的低信号。脑 FDG-PET 显示不同区域的低代谢，包括运动皮层和额颞叶。用脑脊液 (CSF) 或成像生物标志物证实淀粉样蛋白沉积。在 NGS 测试中发现了 PSEN1 中的两个可能的杂合致病突变（p.Pro88Leu 和 p.Leu166Pro）。结论 临床定义的 PLS 是一种包含不同神经退行性疾病的综合征。NGS 检测应该是 PLS 患者诊断检查的一部分，至少在那些有危险信号的患者中，例如早发性、认知障碍、