The Third Affiliated Hospital of Shenzhen University, Cognitive Impairment Ward of Neurology Department, Shenzhen, Guangdong Province, China.
Medicine (Baltimore). 2021 Apr 23;100(16):e25585. doi: 10.1097/MD.0000000000025585.
The sortilin-related receptor 1 gene (SORL1) encodes a key protein (SORLA) involved in the pathophysiology of Alzheimer disease (AD). SORLA also mediates a trophic pathway that acts through glial cell line-derived neurotrophic factor (GDNF), a critical survival factor for the midbrain dopaminergic (DA) neurons.
Four patients presented to our hospital with complaints of progressive memory decline, who developed extrapyramidal signs (EPS) and psychiatric symptoms.
All 4 patients were diagnosed with AD based on their symptoms, findings from cranial magnetic resonance imaging, and cerebrospinal fluid analysis.
We also performed whole-exome sequencing (WES) and found 4 novel mutations in SORL1. Donepezil, rivastigmine, memantine, madopar, quetiapine, and risperidone were administrated as therapy.
The four mutations would change the thermal stability of SORLA domain. This could be associated with parkinsonian and psychiatric features in AD. These patients showed improvements in parkinsonian and psychiatric features.
These cases suggest that SORL1 mutations might result in aggregation of a-synuclein through altered function of GDNF and further lead to appearance of core dementia with Lewy bodies features.
早老素相关蛋白 1 基因（SORL1）编码一种关键蛋白（SORLA），该蛋白参与阿尔茨海默病（AD）的病理生理学。SORLA 还介导神经胶质细胞源性神经营养因子（GDNF）的营养途径，GDNF 是中脑多巴胺（DA）神经元的关键存活因子。
4 名患者因进行性记忆减退就诊，伴有锥体外系体征（EPS）和精神症状。
根据症状、头颅磁共振成像和脑脊液分析，4 名患者均被诊断为 AD。
我们还进行了全外显子组测序（WES），发现 SORL1 中有 4 个新突变。给予多奈哌齐、加兰他敏、美金刚、美多巴、喹硫平、利培酮治疗。
这 4 个突变会改变 SORLA 结构域的热稳定性。这可能与 AD 的帕金森和精神特征有关。这些患者的帕金森和精神特征有所改善。
这些病例表明，SORL1 突变可能通过改变 GDNF 的功能导致α-突触核蛋白聚集，进而导致具有路易体特征的核心痴呆出现。
