About

Mark P Fitzgerald, MD, PhD, is an Associate Professor of Clinical Neurology and an Attending Physician at the Children's Hospital of Philadelphia, affiliated with the University of Pennsylvania. His clinical expertise includes neonatal and early life epilepsies, with a particular focus on genetic epilepsy. His research interests are centered on neurodevelopmental and epilepsy outcomes in patients with neonatal and early-onset epilepsy, especially those with a genetic etiology. Fitzgerald has contributed to the understanding of the genetic basis of epilepsies and neurodevelopmental disorders, as evidenced by his involvement in studies on pathogenic variants affecting synaptic function and neurodevelopmental syndromes. His work includes investigating the phenotype spectrum of related disorders and developing models to predict seizures in neonates, thereby advancing the field of pediatric neurology and epilepsy.

Research topics

• Medicine
• Emergency medicine
• Family medicine
• Cancer research
• Cell biology
• Intensive care medicine
• Psychiatry
• Internal medicine
• Genetics
• Biology
• Multimedia
• Pediatrics

Selected publications

• Genetic testing for familial epilepsies: Diagnostic yield and genetic findings

  Epilepsia · 2026-03-08

  articleOpen access

  OBJECTIVE: Genetic testing has become a routine part of clinical epilepsy care. Family history is an indication for genetic testing, but the diagnostic yield, predictors of a genetic diagnosis, and association with familial patterns are not well understood. METHODS: This was a retrospective cohort study of genetic testing performed at pediatric and adult epilepsy genetics clinics. Eligible patients (probands) had epilepsy and one or more first-degree relatives or two or more other relatives with epilepsy. Genetic testing strategies were patient specific, reflecting real-world clinical practice. Familial patterns were classified based on affected relatives of the proband. Diagnostic variants were tested in the proband's parents when possible. RESULTS: (1) = 9.6, p = .002) and earlier age at seizure onset (Mann-Whitney U test, p < .001). The likelihood of a genetic diagnosis was not associated with epilepsy type, drug resistance, brain magnetic resonance imaging (MRI) findings, number of affected first-degree relatives, total number of affected relatives, or having an affected parent with epilepsy. Among those with genetic diagnoses, variant segregation matched the familial pattern of affected individuals in 79%. The other 21% of families had unexpected segregation, including de novo variants in patients with affected ancestors and inherited variants in patients with no known affected ancestors. SIGNIFICANCE: Familial epilepsy has a substantial rate of genetic diagnosis and is an appropriate indication for genetic testing. Pedigree-related factors did not influence the likelihood of genetic diagnosis, suggesting that all families can be considered for genetic testing, independent of inheritance patterns and number of affected relatives. Familial patterns can help interpret genetic test results, while also revealing the complexities of incomplete penetrance and independent epilepsy etiologies in families.

  PublisherDOI

• A clinical and genotype-phenotype analysis of MACF1 variants

  The American Journal of Human Genetics · 2025-09-08 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Mosaic Ring 20 Syndrome

  Neurology Genetics · 2025-07-16 · 1 citations

  articleOpen accessSenior author

  Background and Objectives: Ring 20 syndrome is a rare childhood-onset neurodevelopmental disorder caused by a postzygotic event leading to a structural change in the 20th chromosome. Next-generation sequencing (NGS) does not identify an abnormality in the most common mosaic form. Through a systematic review of the literature, we sought to identify clinically distinct characteristics that would trigger an order for a karyotype, which is the only definitive diagnostic test for this condition. Methods: A systematic literature review was performed reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. PubMed and Web of Science were searched from inception through January 8, 2025. Included studies reported on mosaic ring 20 syndrome. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined. Results: A total of 70 publications reporting on 148 patients were included. Our review clearly reveals a distinct set of signs that should alert the informed neurologist to order a karyotype analysis at the first evaluation because it is currently the only method to properly diagnose this condition. Over 90% of cases which mention the seizure type describe multiply recurrent nonconvulsive status epilepticus. Patients generally do not have dysmorphia and are developing normally over the average of 7 years before seizure onset. The diagnosis of mosaic ring 20 syndrome should be considered in the setting of childhood-onset treatment-resistant epilepsy, particularly in the absence of focal abnormalities on brain MRI abnormalities, distinctive EEG findings, and pathogenic variants on short-read NGS. Discussion: The diagnosis of mosaic ring 20 syndrome is via karyotype analysis. The current lag time from seizure onset to definitive diagnosis is 7.7 years. More widespread recognition of the distinctive clinical features of mosaic ring 20 syndrome should help shorten the diagnostic delay for affected individuals.

