- Clinical Genetics and Genomics
Clinical Scholar, Neurology & Neurological Sciences
Doctor of Philosophy, Columbia University (2013)
Bachelor of Arts, Yale University (2006)
Doctor of Medicine, Columbia University (2015)
Board Certification: American Board of Medical Genetics and Genomics, Clinical Genetics and Genomics (2023)
Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2020)
Fellowship: Stanford University Division of Medical Genetics (2022) CA
Residency: Stanford University Division of Medical Genetics (2022) CA
Residency: Stanford University Child Neurology Residency (2020) CA
Medical Education: Columbia University College of Physicians and Surgeons (2015) NY
PhD, Columbia University, Neurobiology
MD, Columbia University
BA, Yale University, Neuroscience
Paul Fisher, Postdoctoral Faculty Sponsor
Additional Clinical Info
- A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder LIPPINCOTT WILLIAMS & WILKINS. 2023
What Have Organoids and Assembloids Taught Us About the Pathophysiology of Neuropsychiatric Disorders?
Neuropsychiatric research has been impeded by limited access to human brain tissue, especially from early stages of neurodevelopment when the pathophysiology of many childhood-onset disorders is initiated. Neural organoids are 3-dimensional, self-organizing, multicellular structures generated from pluripotent stem cells that recapitulate some of the cell diversity, cytoarchitecture, and functional features of domains of the developing nervous system. Assembloids are 3-dimensional, self-organizing cultures created by the combination of two or more distinctly patterned organoids or an organoid plus additional cell or tissue type(s) that are used to model cell migration and connectivity. Here we review recent advances in neuropsychiatric disorder research using organoid and assembloid models to study the role of disease-relevant genes and mutations, as well as the impact of environmental risk factors on neural development. We also highlight some of the advantages and limitations of these model systems in bringing insights into the pathophysiology of neuropsychiatric disorders.
View details for DOI 10.1016/j.biopsych.2022.11.017
View details for PubMedID 36739210
A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder.
2022; 138: 101-106
BACKGROUND: CACNA1C encodes the voltage-gated L-type calcium channel CaV1.2. A specific gain-of-function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relates to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development.METHODS: Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher exact test for comparison of categorical variables between participants with and without cardiac arrhythmia.RESULTS: Twenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention-deficit/hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia.CONCLUSIONS: In our CRD cohort, there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.
View details for DOI 10.1016/j.pediatrneurol.2022.10.013
View details for PubMedID 36436328
Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.
Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.Exposures: Genetic test results.Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595(368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
View details for DOI 10.1001/jamaneurol.2022.3651
View details for PubMedID 36315135
Delineating the Epilepsy Phenotype of NGLY1 Deficiency.
Journal of inherited metabolic disease
To delineate the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort.We collected detailed clinical and electroencephalographic data from 29 individuals with bi-allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in-person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping.Of 29 individuals (mean 11.4 years, range 3-27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. EEGs were abnormal in 80% (12/15) of participants with or without epilepsy, though encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays.Epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/jimd.12494
View details for PubMedID 35243670
Evaluation of Seizure Risk in Infants After Cardiopulmonary Bypass in the Absence of Deep Hypothermic Cardiac Arrest.
BACKGROUND: Guidelines recommend evaluation for electrographic seizures in neonates and children at risk, including after cardiopulmonary bypass (CPB). Although initial research using screening electroencephalograms (EEGs) in infants after CPB found a 21% seizure incidence, more recent work reports seizure incidences ranging 3-12%. Deep hypothermic cardiac arrest was associated with increased seizure risk in prior reports but is uncommon at our institution and less widely used in contemporary practice. This study seeks to establish the incidence of seizures among infants following CPB in the absence of deep hypothermic cardiac arrest and to identify additional risk factors for seizures via a prediction model.METHODS: A retrospective chart review was completed of all consecutive infants≤3months who received screening EEG following CPB at a single center within a 2-year period during 2017-2019. Clinical and laboratory data were collected from the perioperative period. A prediction model for seizure risk was fit using a random forest algorithm, and receiver operator characteristics were assessed to classify predictions. Fisher's exact test and the logrank test were used to evaluate associations between clinical outcomes and EEG seizures.RESULTS: A total of 112 infants were included. Seizure incidence was 10.7%. Median time to first seizure was 28.1h (interquartile range 18.9-32.2h). The most important factors in predicting seizure risk from the random forest analysis included postoperative neuromuscular blockade, prematurity, delayed sternal closure, bypass time, and critical illness preoperatively. When variables captured during the EEG recording were included, abnormal postoperative neuroimaging and peak lactate were also highly predictive. Overall model accuracy was 90.2%; accounting for class imbalance, the model had excellent sensitivity and specificity (1.00 and 0.89, respectively).CONCLUSIONS: Seizure incidence was similar to recent estimates even in the absence of deep hypothermic cardiac arrest. By employing random forest analysis, we were able to identify novel risk factors for postoperative seizure in this population and generate a robust model of seizure risk. Further work to validate our model in an external population is needed.
