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. 2023 Oct 7;33(23):11400–11407. doi: 10.1093/cercor/bhad374

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

Ana B W Greenberg 1, Neel H Mehta 2, Kedous Y Mekbib 3, Emre Kiziltug 4, Hannah R Smith 5, Bradley T Hyman 6, Diane Chan 7, William T Curry Jr 8, Steven E Arnold 9, Matthew P Frosch 10, Phan Q Duy 11, Kristopher T Kahle 12,13,14,✉
PMCID: PMC10690850  PMID: 37814356

Abstract

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.

Keywords: aging, biomarker, dementia, mendelian disorder, neurogenetics

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus primarily identifiable by hallmark ventriculomegaly and a “classical triad” of progressive, nonspecific symptoms: gait impairment, cognitive decline, and urinary incontinence (Nassar and Lippa 2016; Williams et al. 2019). iNPH continues to be underdiagnosed because of unstandardized and widely inaccessible diagnostic processes, and lack of knowledge surrounding the condition as opposed to more prevalent, alternative diagnoses, like Alzheimer’s disease (AD; Serulle et al. 2014; Martín-Láez et al. 2015). Indeed, no clinical or neuroradiological techniques are validated to distinguish AD from iNPH (Di Ieva et al. 2014). It is estimated that 1.6% to 5.4% of individuals with dementia are, in fact, living with iNPH (Di Ieva et al. 2014). While AD is a form of irreversible degenerative dementia, the dementia and associated debilitating symptoms of iNPH are potentially dramatically “reversible” by neurosurgical cerebrospinal fluid (CSF) shunting (Di Ieva et al. 2014; Jaraj et al. 2014). Therefore, it is important to find specific biomarkers that distinguish between AD and iNPH. In addition, the ability to predict the response to neurosurgical shunting in iNPH is something that has yet to be accomplished.

Significant gaps in our understanding of the molecular pathogenesis of iNPH impede the development of preventive, diagnostic, and therapeutic measures. Patients with iNPH are characterized by abnormal CSF circulation and evidence of delayed cerebral clearance. Although there are no biomarkers to aid in the diagnostics, and the etiology of iNPH remains unclear, there is an increasing amount of proof indicating a potential genetic component in iNPH (Adams et al. 1965; Portenoy et al. 1984; Katsuragi et al. 2000; Zhang et al. 2008; Takahashi et al. 2011; Lundin 2018). The prevalence of familial iNPH, i.e. at least 2 patients with iNPH, in the first-degree relatives has been reported to range from 4.8% to 7% (Portenoy et al. 1984; Lundin 2018). Data also contain a pair of identical twins having iNPH and a family in which an autosomal dominant inheritance pattern is observed (Adams et al. 1965; Portenoy et al. 1984; Katsuragi et al. 2000; Zhang et al. 2008; Takahashi et al. 2011; Lundin 2018). However, no systematic, unbiased genetic analyses of iNPH have been performed to date. Because of its clinical similarities to AD, the little genetic research that has been done has usually taken a candidate gene approach using genetic risk factors for AD. For example, the AD risk allele APOE ε4 was not significantly enriched in NPH than the general population (Pyykkö et al. 2012; Yang et al. 2016).

iNPH is largely thought to occur sporadically; however, there have been several reports of familial cases of iNPH (Portenoy et al. 1984; Zhang et al. 2008; Cusimano et al. 2011; Takahashi et al. 2011; McGirr and Cusimano 2012; Liouta et al. 2014; Huovinen et al. 2016; Eleftheriou and Lundin 2017), and several recent studies in humans and mouse models have proposed molecular genetic etiologies (Iseki et al. 2009; Kato et al. 2011; Sato et al. 2016; Korhonen et al. 2018; Morimoto et al. 2019; Yang et al. 2021a, 2021b). Notably, familial case studies propose that transmission occurs through an autosomal dominant mechanism. However, there is no conclusive agreement among genetic studies as to the gene(s) responsible for familial transmission, and evidence for familial forms of iNPH remains uncertain. Here, we summarize the evidence—old and new—for Mendelian contribution to iNPH, and we present 8 novel individual iNPH families, constituting the largest iNPH family case series reported to date. Our analysis provides strong evidence for autosomal dominant transmission of an iNPH trait in a subset of patients that positively respond to shunting and have an absence of neurodegenerative AD pathology. Genomic investigation of these families holds potential for the identification of a bona fide disease gene for iNPH.

