About

Eric David Marsh, M.D., Ph.D., is a Professor of Neurology at the Children's Hospital of Philadelphia and the Director of the Orphan Disease Center. His clinical expertise includes Pediatric Epileptology and Pediatric Neurology. His research focuses on interneuron development, epilepsy models, intracranial EEG recordings, and electrophysiology. He is affiliated with the Department of Neurology and the Division of Child Neurology at the University of Pennsylvania, with educational background from Haverford College, New York University- Sackler School of Biomedical Sciences, and New York University School of Medicine.

Research topics

• Medicine
• Genetics
• Biology
• Neuroscience
• Psychiatry
• Internal medicine
• Pediatrics
• Pathology
• Chemistry
• Psychology
• Bioinformatics

Selected publications

• Functional Characterization of Parallel Fiber-Purkinje Cell Synapses in Two Friedreich’s Ataxia Mouse Models

  The Cerebellum · 2025-02-05 · 2 citations

  articleOpen access

  Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by GAA expansions in the FXN gene, which codes for the protein frataxin (FXN). These mutations reduce FXN expression, leading to mitochondrial dysfunction and multisystemic disease. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, may drive the neurological phenotypes of FRDA, but the mechanisms underlying such neurological phenotypes remain unclear. To investigate the neural circuit basis of this dysfunction, we employed field recordings to measure Purkinje cell (PC) function and synaptic properties along with western blotting and immunohistochemistry to determine their density and structure in two established FRDA mouse models, the shRNA-frataxin (FRDAkd) and the frataxin knock in-knockout (KIKO) mice. Western blotting demonstrated subtle changes in mitochondrial proteins and only a modest reduction in the density of calbindin positive cells PCs in the cerebellar cortex of the FRDAkd mice, with no change in the density of PCs in the KIKO mice. Though PC density differed slightly in the two models, field recordings of parallel fiber-PC synapses in the molecular layer demonstrated concordant hypo-excitability of basal synaptic transmission and impairments of long-term plasticity using induction protocols associated with both potentiation and depression of synaptic strength. These results indicate that synaptic instability might be a common feature in FRDA mouse models.

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• Altered oscillatory coupling reflects possible inhibitory interneuron dysfunction in Rett syndrome

  medRxiv · 2025-07-21

  preprintOpen access

  Abstract Rett syndrome is a rare neurodevelopmental disorder caused primarily by pathogenic variants in the MECP2 gene, leading to lifelong cognitive impairments. To understand the broad neural disruptions in Rett syndrome, it is essential to examine large-scale brain dynamics at the level of neural oscillations. Phase-amplitude coupling—a form of cross-frequency interaction that supports information integration across temporal and spatial scales—is a promising candidate measure for capturing such widespread neural dysfunction. Phase-amplitude coupling depends on the coordinated activity of specific neuronal subtypes, and while multiple subtypes are implicated in different aspects of the Rett syndrome phenotype, their role in shaping large-scale oscillatory dynamics in Rett syndrome is not well understood. To investigate this, we utilized a multi-level approach, combining EEG recordings with computational modeling to identify alterations in phase-amplitude coupling in Rett syndrome and probe their underlying cellular and circuit-level mechanisms. We recorded resting-state EEG from 38 individuals with Rett syndrome and 30 age- and sex-matched typically developing individuals. Phase-amplitude coupling was quantified: modulation index was obtained to determine coupling strength, and phase bias was assessed to examine the preferred phase of coupling. We characterized phase-amplitude coupling across all low and high frequency combinations and electrodes, as well as within canonical theta-gamma and alpha-gamma frequency pairs across four predefined cortical regions. Finally, we modeled a biophysically-constrained Layer 4 cortical network to propose a possible mechanism underlying changes to oscillatory dynamics. We found significantly stronger phase-amplitude coupling in Rett syndrome across widespread cortical regions and frequency pairs, with a pronounced increase in theta-gamma and alpha-gamma coupling in anterior, posterior, and whole-brain regions ( P < 0.05). Individuals with Rett syndrome also exhibited a more positive alpha-gamma phase bias in anterior and whole-brain regions ( P < 0.05). Biophysically constrained modelling demonstrated that reduced VIP-expressing interneuron activity alone could recapitulate the pattern of increased theta-gamma and alpha-gamma phase-amplitude coupling observed in Rett syndrome ( P < 0.001). These findings identify alterations in awake-state phase-amplitude coupling in Rett syndrome and propose a mechanistic link to VIP+ interneuron dysfunction. Elevated phase-amplitude coupling may serve as a promising biomarker of cortical dysfunction and a translational bridge from neural circuitry to clinically observable EEG signatures. By implicating VIP+ interneurons, our results open new avenues for testing interventions in preclinical models to identify potential novel therapeutic targets for individuals with Rett syndrome.