  PublisherOA PDFDOI

• Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

  Nature Genetics · 2025-10-22 · 2 citations

  articleOpen access

  The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.

  PublisherOA PDFDOI

• White Matter Microstructural Abnormalities in Neonatal Onset Genetic Epilepsy

  Annals of Clinical and Translational Neurology · 2025-01-01

  preprintOpen access

  OBJECTIVE: Recent evidence indicates that epilepsy is associated with abnormal white matter. If seizures alter white matter, then the impact upon network function, epileptogenesis, and cognition could be pronounced in neonates undergoing rapid developmental myelination. Neonates with epilepsy due to nonstructural genetic causes provide a unique opportunity to determine whether neonates experiencing seizures have abnormal white matter structure. METHODS: This was a retrospective case-control study of term neonates treated in a level IV NICU between 2013 and 2020. Cases had confirmed or suspected genetic epilepsy, normal MRI, and no conditions known to independently impact white matter. Healthy controls had normal MRI and no relevant clinical diagnoses. White matter was assessed via fractional anisotropy (FA) and mean diffusivity (MD) from Diffusion Tensor Imaging (DTI) using Tract Based Spatial Statistics (TBSS). RESULTS: Fifty-eight neonates (19 cases, 39 controls) were included. There was significantly increased FA and decreased MD in the superior corona radiata of neonates with genetic epilepsy compared to healthy controls, controlling for sex and postmenstrual age at time of MRI. Additional association tracts (anterior and posterior corona radiata, tapetum, external capsule, superior and inferior fronto-occipital fasciculus) approached significance (p < 0.2). There was no significant correlation between mean FA or MD and EEG seizure burden or developmental outcome. INTERPRETATION: White matter microstructure is abnormal, with higher FA and lower MD, in major association tracts of neonates with genetic epilepsy compared to healthy controls. These results indicate that white matter is impacted early in neonatal epilepsies, emphasizing the global impact of early-onset seizures.

  PublisherDOI

• Phenotype Spectrum of <scp>TRPM3</scp>‐Associated Disorders

  Annals of Neurology · 2025-01-03 · 5 citations

  articleOpen access

  OBJECTIVE: Monoallelic variants in the transient receptor potential melastatin-related type 3 gene (TRPM3) have been associated with neurodevelopmental manifestations, but knowledge on the clinical manifestations and treatment options is limited. We characterized the clinical spectrum, highlighting particularly the epilepsy phenotype, and the effect of treatments. METHODS: We analyzed retrospectively the phenotypes and genotypes of 43 individuals with TRPM3 variants, acquired from GeneMatcher and collaborations (n = 21), and through a systematic literature search (n = 22). We included all patients with a pathogenic TRPM3 variant. RESULTS: The median age at the time of the study was 10 years, with a preponderance of girls (60%) versus boys (40%). Frequent findings were developmental delay and/or intellectual disability (93%), global or axial hypotonia (77%), ocular involvement (70%), musculoskeletal anomalies (65%), and dysmorphic features (58%). Epilepsy was diagnosed in 31 patients (72%), classified in all as developmental and epileptic encephalopathy with or without spike wave activation in sleep (DEE/DEE-SWAS). Patients with the variant p.Val1002Met (n = 24) significantly more often had developmental delay and epilepsy. The most effective anti-seizure medication was primidone. All treated patients showed an improvement in seizure frequency, motor and speech development, and/or learning capability with this drug. INTERPRETATION: Developmental delay/intellectual disability and epilepsy are dominant phenotypic features in patients with TRPM3 variants. Given that epilepsy can negatively impact development, screening for awake and sleep electroencephalogram abnormalities and other manifestations are essential to offer early intervention. The TRPM3 channel blocker primidone has shown promising effects and should be considered in every child with a TRPM3 gain-of-function variant. ANN NEUROL 2025;97:561-570.