Materials and methods

Following modified standard guidelines (Nakajima et al. 2021), iNPH cases were tabulated as “suspected” if asymptomatic ventriculomegaly or one classical triad symptom was present, “possible” if > 1 classical triad symptom was present, “probable” if > 1 classical triad symptom was present and radiographic features of ventriculomegaly were present, and “definite” if the individual showed marked improvement of symptoms following shunt placement. A diagnosis of iNPH was only graded as such if grading features were not obviously or completely explained by another preceding or comorbid condition.

Literature search

We searched PubMed and Google Scholar using various combinations of pertinent terms, including “idiopathic normal pressure hydrocephalus,” “familial,” and “genetic.” Articles selected for inclusion in this review presented original data investigating the familial and hereditary basis of iNPH in case-based or genetic-focused formats.

Novel clinical case series

Reports of this clinical case series adhered to EQUATOR guidelines (STROBE, von Elm et al. 2008, and CARE, Gagnier et al. 2013, checklists). Patients suspected for iNPH primarily underwent clinical observation by a neurologist and were then referred for a neurosurgical consultation at Massachusetts General Hospital, where selected patients also underwent preoperative and postoperative clinical evaluation. All included patients were classified as probable iNPH cases according to diagnostic guidelines set forth by Nakajima et al. (2021; modified for exclusion of CSF analysis as diagnostic criterion). For preoperative screening, patients who exhibited triad symptoms in conjunction with radiographic evidence of ventriculomegaly (including decreased callosal angle and Evan’s index ≥ 0.3; in absence of another cause) then underwent a CSF-diversion trial. Patients who exhibited transient improvement in any triad symptom following the temporary CSF-diversion were then considered as candidates for shunt surgery. All shunts placed used a ventriculoperitoneal (VP) shunt system.

During installment of the shunt system, cortical tissue was collected from the right parieto-occipital area. Briefly, prior to installment of the VP shunt, cortical tissue that would otherwise be destroyed or discarded because of its presence in the stereotactically defined corticectomy tract employed to accommodate the subsequently placed CSF ventricular catheter, and therefore, less than the diameter of the catheter itself, was acquired from the right parieto-occipital neocortex. Acquired cortical tissue was then assessed for presence of amyloid-beta (Aβ) and hyperphosphorylated tau (HPτ) pathology.

Postoperative assessment included clinical evaluation of all triad symptoms as compared with the patient’s functional status prior to shunt placement. For our analysis, postoperative improvement (or lack thereof) observational measures were extracted and synthesized from multidisciplinary evaluations, including from neurosurgery, neurology, and physical/occupational therapy in the follow-up assessments within 2 to 3 months and 1 year after shunt placement. Gait was assessed for speed and pattern with visual and timed measurements including the Timed Up and Go test; cognitive status and changes in urinary control were assessed by self-reported and/or spouse or caretaker observations. Cases and pedigrees presented in this portion include all patients with a reported family history of iNPH who underwent shunt surgery between December 2021 and October 2022.

As a descriptive analytic method, we qualitatively compared the characteristics and outcomes of familial versus sporadic iNPH patients with cortical tissue samples. Sporadic patients were drawn from the underlying consecutive iNPH cohort shunt-treated at Massachusetts General Hospital within the given time period (December 2021 to October 2022). Taken together, this group of familial and sporadic iNPH patients constitutes a consecutive, shunt-treated, pre- and post-operatively assessed cohort with cortical tissue samples for analysis. Permission for this clinical report was obtained from the Institutional Review Board (IRB) at Massachusetts General Hospital (MA, USA; IRB Protocol Number: 2021P001922), and all patients provided written, informed consent.

Results

Literature search

  • (i) Case-based reports

The current body of case-based evidence for genetic inheritance of iNPH suggests an autosomal dominant mechanism. From the 9 case-based studies included in this review, there were a total of 22 iNPH pedigrees with 68 affected individuals (38 definite, 13 probable, and 12 possible, and 5 suspected iNPH; Table 1). Of the 22 pedigrees presented from past reports, 10 pedigrees (Table 1, pedigrees 3, 4, 11, 12, 15 to 19, 21) reveal longitudinal expression of iNPH indicative of autosomal dominant transmission, and the remaining 12 pedigrees exhibit specific cases of familial aggregation.

