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From brain to heart: an update on the phenotypic spectrum of SCN1B-related diseases

Lucrezia Piccicacchi¹, Sopio Gverdtsiteli², Ingrid Scheffer³, Aeby Alec⁴, Nour Elkhateeb⁵, Laila Selim⁶, Dan Roden⁷, Gaetan Lesca⁸, Eleni Panagiotakaki⁸, Luca Bergonzini⁹, Mehran Beiraghi Toosi¹⁰, Damien Lederer¹¹, Alan Bayat², Niels Matthiesen¹², Konrad Platzer¹³, Sebastian Ortiz², Marina Trivisano¹⁴, Guido Rubboli², Elena Gardella², Rikke Steensbjerre Møller²

¹NHS Grampian , ²Danish Epilepsy Centre , ³Florey Institute of Neuroscience and Mental Health, ⁴Hôpital Universitaire de Bruxelles, ⁵Great Ormond Street Hospital , ⁶Cairo University Hospital, ⁷Vanderbilt University, ⁸Université de Lyon, ⁹Università di Bologna, ¹⁰Mashhad University of Medical Sciences, ¹¹Institut de Pathologie et de Génétique, Charleroi (IPG), ¹²Aarhus University Hospital, ¹³Institute of Human Genetics, University of Leipzig Medical Center, ¹⁴Bambino Gesù Children’s Hospital, IRCCS

SCN1B encodes for the regulatory beta 1 subunit of voltage gated sodium channels, expressed in multiple tissues, including brain and heart. Variants in SCN1B are associated with epilepsy and cardiac conduction disease. Here, we present an overview of the phenotypic spectrum of SCN1B, focusing on epilepsy and cardiac features. We gathered genetic, clinical and electrophysiological data on individuals with pathogenic and likely pathogenic variants in SCN1B through a literature review and international collaboration.

We identified 27 pathogenic/likely pathogenic variants in SCN1B in 127 individuals. Seizures were present in 87% of individuals, 94% had febrile seizures and 39 % had an epilepsy syndrome. Less than 20% of individuals had cardiac investigations and in 58 % of those tested cardiac pathology was identified. Cardiac disease included arrhythmias (71 %), heart failure (21 %), cardiomyopathy (28 %) and structural heart disease (28 %). Brugada syndrome was identified in three individuals from a SCN1B p.(Trp179*) family. 

For the highly recurrent SCN1B p.(Arg85His), we identified 24 individuals, from 13 unrelated families. Seizures were present in 79 % of individuals, with 68 % having febrile seizures. An epilepsy syndrome diagnosis was present in 36 %, including GEFS+ (n=4), EIDEE (n=1) and Dravet-like (n=1) in heterozygotes and Dravet-syndrome (n=1) in a homozygous individual. Cardiac disease was identified in 29 %; however, only 37 % of individuals had appropriate investigations. 

Here, we confirm the phenotypic heterogeneity of SCN1B variants and highlight a lack of cardiac follow-up in individuals with a pathogenic SCN1B variant, despite documented cases of arrhythmias, including Brugada syndrome, as well as cardiomyopathy and structural heart disease. Furthermore, we report co-existing cardiac and epilepsy phenotypes in several individuals with SCN1B R85H. Further characterisation of cardiac phenotypes in individuals with SCN1B will ensure appropriate counselling of families on management and prognosis, particularly around the risk of sudden cardiac death. 

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When Epilepsy Takes an Unexpected Turn: Adult Presentation of Mosaic SMC1A-Related Epilepsy

Mohamed Taha¹, Saul Crandon², Colette Mallon¹, Sharon Mulhern³, Natasha Fullerton⁴, Joseph Symonds⁵, Claire Gall¹

¹Department of Neurology, Institute of neurological sciences, NHSGGC, ²Department of Clinical Neurophysiology, Institute of neurological sciences, NHSGGC, ³Department of Clinical Neuropsychology, Institute of neurological sciences, NHSGGC, ⁴Department of Neuroradiology, Institute of neurological sciences, NHSGGC, ⁵Department of Paediatrics Neuroscience, Royal hospital for children, NHSGGC

Introduction: Refractory seizure clusters after a long period of seizure freedom in individuals with an established diagnosis of epilepsy, with no prior history of drug-resistant epilepsy, should prompt a thorough review of the underlying aetiology of epilepsy. This case highlights an unusual presentation of SMC1A-related epilepsy.