View details for DOI 10.1007/s12028-021-01313-1
View details for PubMedID 34322828
Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.
American journal of medical genetics. Part A
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.
View details for DOI 10.1002/ajmg.a.62160
View details for PubMedID 33683010
Acute Hyperextension "Surfer's" Myelopathy in a Gymnast: Bending over Backwards for Diagnosis
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058004287
Continuous EEG for Seizure Detection in Neonates after Cardiac Bypass without Deep Hypothermic Cardiac Arrest
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058004299
A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis.
A previously healthy 15-year-old boy presented with 3 months of progressive psychosis, insomnia, back and groin pain, and hyperhidrosis. On examination, the patient was disheveled, agitated, and soaked with sweat, with systolic blood pressure in the 160s and heart rate in the 130s. Aside from occasional auditory and visual hallucinations, his neurologic examination was normal. The patient was admitted for an extensive workup, including MRI of the brain and spine and lumbar puncture, which were normal. Through collaboration with various pediatric specialists, including psychiatry and neurology, a rare diagnosis was ultimately unveiled.
View details for DOI 10.1542/peds.2019-3786
View details for PubMedID 32444380
- Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures NATURE NEUROSCIENCE 2019; 22 (3): 484-+
Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency.
Annals of neurology
Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2(-/-) ) mice by 2-3 fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.To test these hypotheses, we assessed two therapies in Tk2(-/-) mice: 1) dT+dC and 2) co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2(-/-) animals compared to dCMP+dTMP.Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ana.24922
View details for PubMedID 28318037
Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice
In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia.
View details for DOI 10.1038/tp.2015.75
View details for Web of Science ID 000367658600001
View details for PubMedID 26057047
Long Survival in Patients With Leigh Syndrome and the m.10191T > C Mutation in MT-ND3: A Case Report and Review of the Literature
JOURNAL OF CHILD NEUROLOGY
2014; 29 (10): NP105-NP110
We report an unusual case of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood because of a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.
View details for DOI 10.1177/0883073813506783
View details for Web of Science ID 000342823700005
View details for PubMedID 24284231
Copy number variation and psychiatric disease risk.
Methods in molecular biology (Clifton, N.J.)
2012; 838: 97-113
Psychiatric disorders are multifactorial in nature with complex genetic architecture. A number of recent studies, building upon earlier findings of copy number variants (CNVs) at the 22q11.2 locus, suggest that rare CNVs represent an important component of genetic heterogeneity in the etiology of complex psychiatric diseases, such as schizophrenia. De novo CNVs are found with higher frequency among sporadic cases, whereas inherited CNVs are enriched among familial cases. Despite substantial progress, a number of challenges remain, such as pinpointing causative relationships between specific gene(s) affected by CNVs and disease phenotypes as well as distinguishing abnormal structural mutations from neutral polymorphisms and establishing a clear association between individual pathogenic CNV and disease phenotypes.
View details for DOI 10.1007/978-1-61779-507-7_4
View details for PubMedID 22228008
Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (49): E1349-E1358
Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
View details for DOI 10.1073/pnas.1114113108
View details for Web of Science ID 000297683800012
View details for PubMedID 22049344
A Case of Abulia From Left Middle Cerebral Artery Stroke in an Adolescent Treated Successfully With Short Duration Olanzapine.
; 43 (3): 86–89
Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower. It presents with a challenging array of overlapping symptoms, making effective identification and treatment difficult.We describe the first known report of an adolescent with a ventricular assist device who developed abulia following a left middle cerebral artery (MCA) stroke who responded successfully to treatment with olanzapine.The neurobiological etiology of abulia is still unclear but is postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. There have been reports of poststroke patients with abulia being treated by modulating this dopamine circuitry and in some cases with short-term low-dose olanzapine.Further research is needed to develop a better understanding of the pathophysiology of abulia leading to more effective treatment algorithms including more specific diagnostic tools and effective pharmacological interventions.
View details for DOI 10.1097/WNF.0000000000000389
View details for PubMedID 32384311