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• Efficacy and Safety of Trofinetide for the Treatment of Rett Syndrome: Results from the Pivotal Phase 3 LAVENDER Study

  Neuropediatrics · 2025-09-26

  article
  PublisherDOI

• Considerations and procedures for acquiring EEG as part of multi-site studies for Rett syndrome and other genetic neurodevelopmental disorders

  Frontiers in Integrative Neuroscience · 2025-06-09 · 2 citations

  articleOpen accessSenior author

  There is increasing interest in the utility of electrophysiological measures such as resting EEG and evoked potential (EPs) to serve as biomarkers to facilitate therapeutic development for rare genetic neurodevelopmental disorders (NDDs). Research on this topic thus far has been encouraging, but has also revealed the necessity for unique methods when acquiring EEG and EPs in children with genetic NDDs. Details of these methods are typically beyond the scope of research publications, yet are crucial to the quality and ultimately, usability of the data. In the current manuscript, we detail the methods that we have developed for acquiring EEG and EPs as part of multi-site studies with participants with Rett syndrome, CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. By making our methods accessible, we hope to support other groups interested in acquiring EEG and/or EPs as part of clinical trials or research studies with individuals with genetic NDDs, including groups without prior experience with EEG/EP acquisition. The paper is presented as step-by-step procedures followed by a discussion of issues that may arise during acquisition and ways to troubleshoot these issues. We then discuss considerations for choosing EEG equipment and study paradigms and briefly, considerations for data analysis.

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• Medical Biases and Misconceptions Impact Diagnoses in Males With Loss of Function <scp><i>MECP2</i></scp> Variants

  American Journal of Medical Genetics Part A · 2025-06-14 · 2 citations

  articleOpen access

  Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. These variants were historically believed to be incompatible with life in males; however, recent advances in genetic testing have revealed significant clinical heterogeneity. The current study aimed to improve our understanding of diagnostic experiences in males with confirmed pathogenic alteration of MECP2. An international sample of caregivers completed a survey of diagnostic experiences (N = 47) and phenomenological interviews (n = 32). Median [interquartile range; IQR] age of genetic diagnosis was 3 years [1.08, 6.75]. Multivariate analysis showed that for every year increase in year of birth, age of diagnosis (in years) decreased by 0.31. Qualitative findings demonstrate that medical biases and widespread misconceptions contribute to delays in accurate clinical diagnosis, which negatively impacts child health and family functioning. As genetic testing becomes more widely available, age of genetic diagnosis is decreasing, resulting in more providers and families with unexpected results and a notable lack of male-specific anticipatory guidance and clinical recommendations. Diagnostic providers must increase their awareness of males with confirmed pathogenic alterations of MECP2 and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options.

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• Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2–4 years with Rett syndrome

  Med · 2025-03-04 · 8 citations

  articleOpen access

  BACKGROUND: Trofinetide is the first available treatment for Rett syndrome (RTT) and is approved in the United States in adults and pediatric patients aged ≥2 years. The DAFFODIL study was conducted in girls aged 2-4 years with RTT to examine the safety, tolerability, and efficacy of trofinetide and to validate that the recommended dosage, according to body weight, achieved target exposure. METHODS: DAFFODIL was a phase 2/3, open-label study of trofinetide consisting of two treatment periods (12 weeks [period A] and ∼21 months [period B]). Pharmacokinetic samples were collected at regular intervals during period A. Assessments included treatment-emergent adverse events (TEAEs) and exploratory efficacy (Clinical Global Impressions-Improvement [CGI-I], CGI-Severity, caregiver GI-I [CaGI-I], and overall quality of life rating of the Impact of Childhood Neurologic Disability Scale [ICND-QoL]). Optional caregiver exit interviews were also conducted. FINDINGS: Fifteen participants were enrolled. Overall, the most common TEAEs were diarrhea (80.0%) and vomiting (53.3%), which were mild or moderate in severity. Steady-state exposure at clinical doses fell within the target exposure range. RTT symptoms improved throughout the study as measured by the CGI-I, CaGI-I, and change from baseline in the ICND-QoL. In caregiver interviews (n = 7), all caregivers reported they were "very satisfied" or "satisfied" with trofinetide benefits. CONCLUSIONS: Trofinetide has acceptable tolerability in girls 2-4 years of age with RTT and provides long-term efficacy. Weight-based dosage achieves target exposure in younger children. FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA). This study was registered at ClinicalTrials.gov (NCT04988867).

