Publications by authors named "Daniel Duran"

36 Publications

Coronavirus Disease 2019 and Pituitary Apoplexy: A Single-Center Case Series and Review of the Literature.

World Neurosurg 2021 08 12;152:e678-e687. Epub 2021 Jun 12.

Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Background: Pituitary apoplexy (PA) is a rare, but life-threatening, condition characterized by pituitary infarction and hemorrhage, most often in the setting of a preexisting adenoma. The risk factors and mechanisms associated with PA are poorly understood. Although neurovascular manifestations of coronavirus disease 2019 (COVID-19) infection have been documented, its association with PA has not yet been determined.

Methods: From a prospectively collected database of patients treated at a tertiary care center for pituitary adenoma, we conducted a retrospective medical record review of PA cases during the COVID-19 pandemic from March 2020 to December 2020. We also conducted a literature review to identify other reported cases.

Results: We identified 3 consecutive cases of PA and concomitant COVID-19 infection. The most common symptoms at presentation were headache and vision changes. The included patients were successfully treated with surgical decompression and medical management of the associated endocrinopathy, ultimately experiencing improvement in their visual symptoms at the latest follow-up examination. COVID-19 infection in the perioperative period was corroborated by polymerase chain reaction test results in all the patients.

Conclusions: With the addition of our series to the literature, 10 cases of PA in the setting of COVID-19 infection have been confirmed. The present series was limited in its ability to draw conclusions about the relationship between these 2 entities. However, COVID-19 infection might represent a risk factor for the development of PA. Further studies are required.
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http://dx.doi.org/10.1016/j.wneu.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196470PMC
August 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

Clin Genet 2021 08 2;100(2):176-186. Epub 2021 Jun 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.
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http://dx.doi.org/10.1111/cge.13973DOI Listing
August 2021

Associations of meningioma molecular subgroup and tumor recurrence.

Neuro Oncol 2021 05;23(5):783-794

Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.

Background: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients.

Methods: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling.

Results: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence.

Conclusion: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.
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http://dx.doi.org/10.1093/neuonc/noaa226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099468PMC
May 2021

A new tiger beetle from the Trans-Mexican Volcanic Belt (Coleoptera, Cicindelidae, Cicindelini).

Zootaxa 2020 Jul 10;4810(2):zootaxa.4810.2.11. Epub 2020 Jul 10.

Department of Environmental Science, Rowan University, Glassboro, NJ 08028, USA..

A new tiger beetle species, Cicindelidia cyanipleura Duran and Roman n. sp., of the tribe Cicindelini, is described from the southwestern section of the Trans-Mexican Volcanic Belt. Superficially, it appears to be most closely related to C. rufiventris (Dejean, 1825) but is distinguished on the basis of multiple morphological characters and behavior. Given the rock-loving natural history of the species, escape behavior, polished pronotum, and small body size, it may be more closely related to the petrophiles C. laetipennis (Horn, 1913) or C. politula (LeConte, 1875), from which it is distinguished on the basis of multiple morphological characters and biogeography.
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http://dx.doi.org/10.11646/zootaxa.4810.2.11DOI Listing
July 2020

Genomic alterations in Turcot syndrome: Insights from whole exome sequencing.

J Neurol Sci 2020 10 25;417:117056. Epub 2020 Jul 25.

Department of Neurology, Yale School of Medicine, New Haven, CT, United States of America; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.117056DOI Listing
October 2020

Geographic Life History Differences Predict Genomic Divergence Better than Mitochondrial Barcodes or Phenotype.

Genes (Basel) 2020 02 29;11(3). Epub 2020 Feb 29.

Department of BioSciences, Rice University, Houston, TX 77005, USA.

Species diversity can be inferred using multiple data types, however, results based on genetic data can be at odds with patterns of phenotypic variation. Tiger beetles of the (LeConte, 1875) species complex have been taxonomically problematic due to extreme phenotypic variation within and between populations. To better understand the biology and taxonomy of this group, we used mtDNA genealogies and multilocus nuclear analyses of 34,921 SNPs to elucidate its evolutionary history and evaluate the validity of phenotypically circumscribed species and subspecies. Genetic analyses recovered two divergent species that are also ecologically distinct, based on adult life history. These patterns are incongruous with the phenotypic variation that informed prior taxonomy, and most subspecies were not supported as distinct evolutionary lineages. One of the nominal subspecies was found to be a cryptic species; consequently, we elevate (Horn, 1913) to a full species. Although nuclear and mtDNA datasets recovered broadly similar evolutionary units, mito-nuclear discordance was more common than expected, being observed between nearly all geographically overlapping taxonomic pairs. Additionally, a pattern of 'mitochondrial displacement' was observed, where mitochondria from one species unidirectionally displace others. Overall, we found that geographically associated life history factors better predict genomic divergence than phenotype and mitochondrial genealogies, and consequently taxon identifications based on mtDNA (e.g., DNA barcodes) may be misleading.
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http://dx.doi.org/10.3390/genes11030265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140875PMC
February 2020

Modulation of brain cation-Cl cotransport via the SPAK kinase inhibitor ZT-1a.

