The impact of neurocognitive and psychiatric disorders on the risk of idiopathic normal pressure hydrocephalus: A bidirectional Mendelian randomization study.

BACKGROUND: Neurocognitive and psychiatric disorders have been proved that they can comorbid more often with idiopathic normal pressure hydrocephalus (iNPH) than general population. However, the potential causal association between these disorders and iNPH has not been assessed. Thus, our study aims to investigate the causal relationship between them based on a bidirectional Mendelian randomization (MR) analysis. METHODS: Random effects of the inverse variance weighted (IVW) method were conducted to obtain the causal association among the neurocognitive disorders, psychiatric disorders, and iNPH. Genome-wide association studies (GWAS) of 12 neurocognitive and psychiatric disorders were downloaded via the OpenGWAS database, GWAS Catalog, and Psychiatric Genomics Consortium, whereas GWAS data of iNPH were obtained from the FinnGen consortium round 9 release, with 767 cases and 375,610 controls of European ancestry. We also conducted the sensitivity analysis in these significant causal inferences using weighted median model, Cochrane's Q test, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier detect and the leave-one-out analysis. RESULTS: For most of the neurocognitive and psychiatric disorders, no causal association was established between them and iNPH. We have found that iNPH (odds ratio [OR] = 1.030, 95% confidence interval [CI]: 1.011-1.048, p = .001) is associated with increased risk for schizophrenia, which failed in validation of sensitivity analysis. Notably, genetically predicted Parkinson's disease (PD) is associated with increased risk of iNPH (OR = 1.256, 95% CI: 1.045-1.511, p = .015). CONCLUSION: Our study has revealed the potential causal effect in which PD associated with an increased risk of iNPH. Further study is warranted to investigate the association between PD and iNPH and the potential underlying mechanism.

[Epidemiology, Natural History, and Genetic Factors of Idiopathic Normal Pressure Hydrocephalus].

According to a cohort study in a Japanese rural area, the prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the 80s was 7.7% among the older inhabitants, despite only a small percentage of the population seeking consultation. The 16-year observation of the cohort revealed that people were in the state of asymptomatic ventriculomegaly with features of iNPH on magnetic resonance imaging or asymptomatic ventricular enlargement several years before presenting symptoms and intracranial changes of iNPH. SFMBT1 was found to be a risk gene for iNPH, and investigating these risk genes will further the study of iNPH pathophysiology.

A role for mutations in AK9 and other genes affecting ependymal cells in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous CWH43 deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, and MYH13) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in AK9, which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated AK9 mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. AK9+/- mice displayed normal brain development and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH.

Cases of familial idiopathic normal pressure hydrocephalus implicate genetic factors in disease pathogenesis.

Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.

Association between vascular risk factors and idiopathic normal pressure hydrocephalus: a Mendelian randomization study.

BACKGROUND AND OBJECTIVE: Patients with idiopathic normal pressure hydrocephalus (iNPH) have a higher prevalence of hypertension and diabetes. However, the causal effects of these vascular risk factors on iNPH remain unclear. This study aimed to explore the causal relationship between vascular risk factors (VRFs) and iNPH. METHODS: We conducted the Mendelian randomization (MR) analysis of iNPH. We included nineteen vascular risk factors related to hypertension, diabetes, lipids, obesity, smoking, alcohol consumption, exercise, sleep, and cardiovascular events as exposure factors. We used the inverse-variance weighted method for causal effect estimation and weighted median, maximum likelihood, and MR Egger regression methods for sensitivity analyses. RESULTS: We found that genetically predicting essential hypertension (OR = 1.608 (1.330-1.944), p = 0.013) and increased sleep duration (OR = 16.395 (5.624-47.799), p = 0.009) were associated with higher odds of iNPH. Type 1 diabetes (OR = 0.869 (0.828-0.913), p = 0.004) was associated with lower odds of iNPH. For the other 16 VRFs, there was no evidence that they were significantly associated with iNPH. Sensitivity analyses showed that essential hypertension and type 1 diabetes were significantly associated with iNPH. CONCLUSION: In our MR study on VRFs and iNPH, we found essential hypertension to be a causal risk factor for iNPH. This suggests that hypertension may be involved in the pathophysiological mechanism of iNPH.