Case Presentation: We report a 25-year-old woman living with epilepsy diagnosed at age 16 years, after two unprovoked bilateral tonic-clonic seizures from waking. She has established diagnosis of childhood attention deficit disorder and dyspraxia. She remained seizure-free on Levetiracetam for eight years. In 2023, she developed abrupt recurrent seizure clusters presenting as focal to bilateral tonic-clonic seizures, focal motor seizures with impaired consciousness, and focal non-motor with impaired consciousness seizures. Clusters were often, but not exclusively, perimenstrual and led to repeated emergency department and intensive care admissions for status epilepticus despite escalation to adjuvant Lamotrigine, Lacosamide and Clobazam, with rescue Midazolam and repeated phenytoin loading.

Investigations: Pseudo-refractory causes, CNS infection, autoimmune encephalitis, metabolic disorders, mitochondrial disease and structural lesions were excluded. MRI brain showed disproportionate early volume loss, prominent Virchow-Robin spaces and a non-specific right frontal T2/FLAIR signal abnormality. Repeated EEGs demonstrated bifrontal high-amplitude slowing; five days video telemetry also showed runs of 1 Hz frontally dominant spike-and-slow-wave discharges prominent during sleep. Interictal FDG-PET showed relative bifrontal hypometabolism without convincing lateralisation. Chromosomal microarray, karyotype, mitochondrial gene testing and a 104-gene Scottish epilepsy panel were unrevealing. Review in a neuropaediatric-led genetic epilepsy clinic identified the combination of female sex, neurodevelopmental history and prominent afebrile seizure clustering as suggestive of SMC1A-related epilepsy. Additional testing identified a mosaic pathogenic SMC1A variant, c.3540C>A p.(Cys1180Ter), detected at reduced levels in blood and confirmed in saliva, predicted to introduce a premature stop codon. SMC1A loss-of-function variants typically cause female-predominant developmental and epileptic encephalopathy with early-onset drug-resistant cluster seizures; mosaicism may explain later presentation and milder cognitive features.

Management and outcome: Care was coordinated by adult epilepsy, neurophysiology, neuropsychology, neuroradiology, clinical genetics and neuropaediatric teams. Sodium Valproate was introduced with counselling and second-opinion review, producing a marked reduction in seizure burden, including a prolonged admission-free period. Neuropsychology demonstrated borderline premorbid function with stable impairments in memory, attention, executive function and visuospatial processing over time.

Conclusion: SMC1A-related epilepsy may present to adult neurologists as late-onset refractory seizure clusters after years of apparent stability. Recognition of specific genetic causes can guide early appropriate management, and help patients and families understand and live well with SMC1A-related epilepsy.

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Lessons Learned from a Regional Whole Genome Sequencing Pathway for Epilepsy Patients in the West Midlands: A Genomic Practitioner-Led Approach

Larisa Trower¹, Karen Cross¹, Aung Saw², Amitav Parida³, Shanika Samarasekera², Mary O’Driscoll1

¹West Midlands Regional Clinical Genetics Service, Birmingham Health Partners, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, ²Department of Neurology, University Hospital Birmingham NHS Foundation Trust, ³Department of Paediatric Neurology, Birmingham Children’s Hospital

Introduction: Over the last few decades, genomic testing has transformed epilepsy care from a syndrome-based approach to one focused on precision medicine. However, despite the National Health Service (NHS) being the first healthcare system worldwide to incorporate whole genome sequencing (WGS) into routine clinical care, equitable and efficient access to WGS remains a challenge. In 2024, a genomic practitioner-led pathway was introduced across the West Midlands region to improve access to WGS. This study describes the key lessons learned from this two-year regional pathway.