Table 1.

Summary of iNPH pedigrees from case-based studies.

Study Pedigree # Proband Affected relative(s)
Sex (M/F) iNPH grade a Sex (M/F) Relationship to proband iNPH grade a
Cusimano et al. (2011) 1 F D F Sister D
F Sister S
Eleftheriou et al. (2017) 2 F D F Identical twin D
Huovinen et al. (2016)b 3 M D M Son D
4 M D F Sister D
M Mother Pr
5 M D M Brother D
6 F D F Sister D
F Sister Pr
M Brother Po
7 M D F Sister D
8 F D F Identical twin D
9 F D F Sister D
10 M D M Nephew D
11 M D M Father D
12 M D M Brother D
F Sister D
F Mother S
F Maternal aunt S
13 M D M Brother D
14 M D F Sister D
Liouta et al. (2014) 15 F D F Sister D
F Daughter S
F Niece S
McGirr and Cusimano (2012) 16 F Pr F Sister Pr
F Sister Po
F Sister Po
F Mother Po
17 M Pr F Sister Po
F Mother Po
18 F D M Maternal uncle D
F Maternal cousin D
M Maternal cousin Pr
Morimoto et al. (2019) 19 F Pr M Brother Po
M Brother Pr
F Mother Po
Portenoy et al. (1984) 20 M D F Sister D
Takahashi et al. (2011) 21 M Pr F Sister Pr
F Sister Po
M Paternal grandfather Po
F Paternal aunt Po
M Paternal cousin Pr
F Paternal cousin Pr
F Paternal cousin Pr
Zhang et al. (2008) 22 M D M Brother Po
F Sister D
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Abbreviations: D = definite iNPH; Pr = probable iNPH; Po = possible iNPH; S = suspected iNPH.

aiNPH grades were assigned with reference to standard guidelines set forth in Nakajima et al. (2021).

bAn additional 42 iNPH patients from 42 families with possible iNPH history were also identified but not reported in detail.

  • (ii) Genetic studies

Despite the case-based evidence for a heritable form of iNPH, familial iNPH is not a widely accepted or well-understood phenomenon. A likely factor underlying these latter points is that the current body of genetic studies remains inconclusive. Several candidate genes underlying iNPH etiology have been proposed in the literature, but no conclusive link between candidate risk factors and the onset of iNPH has been established, and the pathogenic roles of these candidate genes remain largely uninvestigated. Furthermore, the pattern of inheritance, if any, for iNPH continues to be unresolved by genetic studies.

  • a) Evidence for Scm-like with 4 MBT domains protein 1

Several studies have investigated the association of segmental copy number loss of the Scm-like with 4 MBT domains protein 1 (SFMBT1) gene in iNPH patients (Kato et al. 2011; Sato et al. 2016; Korhonen et al. 2018). One Japanese study investigated genetic predisposing factors to iNPH in 8 individuals with a “preclinical” stage of iNPH, asymptomatic ventriculomegaly (Iseki et al. 2009; Kato et al. 2011). Authors found that 50% of these suspected/preclinical iNPH patients had a segmental copy number loss in SFMBT1, and that this mutation was rare in healthy controls. Another study from the same group showed that this mutation was found to be significantly overrepresented in definite (shunt-responsive), sporadic iNPH patients as compared with healthy controls (Sato et al. 2016). A study of Finnish and Norwegian populations showed no notable aggregation of the copy number loss in SFMBT1 in iNPH patients with suspected familial history (Korhonen et al. 2018). This study also showed no significant difference in the frequency of the copy number loss variant between shunt-responsive and nonresponsive iNPH patients.

Thus, the identification of this copy number loss variant in prospective iNPH patients holds uncertain clinical value in that it does not appear to predict shunt-responsiveness. Additionally, it is unlikely that copy number loss in SFMBT1 is responsible for familial iNPH, but perhaps is instead a genetic predisposition factor for shunt-responsive (sporadic) iNPH.

  • b) Evidence for cilia- and flagella-associated protein 43

A Japanese study using whole exome sequencing (WES) in one multiply affected probable iNPH family suggests association of a heterozygous loss-of-function mutation in the cilia- and flagella-associated protein 43 (CFAP43) gene with the occurrence of iNPH (Morimoto et al. 2019). This same study showed that Cfap43-deficient mice exhibit an iNPH-like phenotype, including ventriculomegaly, with structural defects in motile cilia. These findings strongly suggest that this one traced occurrence of familial iNPH may have been because of haploinsufficiency of CFAP43, and the identification of a similar phenomenon in mice points to CFAP43 as a candidate with potentially broader implications outside of this one studied family.