  PublisherOA PDFDOI

• <i>USP25</i> in genetic generalized epilepsy: a gene under scrutiny

  Brain · 2025-10-25 · 1 citations

  article

  not available

  PublisherDOI

• A research roadmap for SCN8A-related disorders: addressing knowledge gaps and aligning research priorities across stakeholders

  Orphanet Journal of Rare Diseases · 2025-08-19 · 4 citations

  reviewOpen access

  BACKGROUND: Despite significant scientific progress since the 2012 discovery that variants in the SCN8A gene can cause human epilepsy, disease mechanisms and best practices for management of SCN8A-related disorders (SCN8A-RD) remain incompletely understood. To accelerate the rate of progress, the International SCN8A Alliance sponsored a conference in Boston, Massachusetts, on August 16-18, 2024. The goals were to identify core knowledge gaps and research priorities, and to establish a collaborative research strategy to improve quality of life. In addition to a number of family leaders representing caregiver priorities, the meeting included laboratory scientists, clinicians, and representatives from the biopharmaceutical industry. MAIN BODY: The scientific literature and requests for proposals from epilepsy funding agencies were reviewed prior to the meeting. Stakeholder-specific surveys were conducted focusing on knowledge gaps, research priorities, and scientific roadblocks. Interviews with biotechnology leaders were conducted to identify their priorities. These data were analyzed to assess responsiveness to caregiver concerns and to identify top research priorities for advancing the field. The Caregiver survey (n = 175) revealed top challenges and identified novel therapeutics and management of non-seizure phenotypes/comorbidities as top priorities. Clinician (n = 46) and scientist (n = 23) surveys identified a number of common research priorities, partially overlapping with caregiver concerns. Five core areas emerged from integrated analysis of all four stakeholder surveys and became the focus areas of five Working Groups: (1) Transformative Therapeutics, (2) Non-Seizure Outcomes, (3) Current Therapeutics, (4) Biomarkers, and (5) Whole Brain/Whole Body. CONCLUSIONS: Taking account of the concerns and priorities of the caregiver community, the five working groups identified research directions to address knowledge gaps that include both short- and long-term priorities to improve understanding of disease mechanisms and management for the spectrum of SCN8A-RD phenotypes. Challenges included identification of suitable funding mechanisms and the lack of expertise in certain methodologies and research areas. This Research Roadmap is expected to accelerate progress toward the goals of improved quality of life and transformative care for all those with SCN8A-RD.

  PublisherOA PDFDOI

• Contrast Enema for Neonatal Distal Bowel Obstruction: The Diagnostic and Pathological Yield

  Journal of Clinical and Medical Images · 2024-01-01

  articleOpen access1st authorCorresponding

  Purpose Neonatal distal bowel obstruction (DBO) can present a diagnostic challenge [1, 2] As different aetiologies have similar clinical manifestations with not all surgical intervention [2, 3]. Contrast enemas (CE) can help differentiate the aetiology avoiding the need for surgery [2-4]. We reviewed 20years of CE to evaluate their diagnostic and pathological yield in neonatal DBO

  PublisherOA PDFDOI

• Assessing the Clinical and Treatment Landscape of Genetic Epilepsies Through 3,760 Individuals (S24.007)

  Neurology · 2024-04-09

  articleSenior author

  To delineate disease trajectories and longitudinal treatment landscapes in genetic epilepsies through Real-World Data captured from routine clinical care.

  PublisherDOI

Frequent coauthors

• Nicholas S. Abend

  Children's Hospital of Philadelphia

  89 shared

• Ingo Helbig

  University of Pennsylvania

  69 shared

• Shavonne L. Massey

  Children's Hospital of Philadelphia

  68 shared

• France W. Fung

  University of Pennsylvania

  54 shared

• Sudha Kilaru Kessler

  Children's Hospital of Philadelphia

  49 shared

• Gaétan Lesca

  Institut NeuroMyoGène

  28 shared

• Katherine B. Howell

  Royal Children's Hospital

  27 shared

• Marisa S. Prelack

  Children's Hospital of Philadelphia

  25 shared

Education

• Epilepsy Fellowship, Neurology

  Children's Hospital of Philadelphia Division of Neurology

  2017

• Child Neurology Residency, Neurology

  Children's Hospital of Philadelphia Division of Neurology

  2016

• Pediatrics Residency, Pediatrics

  Children's Hospital of Philadelphia

  2013

• MD, School of Medicine

  University of Virginia

  2011

• PhD, Neuroscience

  University of Virginia

  2009