Nat Commun 2020 01 7;11(1):78. Epub 2020 Jan 7.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.

The SLC12A cation-Cl cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.
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http://dx.doi.org/10.1038/s41467-019-13851-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946680PMC
January 2020

A new petrophilous tiger beetle from the Trans-Pecos region of Texas and revised key to the genus (Coleoptera, Carabidae, Cicindelinae).

Zookeys 2019 2;893:125-134. Epub 2019 Dec 2.

178 Winecup Way, Austin, TX 78737, USA Unaffiliated Austin United States of America.

A new rock-dwelling (petrophilous) tiger beetle, Duran & Roman, is described from calcareous canyons and steep hillsides in the Trans-Pecos region of western Texas. It is distinguished from all other based on multiple morphological characters, biogeography, and ecology. A revised key to the genus is provided.
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http://dx.doi.org/10.3897/zookeys.893.47059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901613PMC
December 2019

Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

J Neurosurg 2019 Oct 25:1-10. Epub 2019 Oct 25.

19Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Objective: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.

Methods: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.

Results: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation.

Conclusions: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.
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http://dx.doi.org/10.3171/2019.8.JNS191266DOI Listing
October 2019

EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease.

Trends Mol Med 2019 04 25;25(4):265-286. Epub 2019 Feb 25.

Department of Neurosurgery, Yale School of Medicine, New Haven CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven CT, USA. Electronic address:

Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.
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http://dx.doi.org/10.1016/j.molmed.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456402PMC
April 2019

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Neuron 2019 02 18;101(3):429-443.e4. Epub 2018 Dec 18.

Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.
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http://dx.doi.org/10.1016/j.neuron.2018.11.041DOI Listing
February 2019

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

Neuron 2018 07 5;99(2):302-314.e4. Epub 2018 Jul 5.

Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10), SMARCC1 (p = 8.15 × 10), and PTCH1 (p = 1.06 × 10). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
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http://dx.doi.org/10.1016/j.neuron.2018.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839075PMC
July 2018

De novo mutation in congenital scalp hemangioma.

Cold Spring Harb Mol Case Stud 2018 08 1;4(4). Epub 2018 Aug 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06519, USA.

Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation ( score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo mutation with congenital hemangioma.
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http://dx.doi.org/10.1101/mcs.a002998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071566PMC
August 2018

9p24 triplication in syndromic hydrocephalus with diffuse villous hyperplasia of the choroid plexus.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Hydrocephalus, a disorder of impaired cerebrospinal fluid (CSF) homeostasis, often results from an imbalance between CSF production and reabsorption. Rarely, hydrocephalus is the consequence of CSF hypersecretion in the context of diffuse villous hyperplasia of the choroid plexus (DVHCP). The limited genetic information in previously reported cases suggests a high prevalence of gains of Chromosome 9p in this disease, although the critical genes involved in DVHCP pathogenesis have not been identified. Here, we report a patient with syndromic hydrocephalus with DVHCP associated with a novel 9p24.3-11.2 triplication and 15q13.2-q13.3 microdeletion. We review the clinical, radiological, and pathological features of DVHCP, as well as its surgical management. A better understanding of the genetic basis of DVHCP could spur the development of rational, targeted nonsurgical hydrocephalus treatments.
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http://dx.doi.org/10.1101/mcs.a003145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169828PMC
October 2018

A novel association of campomelic dysplasia and hydrocephalus with an unbalanced chromosomal translocation upstream of .

Cold Spring Harb Mol Case Stud 2018 06 1;4(3). Epub 2018 Jun 1.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in or chromosomal rearrangements involving the long arm of Chromosome 17 harboring the locus. SOX9, a transcription factor, is indispensible in establishing and maintaining neural stem cells in the central nervous system. We present a patient with angulation of long bones and external female genitalia on prenatal ultrasound who was subsequently found to harbor the chromosomal abnormality 46, XY, t(6;17) (p21.1;q24.3) on prenatal genetic testing. Comparative genomic hybridization revealed deletions at 6p21.1 and 17q24.3, the latter being 2.3 Mb upstream of Whole-exome sequencing did not identify pathogenic variants in , suggesting that the 17q24.3 deletion represents a translocation breakpoint farther upstream of than previously identified. At 2 mo of age the patient developed progressive communicating ventriculomegaly and thinning of the cortical mantle without clinical signs of increased intracranial pressure. This case suggests ventriculomegaly in some cases represents not a primary impairment of cerebrospinal fluid dynamics, but an epiphenomenon driven by a genetic dysregulation of neural progenitor cell fate.
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http://dx.doi.org/10.1101/mcs.a002766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983176PMC
June 2018

Tubular approach to minimally invasive microdiscectomy for pediatric lumbar disc herniation.

