Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

Hong Wei Yang,Sijun Zhao,Yan Ma,Dejun Yang,George Wang,Rona S Carroll,Yan Zhang,Tatyana A Johnson,Mark D Johnson,Marciana F Johnson,Lei Han,Anna K Rattray,Huijun Dai,Shaokuan Zheng,Peter J Park,Shuo Zhang,Semin Lee

doi:10.15252/emmm.202013249

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6‐fold and 2.7‐fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol‐anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol‐anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.

Highlights

Idiopathic normal pressure hydrocephalus is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive impairment (Adams et al, 1965)
6% of individuals will develop this disorder by the age of 75 (Hiraoka et al, 2008; Tanaka et al, 2009; MartinLaez et al, 2015), and estimates suggest that 14% of nursing home residents have Idiopathic normal pressure hydrocephalus (iNPH) (Marmarou et al, 2007)
Each of the three cohorts in our study was limited in size, we observed that CWH43 deletions were overrepresented in each one

Summary

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive impairment (Adams et al, 1965). Not all patients who present with ventriculomegaly, gait difficulty, incontinence, and cognitive decline improve after CSF drainage (Relkin et al, 2005; McGirt et al, 2008), such that a diagnosis of iNPH is only confirmed if the symptoms improve after CSF drainage and shunt placement (Relkin et al, 2005; McGirt et al, 2008). This empirical approach to diagnosis, combined with the similarity to other disorders and the lack of knowledge about its pathophysiology, has led some practitioners to question whether iNPH exists (Saper, 2017)

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