[Epidemiology of Idiopathic Normal Pressure Hydrocephalus and Hereditary Hydrocephalus].

Several cohort studies in Japan have revealed that the prevalence of idiopathic normal pressure hydrocephalus(iNPH)is around 1.6% among the elderly population(≧ 50 years old). The incidence of iNPH from the Yamagata(Takahata)cohort was 1.2/ 1,000 person-years in the elderly population. Although the Japanese guidelines for iNPH clearly describe the definition of "possible iNPH with MRI support," it is still difficult to find out not only patients with iNPH but also individuals in its preclinical stage with radiological findings of asymptomatic ventriculomegaly with features of iNPH on MRI(AVIM)or asymptomatic ventricular enlargement(AVE). It is assumed that only less than 10% of patients with iNPH were referred to hospitals in Japan. Several genes associated with congenital hydrocephalus have been found, including ciliopathy-related genes that directly affect the ependymal cilia in ventricles. Loss of the copy number of SFMBT1 was found to be a risk factor for iNPH. Knowledge about risk genes and their mechanisms in congenital and familial NPH may be a clue for the further understanding of the pathophysiology of iNPH.

Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus.

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant's demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH.

An immune response characterizes early Alzheimer's disease pathology and subjective cognitive impairment in hydrocephalus biopsies.

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy ß-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

iNPH-the mystery resolving.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized clinically by degradation of gait, cognition, and urinary continence. INPH is progressive (Andrén et al, 2014), still probably underdiagnosed (Williams et al, 2019) but potentially treatable by CSF diversion (Kazui et al, 2015). Familial aggregation is a strong indicator of genetic regulation in the disease process iNPH (Fig 1). Enlargement of brain ventricles is associated with failed cerebrospinal (CSF) homeostasis by so far mostly unknown mechanisms. A mutation of the cilia gene CFAP43 in iNPH family, confirmed by a knocked-out mouse model (Morimoto et al, 2019), allelic variation of NME8 (Huovinen et al, 2017), a segmental copy number loss in SFMBT1 in selected iNPH patients (Sato et al, 2016), and current results by Yang et al (2021) indicate that cilia dysfunction is one of the key mechanisms behind iNPH.

Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

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.

A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects in motile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinical manifestations include also laterality defects and risk of male infertility. Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecular analysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease. CASE PRESENTATION: Here, we describe a female infant of Moroccan origin with normal pressure hydrocephalus (NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests, such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2 gene. CONCLUSIONS: Since DNAI2 mutations are very rare, this case report contributes to better delineate the important role of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well documented, however, only a small number of human patients show this defect. Furthermore, this study highlights the importance of high-throughput technologies in advancing our understanding of heterogeneous genetic disorders.

Diabetes is associated with familial idiopathic normal pressure hydrocephalus: a case-control comparison with family members.

BACKGROUND: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families. METHODS: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann-Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses. RESULTS: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1-12.9, p = 0.030). CONCLUSIONS: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.

Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities.

OBJECTIVE: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH. METHODS: We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus. RESULTS: In WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia. CONCLUSION: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

Prevalence of C9ORF72 Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus.

BACKGROUND/AIMS: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). METHODS: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). RESULTS: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52-67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. CONCLUSION: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.

Prognostic value of amyloid PET scan in normal pressure hydrocephalus.

