Ciliary Dysfunction: The Hairy Explanation of Normal Pressure Hydrocephalus?

Abstract

Normal pressure hydrocephalus (NPH) is a poorly understood entity characterized clinically by the (often incomplete) triad of gait impairment, cognitive decline, and urinary dysfunction, alongside cerebral ventricular enlargement without obstruction to cerebrospinal fluid (CSF) flow, in the absence of elevated CSF pressure or previous insults causing secondary hydrocephalus (e.g., meningitis, subarachnoid hemorrhage). 1 Diagnosis relies on identification of typical clinicoradiological features, supported by specialized diagnostic testing (typically CSF drainage procedures). 1 The pathophysiological basis of NPH remains unclear. Advanced age, vascular risk factors, and alterations in CSF dynamics have been recognized as potentially contributory. 2 In addition, frequent co-occurrence of degenerative neuropathology (typically Alzheimer's disease) in patients with NPH has burgeoned the concept of "neurodegenerative NPH." 3 Glymphatic dysfunction (and thence impaired waste clearance) has been observed in patients with NPH, and may help to explain both the alteration in CSF dynamics and frequent association with neurodegenerative pathology (through shared disease substrates, namely impaired waste clearance). 4,5 Familial segregation in NPH has on occasion been observed, suggesting that genetic factors may be at play. 2 In this study, 6 Morimoto et al. performed whole-exome sequencing (WES) on a Japanese family with multiple individuals affected by NPH, with the aim of identifying a disease-related gene. Affected patients presented with the typical triad of cognitive decline, gait imbalance, and urinary incontinence and manifested classic neuroimaging and CSF pressure findings. Chronic respiratory tract infections and infertility were common accompanying symptoms. WES, performed on 3 individuals (1 affected, 2 unaffected), identified 72 variants in the affected individual only. After filtering out simple missense variants, 13 deleterious variants remained as candidates. Sanger sequencing of these in 5 family members (2 affected, 3 unaffected) identified a likely causative nonsense variant (chr10:105893468C>T) in the CFAP43 gene, which cosegregated with the disease in the pedigree. Next, using CRISPR/cas9 technology, they generated a CFAP43 knockout mouse. These mice demonstrated

Ependymal Cilia: Physiology and Role in Hydrocephalus

“…Hydrocephalus, on the other hand, is a common occurrence in mice with PCD ( Lee, 2013 ). A link between PCD and hydrocephalus has been established by numerous studies ( Mulroy et al, 2020 ).…”