2025
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors
DeSpenza T, Kiziltug E, Allington G, Barson D, McGee S, O’Connor D, Robert S, Mekbib K, Nanda P, Greenberg A, Singh A, Duy P, Mandino F, Zhao S, Lynn A, Reeves B, Marlier A, Getz S, Nelson-Williams C, Shimelis H, Walsh L, Zhang J, Wang W, Prina M, OuYang A, Abdulkareem A, Smith H, Shohfi J, Mehta N, Dennis E, Reduron L, Hong J, Butler W, Carter B, Deniz E, Lake E, Constable R, Sahin M, Srivastava S, Winden K, Hoffman E, Carlson M, Gunel M, Lifton R, Alper S, Jin S, Crair M, Moreno-De-Luca A, Luikart B, Kahle K. PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors. Nature Neuroscience 2025, 28: 536-557. PMID: 39994410, DOI: 10.1038/s41593-024-01865-3.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsCongenital hydrocephalusCSF dynamicsIncreased CSF productionDe novo mutationsFrequent monogenic causeEverolimus treatmentCSF shuntingNonsurgical treatmentPTEN mutationsAqueductal stenosisInhibitory interneuronsVentriculomegalyProgenitor cellsChoroid plexusMonogenic causeCortical networksIncreased survivalBrain ventriclesCortical deficitsNeural progenitorsGene PTENCSF productionNkx2.1PTEN
2024
De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly
Allington G, Mehta N, Dennis E, Mekbib K, Reeves B, Kiziltug E, Chen S, Zhao S, Duy P, Saleh M, Ang L, Fan B, Nelson-Williams C, Moreno-de-Luca A, Haider S, Lifton R, Alper S, McGee S, Jin S, Kahle K. De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly. Brain 2024, awae395. PMID: 39680505, DOI: 10.1093/brain/awae395.Peer-Reviewed Original ResearchLIM interaction domainNeurodevelopmental disorder genesLIM homeodomain proteinsDe novo variantsIntegrative multiomic analysisRegulated assemblyTranscriptional regulationTranscriptional networksDisorder genesInteraction domainTranscriptional modulationTranscriptional programsMultiomics analysisLdb1Brain morphogenesisSignificant enrichmentDysmorphic featuresSignificance thresholdGenesCerebral ventriculomegalySMARCC1ARID1BCongenital hydrocephalusVariantsDevelopmental delayDysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus
Bertino F, Mukherjee D, Bonora M, Bagowski C, Nardelli J, Metani L, Venturini D, Chianese D, Santander N, Salaroglio I, Hentschel A, Quarta E, Genova T, McKinney A, Allocco A, Fiorito V, Petrillo S, Ammirata G, De Giorgio F, Dennis E, Allington G, Maier F, Shoukier M, Gloning K, Munaron L, Mussano F, Salsano E, Pareyson D, di Rocco M, Altruda F, Panagiotakos G, Kahle K, Gressens P, Riganti C, Pinton P, Roos A, Arnold T, Tolosano E, Chiabrando D. Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. Cell Reports Medicine 2024, 5: 101647. PMID: 39019006, PMCID: PMC11293339, DOI: 10.1016/j.xcrm.2024.101647.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCalcium handlingNeural progenitor cellsMitochondrial calcium handlingMouse neural progenitor cellsFLVCR1 geneMitochondrial calcium levelsVentricular dilatationLive birthsCalcium levelsProgenitor cellsClinical challengeVentricle enlargementPathogenetic mechanismsSevere formCortical neurogenesisNeural progenitorsFLVCR1aMitochondria-associated membranesHydrocephalusMiceFLVCR1CH genesMolecular mechanismsMetabolic activityPathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics
DeSpenza T, Singh A, Allington G, Zhao S, Lee J, Kiziltug E, Prina M, Desmet N, Dang H, Fields J, Nelson-Williams C, Zhang J, Mekbib K, Dennis E, Mehta N, Duy P, Shimelis H, Walsh L, Marlier A, Deniz E, Lake E, Constable R, Hoffman E, Lifton R, Gulledge A, Fiering S, Moreno-De-Luca A, Haider S, Alper S, Jin S, Kahle K, Luikart B. Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2314702121. PMID: 38916997, PMCID: PMC11228466, DOI: 10.1073/pnas.2314702121.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventriculomegalyPathogenic variantsPrefrontal pyramidal neuronsGenetic subsets of patientsDevelopment of ventriculomegalyRadial gliaSubsets of patientsHigh-frequency firingNeuronal connectivityHeterozygous germline variantsAutism spectrum disorderVentricular-subventricular zoneMicrotubule dynamicsImpaired spermatogenesisCSF shuntingExcitatory driveMicrotubule-severing ATPasePyramidal neuronsDisrupt neuronal connectivityGermline variantsVentriculomegalyCSF homeostasisDisrupt microtubule dynamicsPlanar cell polarityTRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus
Duy P, Jux B, Zhao S, Mekbib K, Dennis E, Dong W, Nelson-Williams C, Mehta N, Shohfi J, Juusola J, Allington G, Smith H, Marlin S, Belhous K, Monteleone B, Schaefer G, Pisarska M, Vásquez J, Estrada-Veras J, Keren B, Mignot C, Flore L, Palafoll I, Alper S, Lifton R, Haider S, Moreno-De-Luca A, Jin S, Kolanus W, Kahle K. TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus. Brain 2024, 147: 4292-4305. PMID: 38833623, PMCID: PMC11629693, DOI: 10.1093/brain/awae175.Peer-Reviewed Original ResearchCongenital hydrocephalusCerebral ventriculomegalyStructural brain defectsCohort of patientsAnalysis of human embryosNeurodevelopmental syndromeCorpus callosum dysgenesisWhite matter hypoplasiaSingle-cell transcriptome analysisNeural stem cellsDysmorphic featuresTransmitted variantsPatient cohortVentriculomegalyNHL domainCross-sectional analysisLin-41Subcellular localizationBrain defectsDevelopmental delayHuman embryosProcessing bodiesHomologous positionsPatientsStem cellsBiomechanical instability of the brain–CSF interface in hydrocephalus
Duy P, Mehta N, Kahle K. Biomechanical instability of the brain–CSF interface in hydrocephalus. Brain 2024, 147: 3274-3285. PMID: 38798141, PMCID: PMC11449143, DOI: 10.1093/brain/awae155.Peer-Reviewed Original ResearchBrain-CSF interfaceBrain parenchymaPost-hemorrhagic hydrocephalusLow intracranial pressureAbnormal biomechanical propertiesNormal pressure hydrocephalusPost-infectiousCongenital hydrocephalusImpaired neurodevelopmentCommunicating hydrocephalusCSF homeostasisBiomechanical instabilityHydrocephalusIntracranial pressureAnimal studiesPressure hydrocephalusArachnoid granulationsPrimary derangementBrain surgeryStudy of hydrocephalusAge groupsCSF reabsorptionVentriculomegalyVentricleSecondary enlargementPaediatric hydrocephalus
Kahle K, Klinge P, Koschnitzky J, Kulkarni A, MacAulay N, Robinson S, Schiff S, Strahle J. Paediatric hydrocephalus. Nature Reviews Disease Primers 2024, 10: 35. PMID: 38755194, DOI: 10.1038/s41572-024-00519-9.Peer-Reviewed Original ResearchConceptsSymptoms of elevated intracranial pressureCerebrospinal fluidCentral nervous system infectionChoroid plexus cauterizationEndoscopic third ventriculostomyNervous system infectionNonsurgical treatment strategiesElevated intracranial pressureLong-term outcomesNeural tube defectsCSF-brain interfaceFetal hydrocephalusUtero treatmentAcquired hydrocephalusCSF secretionSurgical closureCSF shuntingHead circumferenceThird ventriculostomyCongenital hydrocephalusAssociated with blockageGene mutationsCerebral ventricleTreatment strategiesCSF pathways184 PTEN Mutations Portend Cerebral Ventriculomegaly With Autism-Like Deficits in Cortical Circuitry