Amyloid positron emission tomography ([18F] florbetaben (FBB) PET) can be used to determine concomitant Alzheimer's disease (AD) in idiopathic normal pressure hydrocephalus (iNPH) patients. FBB PET scans and the tap test were performed in 31 patients with clinically suspected iNPH, and amyloid positive (iNPH/FBB+) and negative (iNPH/FBB-) groups were compared with respect to clinical characteristics. We evaluated prognostic value of FBB PET scans by analyzing the response to the tap test using a linear mixed model. We also performed a multivariable regression analysis to investigate whether amyloid PET positivity can predict the positive tap test response independent of other AD biomarkers. The results showed that the iNPH/FBB+ group (7/31, 22.6%) had a higher percentage of APOE4 carriers, lower Aß42, higher CSF t-tau, and p-tau/Aß42 ratio than the iNPH/FBB- group (24/31, 77.4%), while the two groups did not differ in imaging characteristics. The iNPH/FBB- group had a higher percentage of tap responders and showed a greater improvement in gait scores after the tap test than the iNPH/FBB+ group (group-tap test effect interaction, p = 0.035). A multivariable logistic regression analysis showed that amyloid positivity on PET scans (OR 0.03, p = 0.029) and CSF p-tau (OR 0.87, p = 0.044) were independently associated with the positive tap test response. Among 21 tap responders in the iNPH/FBB- group, 14 patients received shunt surgery and 12/14 (85.7%) patients showed symptom improvement. Our findings suggest that amyloid PET scans can help determine which iNPH patients will benefit from shunt surgery by discriminating concomitant AD.

Alzheimer's Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE: We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

A unique glycan-isoform of transferrin in cerebrospinal fluid: A potential diagnostic marker for neurological diseases.

BACKGROUND: Cerebrospinal fluid (CSF) is sequestered from blood by the blood-brain barrier and directly communicates with brain parenchymal interstitial fluid, leading to contain specific biomarkers of neurological diseases. SCOPE OF REVIEW: CSF contains glycan isoforms of transferrin (Tf): one appears to be derived from the brain and the other from blood. MAJOR CONCLUSIONS: CSF contains two glycan-isoforms; brain-type Tf and serum-type Tf. Glycan analysis and immunohistochemistry suggest that serum-type Tf having α2, 6sialylated glycans is derived from blood whereas brain-type Tf having GlcNAc-terminated glycans is derived from the choroid plexus, CSF producing tissue. The ratio of serum-type/brain-type Tf differentiates Alzheimer's disease from idiopathic normal pressure hydrocephalus, which is an elderly dementia caused by abnormal metabolism of CSF. The ratios in Parkinson's disease (PD) patients were higher than those of controls and did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis reveals the presence of an independent subgroup showing higher ratios in PD patients. The subgroup of PD shows higher levels of CSF α-synuclein than the rest, indicating that PD includes two subgroups, which differ in levels of brain-type Tf and α-synuclein. GENERAL SIGNIFICANCE: Glycosylation in central nervous system appears to be unique. The unique glycan may be a tag for glycoprotein, which is biosynthesized in the central nervous system. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-ß Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-ß (Aß) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aß is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aß-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects. OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aß in the brain samples of iNPH patients. METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aß pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aß deposition. RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aß in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aß deposition. CONCLUSION: Novel AD-associated risk genes have no significant effect on Aß accumulation in the brain of iNPH patients. However, APOE4 affects the Aß deposition in the brain of iNPH and AD patients in a similar manner.

A Segmental Copy Number Loss of the SFMBT1 Gene Is a Genetic Risk for Shunt-Responsive, Idiopathic Normal Pressure Hydrocephalus (iNPH): A Case-Control Study.

Little is known about genetic risk factors for idiopathic normal pressure hydrocephalus (iNPH). We examined whether a copy number loss in intron 2 of the SFMBT1 gene could be a genetic risk for shunt-responsive, definite iNPH. Quantitative and digital PCR analyses revealed that 26.0% of shunt-responsive definite iNPH patients (n = 50) had such a genetic change, as compared with 4.2% of the healthy elderly (n = 191) (OR = 7.94, 95%CI: 2.82-23.79, p = 1.8 x 10-5) and 6.3% of patients with Parkinson's disease (n = 32) (OR = 5.18, 95%CI: 1.1-50.8, p = 0.038). The present study demonstrates that a copy number loss within intron 2 of the SFMBT1 gene may be a genetic risk factor for shunt-responsive definite iNPH.