Genetic Risk Factors in Normal Pressure Hydrocephalus: What We Know and What Is Next

Abstract

Knowledge of the genetic factors in normal pressure hydrocephalus (NPH) is rapidly evolving, with significant advances in recent years. We conducted a systematic review examining genetic contributions to NPH risk. Ovid Embase, Ovid Medline, Web of Science, and Cochrane Central were searched from inception through October 14, 2024, for human studies in English reporting familial NPH cases, genetic variants associated with NPH, and associations with other neurogenetic disorders and exploring transcriptomics. Studies on secondary, obstructive, and congenital hydrocephalus were excluded, and findings were reported narratively. Of 2562 titles and abstracts screened, 56 met inclusion criteria, predominantly involving European populations. More than 30 familial cases were identified, and two cohorts found that 10%-16% of patients with NPH had relatives with NPH symptoms. Whole-genome/exome sequencing, copy-number variant analyses, and genome-wide association studies showed risk variants enriched in NPH cohorts in or near CFAP43, SFMBT1, CWH43, AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, MYH13, FOXJ1, AMZ1/GNA12, and C16orf95, alongside protective variants near SLCO1A2 and MLLT10. These genes are associated with blood-brain and blood-cerebrospinal fluid barriers, cilia, and ependymal function. In addition, higher rates of pathological C9orf72 repeat expansions were observed in an NPH cohort compared with controls. NPH was also more prevalent in frontotemporal dementia cohorts without this expansion and co-occurred with myotonic dystrophy type 1 in several cases. Despite heterogeneity in outcome measures, this review highlights the genetic contribution to NPH risk. Future research should encourage collaborations for big data generation, identify genetic variants addressing diversity, and integrate clinical, environmental, and shunt-response data. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: familial hydrocephalus; genetics; normal pressure hydrocephalus.

FIG. 1

PRISMA flowchart of systematic search and screening. *References found through citation searching: Chalmers et al, Cusimano et al, Riggs et al, and Delavallée et al. **During the screening phase, 1586 studies were excluded, primarily because “NPH” referred to other terms, such as “Neutral Protamine Hagedorn (NPH) Insulin,” “nephronophthisis,” “nephrolithiasis,” and “nephrogenic pulmonary hypertension.” [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Summary of the genes identified through whole‐exome and whole‐genome sequencing, copy‐number variation studies, and genome‐wide association studies (GWASs) that may contribute to cerebrospinal fluid (CSF) production, circulation, or drainage. *The NME8 gene was no longer significant after correction for multiple comparisons, but was linked to periventricular white matter changes, ciliary function, and primary ciliary dyskinesia. **Genes near loci identified through GWASs. Notably, SLCO1A2 and MLLT10 were associated with reduced odds of neutral protamine hagedorn. [Color figure can be viewed at wileyonlinelibrary.com]