2024
Genetics and molecular pathophysiology of normal pressure hydrocephalus.
Mehta N, Maury E, Buller Z, Duy P, Fortes C, Alper S, Erson-Omay E, Kahle K. Genetics and molecular pathophysiology of normal pressure hydrocephalus. Journal Of Neurosurgery 2024, 1-7. PMID: 39178477, DOI: 10.3171/2024.5.jns24980.Peer-Reviewed Original ResearchIdiopathic normal pressure hydrocephalusNormal pressure hydrocephalusPathophysiology of idiopathic normal pressure hydrocephalusIntegrative genetic analysisPressure hydrocephalusPathophysiology of normal pressure hydrocephalusGenomic studiesGenetic analysisGenetic insightsUrinary incontinenceSurgical interventionCerebral ventricleClinical studiesFamilial casesMolecular pathophysiologyCSF dynamicsDisease pathogenesisNeuroinflammatory processesCerebral pressureHydrocephalusGeneticsCognitive impairmentDysregulation 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 polarityAXIN1 mutations in nonsyndromic craniosynostosis.
Timberlake A, Hemal K, Gustafson J, Hao L, Valenzuela I, Slavotinek A, Cunningham M, Kahle K, Lifton R, Persing J. AXIN1 mutations in nonsyndromic craniosynostosis. Journal Of Neurosurgery Pediatrics 2024, 34: 246-251. PMID: 38905707, PMCID: PMC11200303, DOI: 10.3171/2024.5.peds24115.Peer-Reviewed Original ResearchSequence dataAXIN1 mutationsCase-parent triosGenome-wide significanceCS casesNonsyndromic CSGenome sequencing projectsWnt signalingExome sequencing dataRNA sequencing dataPhenotypes associated with mutationsSequencing projectsGenetic testingInhibitor of Wnt signalingLive birthsNonsyndromic casesGenetic etiologyGenetic causeCS patientsAXIN1Nonsyndromic craniosynostosisMutationsHealthy controlsBirth defectsExomeTRIM71 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, awae175. PMID: 38833623, 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 pathwaysAlgebraic Nexus of Fibonacci Forms and Two-Simplex Topology in Multicellular Morphogenesis
Hoyos W, Loarca H, Kahle K, Williams Z, Lamb E, Alcántara J, Kinane T, Cuevas L. Algebraic Nexus of Fibonacci Forms and Two-Simplex Topology in Multicellular Morphogenesis. Symmetry 2024, 16: 516. DOI: 10.3390/sym16050516.Peer-Reviewed Original ResearchMulticellular organismsCellular growth propertiesMulticellular morphogenesisInhibition of replicationSynthetic biologyMulticellular structuresTubular formContact inhibitionMolecular mechanismsCellular aggregatesGrowth propertiesMorphogenesisMultiple stepsFibonacci patternCell replicationReplicationCellular genesisCellsCellular arrangementPhylogenyGrowth patternMolecular propertiesAdhesionOrganizationMechanism283 Decoding Mechanotransduction in Spinal Pseudoarthrosis: A Mouse Model of Spinal Fusion for Developing Mechanosensitive Osteobiologics
Connolly I, Burns R, Kiapour A, Phan D, Esposito E, Kahle K, Shin J, Hadzipasic M, Shankar G. 283 Decoding Mechanotransduction in Spinal Pseudoarthrosis: A Mouse Model of Spinal Fusion for Developing Mechanosensitive Osteobiologics. Neurosurgery 2024, 70: 80-80. DOI: 10.1227/neu.0000000000002809_283.Peer-Reviewed Original ResearchFusion surgerySpinal fusionFusion bedWeek 4Mouse spinePiezo-1Bone formationSpinal fusion surgeryEvidence of bone fusionIliac crest allograftPA tissuesLoss of osteocytesMouse micro-CT imagesMechanosensitive calcium channelsCalcium channelsSpinal pseudoarthrosisCT scanMouse modelPiezo1-dependent mannerBone fusionPseudoarthrosisNormal spineHistological characterizationCT imagesPromote arthrodesis184 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 deletionVentriculomegalyThe genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact
Hale A, Boudreau H, Devulapalli R, Duy P, Atchley T, Dewan M, Goolam M, Fieggen G, Spader H, Smith A, Blount J, Johnston J, Rocque B, Rozzelle C, Chong Z, Strahle J, Schiff S, Kahle K. The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact. Fluids And Barriers Of The CNS 2024, 21: 24. PMID: 38439105, PMCID: PMC10913327, DOI: 10.1186/s12987-024-00513-z.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidOverview of genesEtiology of HCPathogenesis of HCChoroid plexus cauterizationEndoscopic third ventriculostomyIncreased intracranial pressureGenetic architectureGenetic basisImpact of geneticsVentricular shuntSurgical treatmentThird ventriculostomyPhenotypic heterogeneityHeterogeneous diseasePharmacological treatmentGenetic syndromesMolecular pathogenesisIntracranial pressureHydrocephalusTherapeutic measuresGenesGeneticsBrain injuryPathwayUtility of cortical tissue analysis in normal pressure hydrocephalus