J Neurosurg Pediatr 2018 05 23;21(5):449-455. Epub 2018 Feb 23.

Departments of1Neurosurgery.

OBJECTIVE Lumbar disc herniation (LDH) in the pediatric population is rare and exhibits unique characteristics compared with adult LDH. There are limited data regarding the safety and efficacy of minimally invasive surgery (MIS) using tubular retractors in pediatric patients with LDH. Here, the outcomes of MIS tubular microdiscectomy for the treatment of pediatric LDH are evaluated. METHODS Twelve consecutive pediatric patients with LDH were treated with MIS tubular microdiscectomy at the authors' institution between July 2011 and October 2015. Data were gathered from retrospective chart review and from mail or electronic questionnaires. The Macnab criteria and the Oswestry Disability Index (ODI) were used for outcome measurements. RESULTS The mean age at surgery was 17 ± 1.6 years (range 13-19 years). Seven patients were female (58%). Prior to surgical intervention, 100% of patients underwent conservative treatment, and 50% had epidural steroid injections. Preoperative low-back and leg pain, positive straight leg raise, and myotomal leg weakness were noted in 100%, 83%, and 67% of patients, respectively. The median duration of symptoms prior to surgery was 9 months (range 1-36 months). The LDH level was L5-S1 in 75% of patients and L4-5 in 25%. The mean ± SD operative time was 90 ± 21 minutes, the estimated blood loss was ≤ 25 ml in 92% of patients (maximum 50 ml), and no intraoperative or postoperative complications were noted at 30 days. The median hospital length of stay was 1 day (range 0-3 days). The median follow-up duration was 2.2 years (range 0-5.8 years). One patient experienced reherniation at 18 months after the initial operation and required a second same-level MIS tubular microdiscectomy to achieve resolution of symptoms. Of the 11 patients seen for follow-up, 10 patients (91%) reported excellent or good satisfaction according to the Macnab criteria at the last follow-up. Only 1 patient reported a fair level of satisfaction by using the same criteria. Seven patients completed an ODI evaluation at the last follow-up. For these 7 patients, the mean ODI low-back pain score was 19.7% (SEM 2.8%). CONCLUSIONS To the authors' knowledge, this is the longest outcomes study and the largest series of pediatric patients with LDH who were treated with MIS microdiscectomy using tubular retractors. These data suggest that MIS tubular microdiscectomy is safe and efficacious for pediatric LDH. Larger prospective cohort studies with longer follow-up are needed to better evaluate the long-term efficacy of MIS tubular microdiscectomy versus other open and MIS techniques for the treatment of pediatric LDH.
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http://dx.doi.org/10.3171/2017.11.PEDS17293DOI Listing
May 2018

Human genetics and molecular mechanisms of vein of Galen malformation.

J Neurosurg Pediatr 2018 04 19;21(4):367-374. Epub 2018 Jan 19.

1Department of Neurosurgery.

Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas between the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation-arteriovenous malformation syndrome ( RASA1) and hereditary hemorrhagic telangiectasia ( ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attributable in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients' families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.
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http://dx.doi.org/10.3171/2017.9.PEDS17365DOI Listing
April 2018

Malignant Cerebellar Edema Subsequent to Accidental Prescription Opioid Intoxication in Children.

Front Neurol 2017 25;8:362. Epub 2017 Jul 25.

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

We present two recent cases of toddlers who developed malignant cerebellar edema subsequent to accidental ingestion of prescription opioids. Both children presented acute neurological decline, hydrocephalus, and tonsillar herniation requiring emergent ventricular drain placement, suboccipital craniectomy, and partial cerebellectomy. Together with several other reports, these cases suggest the existence of an uncommon yet severe syndrome of acute opioid-induced malignant cerebellar edema. We hypothesize that the condition results from a combination of primary opioid receptor-mediated changes in neuronal metabolism that are exacerbated by secondary hypoxic insult. If recognized promptly, this syndrome can be treated with emergent neurosurgical intervention with good clinical outcomes. These cases also illustrate the unintended consequences and innocent victims of the spiraling prescription opioid epidemic, which will likely increase in prevalence. Recognition of this syndrome by clinicians is thus critical.
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http://dx.doi.org/10.3389/fneur.2017.00362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524743PMC
July 2017

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.

Nat Med 2017 Aug 10;23(8):997-1003. Epub 2017 Jul 10.

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.

The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
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http://dx.doi.org/10.1038/nm.4361DOI Listing
August 2017

Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series.

J Neurosurg Pediatr 2017 May 10;19(5):553-559. Epub 2017 Mar 10.

