Familial vs sporadic normal pressure hydrocephalus: a comparative study

Normal pressure hydrocephalus (NPH) is a syndrome characterized by the buildup of cerebrospinal fluid that results in the clinic triad of gait impairment, urinary incontinence, and cognitive impairment. NPH can be categorized as secondary, idiopathic, or familial. Here, we report a comparison of sporadic to familial types from clinical, radiological, and surgery response aspects as well as a novel gene mutation as a cause of familial NPH.

We analyzed 139 patients evaluated for NPH at our center from 2010 to 2022. Ninety-five patients diagnosed with probable (n = 26) or definite (n = 69) iNPH were included. Clinical, radiological, and gait data were retrospectively collected. In patients with a positive familial history of NPH, we defined the inheritance pattern when possible. The results of performed genetic tests were reported.

Nine patients (9.5%) had a familial history of NPH. Familial and sporadic groups were largely comparable in age, sex, and disease duration. However, familial cases had better cognitive scores (p = 0.022) and a higher prevalence of upper-limb action tremor (56% vs. 14%; p = 0.008). No significant differences were noted in radiological markers, and both groups showed a positive response to ventriculoperitoneal shunting (VPS). Whole exome sequencing identified a novel pathogenic NEIL1 variant in twin patients with familial NPH.

Familial NPH occurred in roughly 1 in 10 reviewed iNPH cases and demonstrates better cognition and increased tremor incidence compared to sporadic cases but otherwise similar characteristics. The genetic underpinning of these cases is heterogeneous and NEIL1 might represent another associated gene.