Methods: Data were collected prospectively by Genomic Practitioners between August 2024 and May 2026. Patient demographics, referral sources, indications, age at symptom onset, type of test requested, and test results were recorded. Results were reviewed by a multidisciplinary team, including neurologists and clinical geneticists.

Findings: A total of 304 patients were referred to the service; 160 samples were processed. Both adult and paediatric patients with seizure onset before two years of age and suspected epilepsy syndromes and/or additional clinical features (such as intellectual disability) were included. In keeping with NICE guideline (NG217), the main indication for referral was the presence of additional clinical features (71%; 215/304), followed by seizure onset before two years of age (26%; 80/304).

At the time of analysis, 119 results were available. The overall diagnostic yield was 32% (38/119). The highest diagnostic yield was observed in patients undergoing trio testing (21/38; 55%), compared with duo (6/38; 16%) and singleton (11/38; 29%).

A multiple-gene panel approach enhanced diagnostic yield, with most positive results obtained when the intellectual disability panel (R29) was added to the early-onset syndromic epilepsy panel (R59) (21/38; 55%), compared with R59 alone (4/38; 11%). Dravet syndrome associated with SCN1A variants was the most common diagnosis (5/38; 13%), followed by Tuberous Sclerosis associated with TSC1 variants (2/38; 5%).

The pathway demonstrated strong patient engagement, reflected by a low did-not-attend (DNA) rate of 6% (17/304) and a low dropout rate of 5% (16/304). The mean turnaround time from referral to completion of consent was 60 days.

Conclusion: The Genomic Practitioner-led WGS pathway significantly improved service efficiency by minimising incomplete referrals and reducing demands on senior clinicians’ time. Trio testing combined with multiple-gene panel analysis proved to be the most effective testing strategy. Genetic diagnoses led to changes in clinical management in 22% of patients (8/38). All patients benefited through access to condition-specific support groups, research opportunities, and information relevant to reproductive decision.

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Completeness and consistency of seizure and epilepsy classification in infant medical records: Comparisons against ILAE criteria within the eLIXIR South London cohort

Jacqueline Nonweiler¹, Emma Casey¹, Despoina Mandelenaki², Sushma Goyal², Charlotte Tye¹, Michael Absoud¹, Sarah Aldridge²

¹Department of Psychology, King’s College London, ²Newcomen Neurodevelopmental Centre, Children’s Neurosciences, Evelina London Hospital

Background: The ILAE framework classifies epilepsy across three levels: seizure type, epilepsy type, and syndrome (Scheffer 2017; Fisher 2017), with dedicated definitions for syndromes of neonatal and infantile onset (Zuberi 2022). Accurate, complete classification of seizures informs management, prognosis, and family counselling, and supports continuity across services. Although documentation in routine clinical practice is likely incomplete or inconsistent, few efforts have examined classification quality specifically in infant-onset seizures, where syndrome recognition is most prognostically consequential.

Aims: To assess the completeness, use of current terminology, and consistency of seizure and epilepsy documentation in infant medical records against current ILAE criteria.

Methods: Within the eLIXIR cohort, medical records of infants (aged <36 months) ascertained at first-instance EEG and subsequent epilepsy diagnosis (between 2021-2023) were reviewed. Documentation was assessed for: (i) completeness: whether seizure type, epilepsy type, and syndrome were each recorded; (ii) clinical ILAE classifications as noted by a consultant neurophysiologist and (iii) EEG reported classification of seizure activity. Analyses were descriptive.

Expected Results: Of n = 305 infants having EEGs, 15% (n = 46) received an epilepsy diagnosis. Presenting seizure type was documented in 90% of epilepsy diagnosed infants (n = 42), epilepsy type in 10% (n = 5) and syndrome in 10% of those with epilepsy diagnosis (n = 5); all three levels were reported only in 4% of cases (n = 2). Paediatric neurologists’ comparisons with EEG reported seizure findings are compared to medical record reports. 