Department of Neurosurgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.

OBJECTIVE Limited data exist on familial moyamoya in children. The purpose of this study was to characterize presentation and outcomes of pediatric moyamoya patients who have relatives diagnosed with moyamoya. METHODS The authors performed a single-institution retrospective analysis of a case series including all surgically treated children with moyamoya with first- or second-degree relatives with moyamoya. Clinical and radiographic characteristics were analyzed, along with surgical outcomes. RESULTS A total of 537 patients underwent surgery for moyamoya during the study period. Eighteen of those patients (3.4% of the total series) had moyamoya and a family history of moyamoya and were included in this study. Of these 18 patients, 14 were non-twin siblings, and the remaining 4 represented 2 pairs of identical (affected) twins. The presentation was predominantly ischemic (72%), but 4 patients (33%) were asymptomatic when they were found to have moyamoya. Bilateral disease was present in 13 patients (72%). Radiographic stroke prevalence (67%), Suzuki grade (3.3), and angiographic findings were comparable to findings in nonfamilial moyamoya patients. Thirty revascularization procedures were performed, with a 3.3% operative stroke rate per hemisphere and no new strokes in an average follow-up period of 4.5 years. CONCLUSIONS In a North American surgical series, familial moyamoya existed in 3.4% of cases, and was distinguished by manifesting in a broad range of ethnic groups, with a higher proportion of male patients and increased rates of asymptomatic and unilateral disease in comparison to nonfamilial moyamoya. Screening indications remain controversial and the current data are used to suggest guidelines. Surgical therapy is warranted, effective, and durable in these patients, but patients should be carefully selected.
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http://dx.doi.org/10.3171/2016.12.PEDS16468DOI Listing
May 2017

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

Nat Commun 2017 02 14;8:14433. Epub 2017 Feb 14.

Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
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http://dx.doi.org/10.1038/ncomms14433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316884PMC
February 2017

Mystery Case: Acute hydrocephalus caused by radiographically occult fourth ventricular outlet obstruction.

Neurology 2017 01;88(5):e36-e37

From the Departments of Neurosurgery (D.D., K.T.K.), Pediatrics (K.T.K.), and Cellular and Molecular Physiology (K.T.K.), Yale School of Medicine (M.H.), New Haven, CT.

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http://dx.doi.org/10.1212/WNL.0000000000003555DOI Listing
January 2017

Digenic mutations of human paralogs in Dent's disease type 2 associated with Chiari I malformation.

Hum Genome Var 2016 8;3:16042. Epub 2016 Dec 8.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.

and its paralog encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, DD2-causing 462 bp deletion disrupting exon 3 of and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10) damaging missense mutation in (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein's critical PH domain. analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP metabolism in this mechanism.
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http://dx.doi.org/10.1038/hgv.2016.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143364PMC
December 2016

Cerebrospinal fluid hypersecretion in pediatric hydrocephalus.

Neurosurg Focus 2016 Nov;41(5):E10

Departments of 1 Neurosurgery and.

Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.
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http://dx.doi.org/10.3171/2016.8.FOCUS16278DOI Listing
November 2016

Functional kinomics establishes a critical node of volume-sensitive cation-Cl cotransporter regulation in the mammalian brain.

Sci Rep 2016 10 26;6:35986. Epub 2016 Oct 26.

Departments of Pediatrics and Cellular &Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06511 USA.

Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr/Thr phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD). In the mammalian brain, we found the Cl-sensitive WNK3-SPAK kinase complex, required for cell shrinkage-induced regulatory volume decrease (RVI) via the stimulatory phosphorylation of NKCC1 (Thr/Thr/Thr), is also essential for the inhibitory phosphorylation of KCC3 (Thr/Thr). This is mediated in vivo by an interaction between the CCT domain in SPAK and RFXV/I domains in WNK3 and NKCC1/KCC3. Accordingly, genetic or pharmacologic WNK3-SPAK inhibition prevents cell swelling in response to osmotic stress and ameliorates post-ischemic brain swelling through a simultaneous inhibition of NKCC1-mediated Cl uptake and stimulation of KCC3-mediated Cl extrusion. We conclude that WNK3-SPAK is an integral component of the long-sought "Cl/volume-sensitive kinase" of the cation-Cl cotransporters, and functions as a molecular rheostat of cell volume in the mammalian brain.
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http://dx.doi.org/10.1038/srep35986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080614PMC
October 2016

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.

Nat Genet 2016 10 22;48(10):1253-9. Epub 2016 Aug 22.

Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
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http://dx.doi.org/10.1038/ng.3651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114141PMC
October 2016

Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.

Sci Signal 2016 08 2;9(439):ra77. Epub 2016 Aug 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration.
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http://dx.doi.org/10.1126/scisignal.aae0546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506493PMC
August 2016
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