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Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

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.

SUBMITTER: Yang HW

PROVIDER: S-EPMC7933959 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

Yang Hong Wei HW Lee Semin S Yang Dejun D Dai Huijun H Zhang Yan Y Han Lei L Zhao Sijun S Zhang Shuo S Ma Yan Y Johnson Marciana F MF Rattray Anna K AK Johnson Tatyana A TA Wang George G Zheng Shaokuan S Carroll Rona S RS Park Peter J PJ Johnson Mark D MD

EMBO molecular medicine 20210118 3

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 significantl ...[more]

PMID: 33459505

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Project description:The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.

Project description:Abstract Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer’s disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer’s disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer’s disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity. De Guilhem de Lataillade et al. report an unexpected higher prevalence of idiopathic normal pressure hydrocephalus in a group of patients with behavioural variant of frontotemporal lobar degeneration than in a group with Alzheimer’s disease. The results suggest a possible pathophysiological link between these entities initially thought to be unrelated. Graphical Abstract Graphical abstract

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Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

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Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

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