Faculty Bibliography
Searched for:
Department/Unit:Neurology
Total Results:
24318
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.
PMCID:10005179
PMID: 36897941
ISSN: 2375-2548
CID: 5673862
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
PMCID:9908558
PMID: 36385166
ISSN: 1476-5578
CID: 5673852
Diagnostic value of intereye difference metrics for optic neuritis in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders
BACKGROUND:The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC). METHODS:Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics. RESULTS:The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%). CONCLUSIONS:Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.
PMCID:10314042
PMID: 36810323
ISSN: 1468-330x
CID: 5672712
Disparities in Neuro-Oncology
PURPOSEOF REVIEW/OBJECTIVE:Health disparities are preventable differences in the diagnosis, treatment, and outcomes of many diseases, including central nervous system (CNS) tumors. This review will summarize and compile the existing literature on health disparities in neuro-oncology and provide directions for future research and interventions. RECENT FINDINGS/RESULTS:Patients from historically marginalized groups are more likely to receive inadequate treatment, develop complications, and experience a shorter life expectancy. Financial toxicity can be particularly severe for patients with CNS tumors due to the high costs of treatment. Additionally, CNS clinical trials and research lack diverse representation.
PMID: 37889427
ISSN: 1534-6293
CID: 5652022
Trainee highlights [Editorial]
PMID: 37596851
ISSN: 1526-4610
CID: 5650802
Case report: Psychedelic-induced seizures captured by intracranial electrocorticography [Case Report]
Classic psychedelics are currently re-emerging as therapeutic agents with unique clinical benefits; however, it is also important to recognize the adverse effects of this drug class. While the risk of seizures with this drug class is known, the literature is lacking in detail. We present a case of psychedelic mushroom-induced seizures in a person with refractory right temporal lobe epilepsy implanted with a responsive neurostimulation (RNS) system. A large increase in typical seizure frequency coincided with the ingestion of a large dose of the mushrooms. This is the first reported case of electrographically confirmed seizures associated with classic psychedelic drug use. With the surge of research and movements toward the clinical application of classic psychedelic compounds, the risk for drug-induced seizures should be considered, including factors such as a history of epilepsy and drug doses and regimens.
PMCID:10343433
PMID: 37456653
ISSN: 1664-2295
CID: 5650642
From diet to disasters, lifestyle factors can affect headaches and migraine [Editorial]
PMID: 37317563
ISSN: 1526-4610
CID: 5650792
Trainee highlights [Editorial]
PMID: 37937890
ISSN: 1526-4610
CID: 5650812
Overlapping and distinct phenotypic profiles in Alzheimer's disease and late onset epilepsy: a biologically-based approach
Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.
PMCID:10965692
PMID: 38545454
ISSN: 1664-2295
CID: 5645052
Investigating the racial gap in prostate cancer screening with prostate-specific antigen among younger men from 2012 to 2020
BACKGROUND:The United States Preventive Services Task Force recommended against prostate-specific antigen (PSA) screening in 2012, which was modified in 2018 into shared decision making for men aged 55-70 years with a life expectancy over 10 years. We studied the trends in PSA screening in younger Black and White men with the implementation of the 2012 and 2018 guidelines. METHODS:Younger Black and White men (aged 40-54 years) were identified using the Behavioral Risk Factor Surveillance System database biennially from 2012 to 2020. Our primary outcome was PSA screening within 2 years of the survey. An adjusted logistic regression model with 2-way interaction assessment between race and survey year was used to investigate the temporal trend of PSA screening in younger Black and White men. RESULTS:A total of 142 892 men were included. We saw steadily decreasing odds of PSA screening among both younger Black and White men in 2014, 2016, 2018, and 2020 compared with 2012 (for younger Black men: odds ratio [OR]2014 = 0.77, 95% confidence interval [CI] = 0.62 to 0.96, OR2016 = 0.51, 95% CI = 0.41 to 0.63, OR2018 = 0.33, 95%CI = 0.27 to 0.42, OR2020 = 0.25, 95% CI = 0.18 to 0.32; and for younger White men: OR2014 = 0.81, 95% CI = 0.76 to 0.87, OR2016 = 0.66, 95% CI = 0.61 to 0.71, OR2018 = 0.41, 95%CI = 0.37 to 0.44, OR2020 = 0.36, 95% CI = 0.33 to 0.39). Younger Black men showed a brisker decrease in PSA screening in 2016, 2018, and 2020 compared with younger White men (all P < .05). CONCLUSIONS:PSA screening among younger men steadily decreased over the past decade since the 2012 United States Preventive Services Task Force guidelines, demonstrating a narrowing racial gap. How such an observed trend translates to long-term clinical outcomes for younger Black men remains to be seen.
PMCID:9991604
PMID: 36708009
ISSN: 2515-5091
CID: 5642492
