Authors :
Presenting Author: Duyu Nie, MD, PhD – Division of Pediatric Neurology and the Children's Neurodevelopment Center (CNDC), Hasbro Children’s Hospital, Providence, RI
Elizabeth Nolan, BA – Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence RI
Carin Papendorp, MD, PhD – Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence RI
Brian Kavanaugh, PsyD – Division of Psychiatry and Human Behavior, Emma Pendelton Bradley Hospital, Brown University, Providence RI
Jennifer Elacio, BS – Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence RI
Carrie Best, MPH – Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence RI
Judy Liu, MD, PhD – Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX
Rationale:
Mutations in the ASH1L (Absent, Small, or Homeotic-like 1) gene have been associated with epilepsy, intellectual disability, and autism spectrum disorder (ASD) [1,2,3]. However, the genotype–phenotype correlation in ASH1L-associated epilepsy and neurodevelopmental multimorbidity remains incompletely understood.Methods:
This was a prospective natural history study. All participants were confirmed to have a pathogenic or likely pathogenic variant of ASH1L based on clinical genetic testing and confirmation by research team. Additional medical records were reviewed upon consent. During in-person visits, participants and families underwent a structured interview with research staff, behavioral and cognitive assessments, a neurological exam and a standard clinical EEG recording.Results:
Of 26 patients (14 females and 12 males) included here, 9 nonsense, 7 missense, 9 frameshift, and 2 splice site variants (total 27) were identified in ASH1L, including two siblings harboring the same splice site variant, and one patient with 2 different missense variants. Epileptic seizures and/or epileptiform EEGs were documented in 14 patients (9 females and 5 males). Both focal (mostly frontal lobe) and generalized interictal epileptiform discharges were reported; however, clinical seizures were predominantly generalized including absence seizures, generalized tonic-clonic (GTC), Jeavons syndrome, and photosensitive epilepsy. Seizures responded to broad spectrum anti-seizure medications (ASMs), mostly with mono- or dual therapy, including Ethosuximide, Valproate, Lamotrigine, Levetiracetam, Clobazam. Of note, epilepsy was more common and more significantly manifested in patients with ASH1L nonsense and frameshift variants. In addition, there were high rates of neurodevelopmental multimorbidity including attention deficits hyperactivity disorder (ADHD), intellectual disability (ID), ASD, and tic disorder. Whereas ASD had a male predisposition, epilepsy predominantly affected female patients in this small cohort.Conclusions:
Our study has demonstrated a higher prevalence and worse phenotypic severity of epilepsy, in female patients with ASH1L mutations, which may implicate sex-specific epigenetic mechanisms of ASH1L in epileptogenesis.
Reference
1. Qin et al. Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures. Nat Commun. 2021 Nov 15;12(1):6589.
2. Liao et al. Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability. Front Neurol. 2025 Jan 20:16:1524532.
3. Tang et al. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia. 2020 May;61(5):995-1007.
Funding: 1.
NIH/NIMH 1R21MH136643-01
2. Eagles Autism Foundation