  • c) Evidence for cell wall biogenesis protein 43 C-terminal homolog

One study examined WES data from 53 shunt-responsive iNPH patients (Yang et al. 2021a). Importantly, 8 of the 53 patients were shown to harbor heterozygous cell wall biogenesis protein 43 C-terminal homolog (CWH43) gene deletions. Of these 8 patients, 3 had familial history of iNPH. The same study also found that mice with heterozygous loss-of-function deletions in Cwh43 exhibited an iNPH-like phenotype, including symptomatic ventriculomegaly and gait impairment, and structural abnormalities in ependymal cilia and the choroid plexus epithelium. In a subsequent paper (Yang et al. 2021b), authors proposed a mechanism for the contribution of CWH43 to iNPH onset. The proposed mechanism was shown in Cwh43-mutant mice and in human HeLa cells harboring a CWH43 deletion, and the authors concluded that CWH43 deletions may lead to iNPH via selective downregulation of L1 adhesion molecule (L1CAM) in the ventricular and subventricular zones. Interestingly, decreased L1CAM expression (because of loss-of-function mutations in L1CAM) has also been implicated in congenital hydrocephalus (Adle-Biassette et al. 2013).

Novel clinical case series

Characteristics of our 8 familial iNPH patients are summarized in Table 2. Of the 8 patients [mean (range) age (yr) = 70 (61 to 80)], 8 (100%) self-identified as not Hispanic, 7 (88%) as white, and 2 (25%) as female. All 8 patients presented with definite (shunt-responsive) iNPH. Of the 8 pedigrees presented, 7 pedigrees revealed longitudinal expression of iNPH, an indication of autosomal dominant transmission (Fig. 1, pedigrees 1 to 5, 7, 8). The remaining pedigree, pedigree 6, is an additional example of familial aggregation. Two patients (patients 1 and 3) reported a family member with a diagnosis of iNPH but did not specify additional clinical details sufficient for grading. These relatives were noted as having an “unspecified” grade of iNPH (Fig. 1 and Table 2, patients/pedigrees 1 and 3).

Table 2.

Summary of novel clinical case series.

Patient 1 Patient 2 Patient 3 Patient 4
Demographics
Age at shunt (yr) 69 61 64 79
Sex (M/F) M M F M
Race Other White White White
Ethnicity Not Hispanic Not Hispanic Not Hispanic Not Hispanic
Family history of iNPHa iNPHb in son Probable iNPH in sister and father; suspected iNPH in mother iNPHb in mother Probable iNPH in 1 sister and mother; suspected iNPH in second sister
Preoperative symptoms
Gait Impairment Impairment Impairment Impairment
Cognitive Impairment Impairment Impairment Impairment
Urinary Not a primary symptom Urgency Urgency Urgency
Response to CSF-drainage Improvement in all primary symptoms Improvement in gait Improvement in all symptoms Improvement in gait
Postoperative symptoms
Gait Improvement Improvement Improvement Improvement
Cognitive Improvement Unclear change Improvement Unclear resolution
Urinary N/A, unchanged Stable urinary control Improvement Improvement
Biopsy pathology Aβ−/HPτ− N/A N/A Aβ−/HPτ−
Patient 5 Patient 6 Patient 7 Patient 8
Demographics
Age at shunt (yr) 80 70 67 70
Sex (M/F) F M M M
Race White White White White
Ethnicity Not Hispanic Not Hispanic Not Hispanic Not Hispanic
Family history of iNPHa Probable iNPH in 2 sisters and mother Probablec iNPH in sister; suspected iNPH in maternal aunt Definite iNPH in father Probabled iNPH in brother; possible iNPH in father
Preoperative symptoms
Gait Impairment Impairment Impairment Impairment
Cognitive Impairment Not a primary symptom Impairment Impairment
Urinary Not a primary symptom Incontinence Incontinence Incontinence
Response to CSF-drainage Improvement in gait Improvement in gait Improvement in gait Improvement in gait and cognition
Postoperative symptoms
Gait Improvement Improvement Improvement Improvement
Cognitive Unclear resolution N/A, unchanged Improvement Improvement
Urinary N/A, unchanged Unclear resolution Improvement Improvement
Biopsy pathology Aβ−/HPτ− Aβ−/HPτ− N/A N/A
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aiNPH grades were assigned with reference to standard guidelines set forth in Nakajima et al. (2021).

bUnspecified grade of iNPH.

cIndividual was shunted for iNPH, but there was no explicit mention of clinical response to shunting. iNPH grade thus remains as probable, not definite.

dIndividual was recently shunted for iNPH, and there was no follow-up evaluation of clinical response to shunt on record at the time of data extraction. Grade remains as probable iNPH.