DeSpenza T, Kizlitug E, Allington G, Barson D, O'Connor D, Robert S, Mekbib K, Singh A, Phan D, Nanda P, Mandino F, Constable T, Lake E, Carter B, Gunel M, Lifton R, Luikart B, Kahle K. 184 PTEN Mutations Portend Cerebral Ventriculomegaly With Autism-Like Deficits in Cortical Circuitry. Neurosurgery 2024, 70: 46-46. DOI: 10.1227/neu.0000000000002809_184.Peer-Reviewed Original ResearchWhole-exome sequencingFetal ventriculomegalyCongenital hydrocephalusExome sequencingChoroid plexus hyperplasiaMutated genesCa2+ imagingMutant mouse modelsPTEN mutantsHuman fetal brainPten mutant miceSporadic CHCerebral ventriculomegalyCSF diversionObstructive hydrocephalusCH patientsCSF secretionPharmacological mTORC1 inhibitionNeurodevelopmental assessmentRadiographic biomarkersFetal brainPTEN mutationsAqueductal stenosisPTEN deletionVentriculomegaly
2023
195 Aberrant Brain Biomechanics Initiates Ventricular Dilation in a Genetic Subtype of Congenital Hydrocephalus
Phan D, Dahl P, Koundal S, Pedram M, Deniz E, Benveniste H, Malvankar N, Kahle K. 195 Aberrant Brain Biomechanics Initiates Ventricular Dilation in a Genetic Subtype of Congenital Hydrocephalus. Neurosurgery 2023, 69: 32-32. DOI: 10.1227/neu.0000000000002375_195.Peer-Reviewed Original ResearchVentricular dilationCongenital hydrocephalusCongenital brain malformationsHuman congenital hydrocephalusCerebrospinal fluid circulationNeural stem cell proliferationCortical hypoplasiaAqueductal obstructionBrain parenchymaBrain malformationsMouse modelHydrocephalus patientsNeurogenesis resultsVentricular expansionNeural stem cell fateCSF circulationIntracranial physiologyCSF flowGenetic subtypesPrimary physiological factorCSF dynamicsCell proliferationCSFSame point mutationHydrocephalus
2022
Molecular genetics of human developmental neurocranial anomalies: towards “precision surgery”
Duy PQ, Timberlake AT, Lifton RP, Kahle KT. Molecular genetics of human developmental neurocranial anomalies: towards “precision surgery”. Cerebral Cortex 2022, 33: 2912-2918. PMID: 35739418, PMCID: PMC10016031, DOI: 10.1093/cercor/bhac249.Peer-Reviewed Original ResearchConceptsFuture clinical trialsSurgical treatmentClinical trialsCongenital hydrocephalusWhole-exome sequencing studiesDisease classification systemDevelopmental anomaliesNeuropsychiatric diseasesNonsyndromic craniosynostosisGenetic counselingPrecision surgeryHuman brainNovel disease genesClassification systemMolecular nomenclatureSequencing studiesHydrocephalusSurgeryPathogenesisTherapyMolecular geneticsPrognosticationDiseaseTrialsBrainImpaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature Neuroscience 2022, 25: 458-473. PMID: 35379995, PMCID: PMC9664907, DOI: 10.1038/s41593-022-01043-3.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventricular dilatationPrimary defectNeuroepithelial cell differentiationRisk genesCerebrospinal fluid homeostasisWhole-exome sequencingNeuroepithelial stem cellsCortical hypoplasiaReduced neurogenesisVentricular dilatationVentricular enlargementCH mutationsPrenatal hydrocephalusDisease heterogeneityBrain surgeryCSF circulationHydrocephalusGenetic subtypesFluid homeostasisNeuroepithelial cellsNovo mutationsBrain transcriptomicsStem cellsCell differentiationBrain ventricles as windows into brain development and disease
Duy PQ, Rakic P, Alper SL, Butler WE, Walsh CA, Sestan N, Geschwind DH, Jin SC, Kahle KT. Brain ventricles as windows into brain development and disease. Neuron 2022, 110: 12-15. PMID: 34990576, PMCID: PMC9212067, DOI: 10.1016/j.neuron.2021.12.009.Peer-Reviewed Original Research
2021
Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus.