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• Symptom Onset in Classic Rett Syndrome: Analysis of Initial Clinical Severity Scale Entries

  Annals of the Child Neurology Society · 2025-06-16 · 1 citations

  articleOpen accessSenior author

  ABSTRACT Objective We aim to assess the clinical features of Rett syndrome (RTT) at registration into the National Institutes of Health–sponsored natural history study (NHS) using the Clinical Severity Scale (CSS). Introduction The CSS was established in 2000 to assess characteristics of individuals with RTT and related disorders. We analyzed the CSS at enrollment into the NHS of all individuals with classic RTT. Methods The CSS of 1258 individuals was used to examine three historical items (age at regression, age at onset of hand stereotypies, and head growth) and 10 clinical features at initial enrollment. Results Among historical items, age at regression was most prominent after age 12 months with 8% regressing before this, hand stereotypies were most common after 18 months with 30% occurring before, and head growth was substantially lower overall. Hand use, ambulation, and communication skills were reduced in most individuals. Discussion and Conclusion These findings reflect core clinical criteria for classic RTT and mirror the top concerns registered independently by parents or caregivers. The CSS is an important analytic tool for the association of relative differences in clinical outcome with specific MECP2 variant groups and has been important in establishing entrance criteria in RTT clinical trials. The range of age‐specific CSS features will continue to inform the RTT natural natural history as well as provide stratification and selection in future clinical trials, especially those involving younger participants.

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• The genetic and phenotypic spectrum of <i>GABRB1</i> -related disorders

  Brain · 2025-06-05 · 3 citations

  articleOpen access

  Pathogenic variants in GABAA receptor subunit genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harbouring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all 11 missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits. Gain-of-function (GoF) effects, characterized by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one variant and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease, including profound intellectual disability, hypotonia and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes, we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus. Seizures were therapy-resistant in all individuals with GoF variants and a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterization of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, although larger prospective studies are needed to confirm these observations.

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• Mapping the Epileptogenic Brain Using Low-Frequency Stimulation: Two Decades of Advances and Uncertainties

  Journal of Clinical Medicine · 2025-03-13 · 1 citations

  reviewOpen access

  Cortical stimulation is the process of delivering brief pulses of electrical current and visualizing the distributed pattern of evoked responses across the brain. Compared to high-frequency stimulation, which has long been used for seizure provocation and functional mapping, low-frequency stimulation (<1-2 Hz) is rarely incorporated into the epilepsy surgery evaluation. Increasingly, researchers have demonstrated that various cortico-cortical evoked potential (CCEP) features, including early and delayed responses, evoked high-frequency oscillations, and derived network metrics, may be useful biomarkers of tissue excitability and abnormal connectivity. Emerging evidence also highlights a potential role of CCEPs in guiding neuromodulatory therapies like responsive neurostimulation. In this review, we examine the past two decades of innovation in low-frequency stimulation as it pertains to pre-surgical evaluation. We begin with a basic overview of single-pulse electrical stimulation and CCEPs, including definitions, methodology, physiology, and traditional interpretation. We then explore the literature examining CCEPs as markers of cortical excitability, seizure onset, and network-level dysfunction. Finally, the relationship between stimulation-induced and spontaneous seizures is considered. By examining these questions, we identify both opportunities and pitfalls along the path towards integrating low-frequency stimulation into clinical practice.

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• Author response: Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy

  2025-12-11

  peer-reviewOpen access

  The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types including myoclonic seizures. Yet, the mechanistic basis of this disease, and of the KCNC1 disease spectrum, is unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is highly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the Ala421Val pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the specific physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to cognitive impairment, epilepsy, and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs (but not excitatory neurons) in current-clamp electrophysiology. In vivo two-photon calcium imaging revealed altered basal activity in Kcnc1-A421V/+ PV-INs and excitatory cells, as well as hypersynchronous discharges correlated with brief paroxysmal movements that were subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the specific impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

  PublisherDOI

Recent grants

• Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder

  NIH · $1.1M · 2021–2026

• Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder

  NIH · $3.6M · 2021–2027

• NIH Grant R01NS082761

  NIH · $1.8M · 2019

• NIH Grant K02NS065975

  NIH · $878k · 2015

• Training Program in Neurodevelopmental Disabilities

  NIH · $8.4M · 1998–2028

Frequent coauthors

• Tim A. Benke

  University of Colorado Denver

  266 shared

• Jeffrey L. Neul

  Vanderbilt University Medical Center

  160 shared

• Alan K. Percy

  University of Alabama at Birmingham

  149 shared

• Sarika U. Peters

  Vanderbilt University Medical Center

  113 shared

• Bernhard Suter

  Texas Children's Hospital

  95 shared

• Jenny Downs

  University of Western Australia

  68 shared

• Scott Demarest

  Children's Hospital Colorado

  66 shared

• David N. Lieberman

  Boston Children's Hospital

  61 shared

Labs

• Eric David Marsh LabPI