Fig. 1.

Fig. 1

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Novel clinical case pedigrees. Depiction of 8 novel, multiply affected iNPH families. Pedigrees 1 to 5, 7, and 8 depict longitudinal transmission of iNPH. iNPH grades were assigned with reference to standard guidelines set forth in Nakajima et al. (2021). Figure created with BioRender.com.

All patients exhibited and/or reported improvement in at least one primary classical triad symptom, and no patient exhibited or reported lasting deterioration in any primary symptom. Of the classical triad symptoms, presence of and changes in gait impairment followed the most consistent pattern across the clinical cases: all 8 patients exhibited and/or reported gait impairment prior to shunt placement, exhibited and/or reported transient amelioration in gait following CSF-drainage, and exhibited and/or reported postoperative improvement in gait. Of all 4 patients with a viable cortical biopsy, all biopsies revealed an absence of neurodegenerative pathology (Aβ−/HPτ−).

Compared with 35 biopsied, sporadic iNPH patients from the same consecutively shunt-treated cohort at Massachusetts General Hospital, preliminary results suggest that our 4 biopsied familial patients were more likely to exhibit negative biopsy pathology and more likely to be shunt-responsive.

Discussion

In this review and clinical case series, we report a combined total of 30 iNPH patients, each with affected relatives. This synthesized cohort constitutes the largest report of its kind. In addition to the sheer volume of this report, the high percentage of patients with traceable, longitudinal familial expression of iNPH adds to the body of case-based evidence for a familial form of iNPH. Despite the evidence for familial aggregation and transmission of iNPH, there is currently no established mechanistic explanation for this documented phenomenon. Identifying the causal gene underlying the familial aggregation of iNPH will thus be crucial for establishing a molecular diagnosis while providing a window into the pathophysiological mechanisms of disease.

Gene discovery efforts thus far within NPH have been sparse, and no bona fide disease-causing gene has been identified. Although a few candidate genes have been suggested (SFMBT1, CFAP43, and CWH43), the statistical evidence underlying these genes is limited and larger and more statistically powered human genetic studies are still needed. On the basis of these few candidate genes, several investigators have proposed dysfunctional ependymal cilia leading to altered CSF circulation as a pathogenic mechanism in some forms of iNPH (Kato et al. 2011; Sato et al. 2016; Korhonen et al. 2018; Morimoto et al. 2019). However, the link between altered ependymal ciliary beating, CSF circulation, and hydrocephalus remains to be clarified in human patients (Sakamoto et al. 2021; Duy et al. 2022a). An alternative hypothesis is that iNPH might in fact arise as a secondary consequence of an underlying neurodegenerative process, given that AD is often a comorbidity among iNPH patients (Malm et al. 2013; Koivisto et al. 2016) and neuropathological evidence of Alzheimer’s is frequently identified in postmortem samples or cortical biopsies in iNPH (Bech-Azeddine et al. 2007; Leinonen et al. 2012a, 2012b). Consistent with the hypothesis that iNPH arises from genetically determined neurodegeneration, the C9ORF2 expansion, a known genetic cause of frontotemporal lobar degeneration, has been found in 1.6% of patients with possible iNPH (Korhonen et al. 2017). Mechanistically, we hypothesize that neurodegeneration may lead to iNPH by disrupting the biomechanical properties of the brain, leading to altered brain-CSF interactions and secondary impact on CSF circulation that altogether favor ventricular enlargement in the absence of a primary anatomical obstruction or reabsorption deficit. Indeed, abnormal brain biomechanics has been reported in animal models (Shapiro et al. 1985; Duy et al. 2022b) and some human patients with hydrocephalus (Wagshul et al. 2021), including those with iNPH (Fattahi et al. 2016; Aunan-Diop et al. 2022). We thus posit that the pathogenesis of iNPH stems from a specific mutant neural gene causing downstream dysfunction in CSF dynamics, and that this mutation is a transmissible risk factor for iNPH. This proposed molecular etiology, and its heritability must be further investigated and identified through broader-scale genomic studies of iNPH patients with and without family histories of the disease.

