背景:分拣素相关受体1基因(SORL1)编码参与阿尔茨海默病(AD)病理生理学的关键蛋白(SORLA)。SORLA还通过神经胶质细胞系衍生的神经营养因子(GDNF)介导营养途径,中脑多巴胺能(DA)神经元的关键生存因素。
方法:到我院就诊的4名患者主诉进行性记忆力下降,出现锥体外系体征(EPS)和精神症状。
方法:所有4例患者均根据症状诊断为AD,头颅磁共振成像的结果,和脑脊液分析.
方法:我们还进行了全外显子组测序(WES),在SORL1中发现了4个新的突变。多奈哌齐,利伐斯的明,美金刚,Madopar,喹硫平,利培酮作为治疗给药。
结果:四种突变会改变SORLA结构域的热稳定性。这可能与AD的帕金森病和精神病学特征有关。这些患者的帕金森病和精神病学特征有所改善。
结论:这些病例提示SORL1突变可能通过GDNF功能改变导致α-突触核蛋白聚集,并进一步导致具有路易体特征的核心痴呆的出现。
BACKGROUND: 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.
METHODS: Four patients presented to our hospital with complaints of progressive memory decline, who developed extrapyramidal signs (EPS) and psychiatric symptoms.
METHODS: All 4 patients were diagnosed with AD based on their symptoms, findings from cranial magnetic resonance imaging, and cerebrospinal fluid analysis.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.