Greenberg A, Mekbib K, Mehta N, Kiziltug E, Duy P, Smith H, Junkkari A, Leinonen V, Hyman B, Chan D, Curry W, Arnold S, Barker F, Frosch M, Kahle K. Utility of cortical tissue analysis in normal pressure hydrocephalus. Cerebral Cortex 2024, 34: bhae001. PMID: 38275188, PMCID: PMC10839843, DOI: 10.1093/cercor/bhae001.Peer-Reviewed Original ResearchConceptsIdiopathic normal pressure hydrocephalus patientsNormal pressure hydrocephalus patientsCerebrospinal fluid shuntsNormal pressure hydrocephalusIdiopathic normal pressure hydrocephalusHydrocephalus patientsPressure hydrocephalusOriginal patient cohortCortical pathologyRisks of treatmentPrognostic adjunctClinical improvementTissue analysisNegative pathologyShunt outcomeClinical outcomesPatient cohortUnfavorable outcomePooled analysisSystematic reviewOriginal cohortPooled statisticsLiving patientsConfounding diagnosesPatientsHydrocephalus
Reeves B, Karimy J, Duy P, Kahle K. Hydrocephalus. 2024, 335-347. DOI: 10.1017/9781108917339.025.Peer-Reviewed Original ResearchPeripheral nerve injuryDegenerative cervical myelopathyCervical myelopathyNerve injuryDisease burdenPatient prognosisPathophysiological underpinningsNeurological conditionsNeurosurgical conditionsNeurosurgical diseasesBasic neuroscienceTranslational researchKey investigative toolInvestigative toolMyelopathyHydrocephalusPrognosisClinicInjuryGliomasDiseaseSurgeonsNeurosurgeons
2023
Neurosurgery elucidates somatic mutations
Maury E, Walsh C, Kahle K. Neurosurgery elucidates somatic mutations. Science 2023, 382: 1360-1362. PMID: 38127765, DOI: 10.1126/science.adj2244.Peer-Reviewed Original ResearchA novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus
Singh A, Allington G, Viviano S, McGee S, Kiziltug E, Ma S, Zhao S, Mekbib K, Shohfi J, Duy P, DeSpenza T, Furey C, Reeves B, Smith H, Sousa A, Cherskov A, Allocco A, Nelson-Williams C, Haider S, Rizvi S, Alper S, Sestan N, Shimelis H, Walsh L, Lifton R, Moreno-De-Luca A, Jin S, Kruszka P, Deniz E, Kahle K. A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus. Brain 2023, 147: 1553-1570. PMID: 38128548, PMCID: PMC10994532, DOI: 10.1093/brain/awad405.Peer-Reviewed Original ResearchAqueductal stenosisDe novo variantsCardiac defectsCerebral ventriculomegalyPatient cohortFetal brain transcriptomeStructural brain disordersTranscription factor NeuroD2Large patient cohortCorpus callosum abnormalitiesHuman fetal brainOptical coherence tomographyWhole-exome sequencingNeural stem cellsCH patientsHuman hydrocephalusControl cohortClinical managementCommon disorderCallosum abnormalitiesFetal brainBrain disordersBrain surgeryCH pathogenesisPatientsTransient Receptor Potential channels (TRP) in GtoPdb v.2023.3
Blair N, Caceres A, Carvacho I, Chaudhuri D, Clapham D, De Clerq K, Delling M, Doerner J, Fan L, Grimm C, Ha K, Hu M, Jabba S, Jordt S, Julius D, Kahle K, Liu B, Liu Q, McKemy D, Nilius B, Oancea E, Owsianik G, Riccio A, Sah R, Stotz S, Tian J, Tong D, Vriens J, Wu L, Xu H, Yang F, Yang W, Yue L, Zhu M. Transient Receptor Potential channels (TRP) in GtoPdb v.2023.3. IUPHAR/BPS Guide To Pharmacology CITE 2023, 2023 DOI: 10.2218/gtopdb/f78/2023.3.Peer-Reviewed Original ResearchTRPC channelsTransient receptor potential channelsCongenital stationary night blindnessCalcium-activated cationStore-operated channelsAdenosine diphosphate riboseNumerous splice variantsNMDA receptorsActivate TRPA1Cation channelsIntracellular ATP levelsChannel activityMicromolar concentrations of La3+Neurodegenerative disorder mucolipidosis type IVDepletion of intracellular calcium storesMucolipidosis type IVTRP channelsRegulation of Ca2+ entryAssociated with conduction defectsDetection of noxious heatDevelopment of heat hyperalgesiaDevelopment of thermal hyperalgesiaDynamic intracellular vesicular structuresExtra-synaptic NMDA receptorsInvolvement of TRP channels345 Structural Cardiac Defects and Vascular Anomalies in Vein of Galen Malformation Patients: A Multi-Institutional Cohort With Genetic Sequencing
Piwowarczyk P, Moyer Q, Mekbib K, Kappel A, Zhao S, Shohfi J, Smith H, Orbach D, See A, Smith E, Kahle K. 345 Structural Cardiac Defects and Vascular Anomalies in Vein of Galen Malformation Patients: A Multi-Institutional Cohort With Genetic Sequencing. Neurosurgery 2023, 69: 55-55. DOI: 10.1227/neu.0000000000002375_345.Peer-Reviewed Original ResearchCapillary malformation-arteriovenous malformation syndromeHereditary hemorrhagic telangiectasiaStructural cardiac defectsCutaneous vascular lesionsCardiac defectsWhole-exome sequencingRecurrent epistaxisVascular abnormalitiesVascular lesionsArteriovenous malformationsGeneral populationExome sequencingRole of EphB4Patent ductus arteriosusBrain arteriovenous malformationsAtrial septal defectGalen malformationDuctus arteriosusClinical featuresInstitutional cohortMoyamoya diseaseVascular anomaliesSeptal defectVascular disordersNeurovascular disorder