Despite insufficient genetic evidence for familial iNPH, the marked characteristics of a familial subset and the need for the identification of the etiology are clear in the literature. While familial iNPH patients have been shown, on average, to undergo shunting at a significantly older age than sporadic patients (Huovinen et al. 2016), symptom onset (of gait and memory impairment) has been shown to begin at a significantly younger age for familial versus sporadic patients (McGirr and Cusimano 2012). This discrepancy between symptom onset and treatment age for familial versus sporadic iNPH patients underscores the need for clinical recognition of and screening for a familial form of iNPH. Furthermore, while it has been suggested that familial iNPH patients may have more severe hallmark symptomology than sporadic, familial patients also have been shown to exhibit higher rates of shunt-responsiveness (Huovinen et al. 2016). From our clinical case series, we identify and corroborate potential characteristic features across our familial iNPH patients, including absence of neurodegenerative pathology, a pattern of preoperative gait impairment and postoperative improvement of gait, and preliminary indication of increased shunt-responsiveness compared with sporadic patients. These observational markers and specific characteristics identified from case reports and our case series further suggest that familial iNPH is a unique form of iNPH with a distinct subset of patients deserving of a tailored clinical paradigm. Comparable, complementary genetic investigation of familial iNPH is the next step in understanding and treating these patients.

Limitations

This study was limited by small sample size. It is likely that the case reports included in the review and our own case series were limited in size because of the difficulty in properly detecting and known underdiagnosis of iNPH (Jaraj et al. 2014; Martín-Láez et al. 2015; Picascia et al. 2015). Because of the overlap in hallmark iNPH symptoms and general senescence, many suspected and possible iNPH patients and relatives were likely undetected.

While our clinical case series puts forth one of the largest sets of multiplex iNPH pedigrees, our conclusions were largely observational in nature, and statistical analysis was hindered by the sample size.

Conclusions

Despite a lacking body of evidence for specific causal genes underlying a heritable form of iNPH, case-based reports, including our novel clinical case series, indicate that a familial subgroup of iNPH likely exists. This review and case series constitutes the largest presentation of multiply affected iNPH pedigrees and of longitudinal transmission of iNPH. This volume of evidence contributes to the growing pool of proof for familial iNPH and thus warrants a larger-scale effort to uncover the heritability of iNPH at a deeper level. Our hope is that this report is a next step toward the identification of a genetic origin of iNPH and in tailoring diagnostic iNPH procedures to optimize clinical outcomes.

Contributor Information

Ana B W Greenberg, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Neel H Mehta, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Kedous Y Mekbib, Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Emre Kiziltug, Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, United States.

Hannah R Smith, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Bradley T Hyman, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

Diane Chan, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

William T Curry Jr., Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Steven E Arnold, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States.

Matthew P Frosch, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, United States.

Phan Q Duy, Department of Neurosurgery, University of Virginia, Charlottesville, VA 22903, United States.

Kristopher T Kahle, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States; Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA 02114, United States.

Author contributions

Ana B.W. Greenberg (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing), Neel H. Mehta (Formal analysis, Writing—review & editing), Kedous Y. Mekbib (Formal analysis), Emre Kiziltug (Formal analysis), Hannah R. Smith (Formal analysis), Bradley T. Hyman (Investigation), Diane Chan (Investigation, Resources), William T. Curry (Resources), Steven E. Arnold (Investigation), Matthew P. Frosch (Investigation), Phan Q. Duy (Conceptualization, Investigation, Project administration, Writing—original draft, Writing—review & editing), and Kristopher T. Kahle (Conceptualization, Funding acquisition, Project administration, Supervision, Writing—original draft, Writing—review & editing)

Funding

K.T.K. is supported by grants from the National Institutes of Health (5RO1NS111029-04), Rudi Schulte Research Institute, and the Hydrocephalus Association.

Conflict of interest statement: None declared.

Data availability

All data used in this study have been included in the main text. Additional data may be available upon request from the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data used in this study have been included in the main text. Additional data may be available upon request from the corresponding author.

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