Anticipated Conclusions: Classification of infant-onset seizures in routine records was frequently incomplete and variably consistent with ILAE standards, and more detailed in EEG reports which are not accessible via routine electronic medical records. Findings support structured documentation (e.g. classification proformas), targeted training, and emphasis on syndrome-level diagnosis to improve prognostic communication. Suggestions and implications for clinical care, including possible AI epilepsy classification, are considered.

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Developmental and educational outcomes in infants with suspected seizures: Evidence from the eLIXIR Study 

Jacqueline Nonweiler¹, Emma Casey¹, Despoina Mandelenaki², Sushma Goyal², Sarah Aldridge², Charlotte Tye¹, Michael Absoud²

¹King’s College London, ²Newcomen Neurodevelopmental Centre, Children’s Neurosciences, Evelina London Hospital

Background: Epilepsy incidence peaks in the first year of life, and infant-onset seizures carry a high risk of adverse neurodevelopment. Existing cohorts typically report cognitive or developmental outcomes but rarely capture educational placement, despite this being the functional outcome most salient to families and education services. First-instance EEG, identifiable through routinely collected electronic health records, provides a consistent and early ascertainment point that enables longitudinal tracking of medical and educational outcomes across a broad clinical spectrum.

Aims: To characterise infants suspected of seizures at first-instance EEG and to examine associations between early clinical features and later developmental trajectories and educational placements.

Methods: Infants were identified within eLIXIR (Early Life Cross-Linkage in Research, Born in South London), a pseudonymised linkage of routinely collected maternity, neonatal, and child health records from Guy’s and St Thomas’ and King’s College Hospital NHS Foundation Trusts, serving a large, diverse, urban population. Retrospective review of electronic health records was conducted for infants aged under 36 months undergoing first-instance EEG. Extracted variables include age at seizure onset, predominant seizure type, history of status epilepticus, and aetiological classification per ILAE criteria. Outcomes were developmental status and educational placement; for the primary analysis, placement was dichotomised as mainstream without support versus any additional educational support. Associations were assessed using chi-square and Fisher’s exact tests as appropriate. Records with missing outcome data were compared with complete records on baseline features to assess potential ascertainment bias.

Expected Results: We report developmentally typical, impaired, and unknown proportions for n = 305 infants, alongside educational placement where available. Status epilepticus, predominant seizure type, and younger age at onset were most strongly associated with developmental delay and specialist school placement. Missing data analysis indicated comparable baseline features between groups.

Anticipated Conclusions: In this infant cohort, younger age at first seizure and history of status epilepticus were most strongly associated with developmental delay and requirement for additional educational support. Reporting educational placement alongside developmental data offers a practical, meaningful outcome description that is under-represented in the infant epilepsy literature, with implications for early counselling, service planning, and resource allocation for families requiring additional support.

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Expanding the UK Epilepsy and Pregnancy Register to Capture Child Neurodevelopmental Outcomes

Ellie Preece¹, Matthew Bluett-Duncan¹, John Craig², Craig Heath³, Beth Irwin², Graeme Sills⁴, Ngawai Moss⁵, Victoria Taylor¹, Kathryn Burrell¹, Rebecca Bromley¹

¹University of Manchester, ²Belfast Health and Social Care Trust, ³NHS Greater Glasgow and Clyde, ⁴University of Glasgow, ⁵Queen Mary University of London

Background: Pregnancy pharmacovigilance and initiatives regarding antiseizure medications (ASMs) have predominantly focused surveillance on infant congenital anomaly outcomes, with less routine investigation of neurodevelopmental outcomes. Due to this, there are large knowledge gaps pertaining to the child neurodevelopmental outcomes for even relatively widely used monotherapy ASMs and polytherapy combinations. A series of studies have been undertaken in preparation for adapting the traditional pregnancy register methodology to incorporate routine longer-term neurodevelopmental follow-up for the UK Epilepsy and Pregnancy Register (UKEPR). The results of the 12-month child screening outcomes from these studies are presented here. 