Allington G, Duy PQ, Ryou J, Singh A, Kiziltug E, Robert SM, Kundishora AJ, King S, Haider S, Kahle KT, Jin SC. Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus. Journal Of Neurosurgery Pediatrics 2021, 29: 168-177. PMID: 34715668, DOI: 10.3171/2021.8.peds21368.Peer-Reviewed Original ResearchManagement of patientsCongenital hydrocephalusFuture clinical trialsCongenital brain disordersOutcome prognosticationUnderlying pathogenesisClinical trialsCurative strategiesTreatment stratificationIncomplete clearanceDiagnostic adjunctPatient benefitClinical practiceBrain disordersBrain ventriclesClinical diagnosisGenetic counselingHuman genetic studiesHydrocephalusPatientsPathogenesisNeurosurgical communitySubsequent enlargementRecent findingsMolecular nomenclatureGenomics of human congenital hydrocephalus
Kundishora AJ, Singh AK, Allington G, Duy PQ, Ryou J, Alper SL, Jin SC, Kahle KT. Genomics of human congenital hydrocephalus. Child's Nervous System 2021, 37: 3325-3340. PMID: 34232380, DOI: 10.1007/s00381-021-05230-8.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusBrain developmentPoor neurodevelopmental outcomesRecent whole-exome sequencing studiesPost-surgical patientsHuman congenital hydrocephalusPathogenesis of hydrocephalusCerebrospinal fluid accumulationDamaging de novoPrimary pathomechanismEarly brain developmentNeural stem cell growthNeurodevelopmental outcomesOutcome prognosticationHuman brain developmentCSF diversionTreatment stratificationWhole-exome sequencing studiesFluid accumulationBrain ventriclesClinical toolHydrocephalusGenetic counselingDisease mechanismsSubstantial minorityExome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus
Sullivan W, Reeves BC, Duy PQ, Nelson-Williams C, Dong W, Jin SC, Kahle KT. Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus. JAMA Pediatrics 2021, 175: 310-313. PMID: 33196764, PMCID: PMC7670396, DOI: 10.1001/jamapediatrics.2020.4878.Peer-Reviewed Original Research
2020
Integrative Genomics Implicates Genetic Disruption of Prenatal Neurogenesis in Congenital Hydrocephalus
Panchagnula S, Jin S, Dong W, Kundishora A, Moreno-De-Luca A, Furey C, Allocco A, Walker R, Nelson-Williams C, Smith H, Dunbar A, Conine S, Lu Q, Zen X, Sierant M, Knight J, Sullivan W, Phan D, DeSpenza T, Reeves B, Karimy J, Marlier A, Castaldi C, Tikhonova I, Li B, Peña; H, Broach J, Kabachelor E, Ssenyonga P, Hehnly C, Ge L, Keren B, Timberlake A, Goto J, Mangano F, Johnston J, Butler W, Warf B, Smith E, Schiff S, Limbrick D, Heuer G, Jackson E, Iskandar B, Mane S, Haider S, Guclu B, Bayri Y, Sahin Y, Duncan C, Apuzzo M, DiLuna M, Hoffman E, Sestan N, Ment L, Alper S, Bilguvar K, Geschwind D, Günel M, Lifton R, Kahle K. Integrative Genomics Implicates Genetic Disruption of Prenatal Neurogenesis in Congenital Hydrocephalus. Neurosurgery 2020, 67 DOI: 10.1093/neuros/nyaa447_572.Peer-Reviewed Original ResearchCongenital hydrocephalusPrenatal neurogenesisGenetic disruptionIntegrative genomicsHydrocephalusNeurogenesisGenes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions
McKnight I, Hart C, Park IH, Shim JW. Genes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions. Experimental Neurology 2020, 335: 113523. PMID: 33157092, PMCID: PMC7750280, DOI: 10.1016/j.expneurol.2020.113523.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCentral nervous systemFamilial Parkinson's diseaseAlzheimer's diseaseCausative genesGenome Data ViewerHuman genetic mutationsDisease-susceptible genesHigh mutation rateGenetic mutationsHuman congenital hydrocephalusHuman clinical studiesPutative genesHuman genesGenomic informationT contentChromosomal characteristicsDNA compositionGenetic basisHigh adenineMutation rateClinical studiesGenesPreclinical modelsThymine contentExome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus
Jin SC, Dong W, Kundishora AJ, Panchagnula S, Moreno-De-Luca A, Furey CG, Allocco AA, Walker RL, Nelson-Williams C, Smith H, Dunbar A, Conine S, Lu Q, Zeng X, Sierant MC, Knight JR, Sullivan W, Duy PQ, DeSpenza T, Reeves BC, Karimy JK, Marlier A, Castaldi C, Tikhonova IR, Li B, Peña HP, Broach JR, Kabachelor EM, Ssenyonga P, Hehnly C, Ge L, Keren B, Timberlake AT, Goto J, Mangano FT, Johnston JM, Butler WE, Warf BC, Smith ER, Schiff SJ, Limbrick DD, Heuer G, Jackson EM, Iskandar BJ, Mane S, Haider S, Guclu B, Bayri Y, Sahin Y, Duncan CC, Apuzzo MLJ, DiLuna ML, Hoffman EJ, Sestan N, Ment LR, Alper SL, Bilguvar K, Geschwind DH, Günel M, Lifton RP, Kahle KT. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nature Medicine 2020, 26: 1754-1765. PMID: 33077954, PMCID: PMC7871900, DOI: 10.1038/s41591-020-1090-2.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusPoor neurodevelopmental outcomesPost-surgical patientsCerebrospinal fluid accumulationNeural stem cell biologyGenetic disruptionWhole-exome sequencingPrimary pathomechanismEarly brain developmentNeurodevelopmental outcomesHigh morbidityCSF diversionMutation burdenFluid accumulationBrain ventriclesCH casesBrain developmentDe novo mutationsPatientsExome sequencingCSF dynamicsDisease mechanismsHydrocephalusNovo mutationsCell types
2019
Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3
Allocco AA, Jin SC, Duy PQ, Furey CG, Zeng X, Dong W, Nelson-Williams C, Karimy JK, DeSpenza T, Hao LT, Reeves B, Haider S, Gunel M, Lifton RP, Kahle KT. Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3. Frontiers In Cellular Neuroscience 2019, 13: 425. PMID: 31616254, PMCID: PMC6775207, DOI: 10.3389/fncel.2019.00425.Peer-Reviewed Original ResearchCongenital hydrocephalusWhole-exome sequencingNeural stem cellsImmunohistochemical studyType 1 Chiari malformationUnaffected parentsStructural brain abnormalitiesAutosomal dominant neurological diseaseHuman congenital hydrocephalusCompound heterozygous mutationsPatient's unaffected parentsEmbryonic brain tissueImpaired NaAqueductal stenosisChiari malformationBrain abnormalitiesCorpus callosumMouse embryonic brainSingle patientChoroid plexusNeurological diseasesΑ3 subunitBrain tissueDifferentiated neuronsBrain developmentVisualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus
Date P, Ackermann P, Furey C, Fink IB, Jonas S, Khokha MK, Kahle KT, Deniz E. Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus. Scientific Reports 2019, 9: 6196. PMID: 30996265, PMCID: PMC6470164, DOI: 10.1038/s41598-019-42549-4.Peer-Reviewed Original ResearchConceptsCSF flow dynamicsCongenital hydrocephalusOptical coherence tomographyCH pathophysiologyVentricular systemCoherence tomographyBrain developmentCurrent treatment modalitiesHuman congenital hydrocephalusCerebrospinal fluid flowAqueductal stenosisCerebral ventricleNeurosurgical indicationsTreatment modalitiesSurgery techniquesBrain ventriclesEpendymal ciliaCSF flowCiliary dysfunctionHuman L1CAMHydrocephalus pathogenesisVivo investigationsHydrocephalusPathophysiologyVentricle
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