Authors :
Presenting Author: Manuela Ochoa-Urrea, MD – The University of Texas Health Science Center at Houston
Anu Cherukara, BS – University of Texas Health Science Center at Houston
Alison Merket, MSc – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Emile Moura Coelho da Silva, MS, CGC – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Sunanjay Bajaj, MD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Tobias Brünger, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Ludovica Montanucci, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Dennis Lal, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Rationale:
SCN2A mutations cause a spectrum of neurodevelopmental disorders, from neonatal-onset epileptic encephalopathies to autism spectrum disorder (ASD) without epilepsy. Protein-truncating variants (PTV) result in loss-of-function (LOF), are associated with later-onset epilepsy and/or developmental delay (DD) and ASD without epilepsy. In contrast, gain-of-function (GOF) typically present with early, severe epilepsy, but only ~20% have ASD or DD.
Due to genetic testing ascertainment bias in children with epilepsy compared to DD, children with PTVs are often undiagnosed or diagnosed late, missing chances for critical early intervention. Treatment and prognosis differ between LOF and GOF variants. We aimed to describe the early and evolving features of SCN2A-PTV individuals through their family lived experiences, to improve early diagnosis and characterize their evolution.
Methods:
We conducted semi-structured interviews from parents of 10 individuals with SCN2A-PTVs asking early developmental signs, milestones, seizure onset, interactions with medical systems, unmet needs, and life impact. Responses were coded and categorized by developmental stage. Proportions of shared features were calculated.Results:
The median age at interview was 106.5 months (IQR 70.8–153). Epilepsy was diagnosed in 40%, with explosive and refractory onset at mean age 2.5 years, leading to drastic changes in family life. Genetic testing was triggered by seizure onset, despite prior DD concerns. Additional 20% had febrile seizures only.
Neonatal period: Poor sleep reported in 40%, difficulty latching in 30%, causing mastitis in 20%.
2–3 months: 50% noted delayed milestones; hypotonia (40%), feeding issues (40%), and irritability (30%) were common.
13–24 months: Language delays (90%), gross motor delays (80%), and sensory symptoms (70%)—initially thought as colicky infant—emerged.
Developmental regression occurred in 70% between 12 and 30 months.
By age 5: All had delays in motor and language domains. Self-feeding and writing remained unattained in 80%.
Puberty (12–17 years): 2/3 had worsening of seizures and behavior. Teen years brought challenges in ADLs, including incontinence in 2/3.
Systemic challenges: 80% reported difficulty accessing services; 50% had delayed diagnoses; 40% reported early concerns being dismissed by providers.
Conclusions:
SCN2A PTVs lead to a recognizable neurodevelopmental trajectory with subtle early feeding and regulatory challenges, followed by delays in motor and language milestones, regression, and evolving behavioral and functional impairments. Despite significant early concerns, diagnostic delays are common, often due to lack of seizures and under-recognition of developmental signs. Awareness of early features—sleep difficulties, sensory, and feeding challenges—may prompt earlier genetic tests. Our findings support the need for broader testing in children with DD and ASD, underscoring the value of incorporating family narratives into syndrome characterization and diagnostic decision-making.
Conference data will include 10+ additional interviews and registry data from 100+ PTV carriers across three registries.
Funding: No funding received.