Methods: Women were recruited during pregnancy and provided health and pregnancy information prospectively. Post-birth child health and demographic information was collected through an expert-developed questionnaire. Child neurodevelopment was assessed using the parental completed Ages and Stages, 3rd Edition (ASQ-3) and the 12-month ASQ-3 outcomes are presented here. 

Results: A total of 341 children were included in this analysis. Exposure groups comprised lamotrigine (LTG) monotherapy (n=107), levetiracetam (LEV) monotherapy (n=76), other monotherapies (n=31), polytherapy (n=86), and no ASM exposure (n=41). Across the total cohort, the proportion of children scoring within the typical developmental range was 88.3% (n = 301) for communication, 63.5% (n= 216) for gross motor, 70.9% (n= 241) for fine motor, 66.2% (n= 225) for problem-solving, and 78.3% (n= 267) for personal-social skills. Among those exposed to polytherapy, the proportions in the typical developmental range were 89.5% (n=77) for communication, 60.5% (n= 52) for gross motor, 66.3% (n=57) for fine motor, 58.1% (n=50) for problem-solving, and 79.1% (n=68) for personal-social skills. 

Overall, 44.1% (n=152) of children scored at least 1 standard deviation (SD) below the mean in two or more developmental domains. Continued follow-up beyond 12 months of age is needed to better characterise the risk profiles of commonly used ASMs in pregnancy. 

Conclusions: Follow-up through 24 months of age will enable delineation of ASM-specific outcomes following prenatal ASM exposure. The LIFETIME Framework is feasible for neurodevelopmental follow-up and provides a standardised approach which can be integrated into pregnancy pharmacovigilance initiatives worldwide.

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Development of transition clinic for epilepsy patients moving from paediatric to adult services

Erin Lilley, Russell Hewett

Institute Of Neurological Sciences, Glasgow

Introduction: Refractory seizure clusters after a long period of seizure freedom in individuals with an established diagnosis of epilepsy, with no prior history of drug-resistant epilepsy, should prompt a thorough review of the underlying aetiology of epilepsy. This case highlights an unusual presentation of SMC1A-related epilepsy. 

Transition is a period of planned and structured multidisciplinary review between both paediatric and adult teams with the aim of optimising the care and treatment of young people with epilepsy as they move from children’s to adult services. 

In 2025, 37 young adults in NHS Greater Glasgow and Clyde were transitioned from paediatric care to adult service over 6 clinics. The epilepsy team saw a need to improve the pathway for transition clinics. In the previous year, loss to follow-up with the team resulted in patients experiencing missed reviews, delays in treatment, poorer outcomes and increased exposure to risks of harm.

The pathway improvement involved:

1. A set proforma for clinical information transfer prepared by the paediatric service.

2. Changing the location of the transition clinic from the paediatric to the adult hospital.

3. The adult rather than the paediatric Neurologist to lead the transition appointment.

By following a pathway the epilepsy team were able to streamline transition appointment allowing for patient centred approach to care with the ultimate aim of improving patient outcomes. 

The adult epilepsy team also developed two questionnaires targeting the young adults and carers to support the development of transition clinic:

1. The primary function of the first was to guide the initial conversations between the patient and their new adult neurologist. 

They were asked to prioritise from 1st to 4th in level of importance: 

a) Discussion with regard to current medication 

b) Discussion with regards to seizure frequency 

c) Discussion of longer term planning 

d) To meet the adult epilepsy neurologist and epilepsy nurse

The top priority in 53% of the respondents was to meet the team. 47% consider longer term planning as the most popular second priority choice. 

2. Feedback on the clinic appointment was also sought through a secondary questionnaire. This quantitative research approach allowed clinicians to adapt treatment plan for patients next appointment within Neurology department..

The adaptation of the transition pathway follows ‘SIGN Epilepsies in children and young people: investigative procedures and management’ suggestions that healthcare professionals should consider the use of a planned, structured, educational approach directed at both patients and carers, to help prepare young people with epilepsy for the move to adult healthcare services.

References: Epilepsies in children and young people: investigative procedures and management (revised June 2026) SIGN 159 – A national clinic guideline