Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.
Cereb Cortex. 2023 Nov 27;33(23):11400-11407. doi: 10.1093/cercor/bhad374.
Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.
特发性正常压力脑积水是一种病因不明的疾病，其诊断方法很奇怪，是通过对其提出的脑脊液分流治疗的阳性反应来确定的。目前还没有特发性正常压力脑积水的疾病基因或生物标志物。对家族性特发性正常压力脑积水进行系统分析，可以帮助进行临床诊断、预后和治疗分层，并阐明疾病的病理生理机制。在这两部分分析中，我们回顾了 22 个家系中特发性正常压力脑积水遗传的文献证据，然后介绍了 8 例家族性特发性正常压力脑积水患者的新病例系列。对于病例系列，我们收集了人口统计学、家族史、术前和术后症状以及皮质病理学等信息。所有新的家族性特发性正常压力脑积水患者在分流治疗后都有所改善，而且没有神经退行性皮质病理学（β淀粉样蛋白和过度磷酸化 tau），这与许多特发性正常压力脑积水的散发病例不同，后者的临床反应各不相同。对本文报告的 30 例家族性特发性正常压力脑积水病例的分析高度提示存在常染色体显性遗传机制。这些受影响的特发性正常压力脑积水家系的最大集合提供了强有力的证据，表明在对分流治疗有积极反应且无神经退行性病变的患者亚群中，存在常染色体显性遗传的特发性正常压力脑积水特征。对这些家族的基因组研究可能会确定第一个真正的特发性正常压力脑积水疾病基因。
