Abstracts

Rationale: Identification of risk factors and mechanisms of sudden unexplained death in epilepsy (SUDEP) can help prevent mortality in epilepsy. Genetic factors may play a role in SUDEP, but the underlying pathophysiology is not clear. Frequency of generalized convulsive seizures is considered a strong risk factor. We present a case of SUDEP associated with strong family history of Synapsin-1 (SYN1)-associated reflex epilepsy to highlight the importance of genetic counseling and early testing in patients with epilepsy and/or developmental delays and their seemingly well-controlled or unaffected siblings.

Methods: We performed a review of medical charts, including EMU admission, clinic notes, and EEG reports, and drafted a pedigree chart which identifies affected family members. This was followed by a systematic review of the literature.

Results: The proband is a 28-year-old male with onset of reflex epilepsy at age 5. Seizures were initially triggered by cool breeze after showering, and later became refractory to treatment, along with mild to moderate intellectual disability. His normally developing younger sister did not have a seizure until the age of 19, reported as a nocturnal convulsive seizure. She died five months later in her sleep, before being started on any anti-seizure medications. No cause was identified in autopsy, meeting definite SUDEP criteria (Devinsky et al. 2018, Epilepsia, 59(6):1220-1233). A strong family history of reflex seizures and intellectual delays exists in the male members of the family (see Figure). Genetic screening using a commercial panel showed that the proband is hemizygous for a pathologic variant of X-linked SYN1 gene (SCN1:c57_63del (TGTACCCA >T)), known to cause X-linked neurodevelopmental disorders and epilepsy in males. Genetic analysis of his sister showed the same SYN1 variant.


Conclusions: Our male patient demonstrated the classic clinical manifestations of SYN1-related intellectual disability with reflex epilepsy, followed by refractory epilepsy. However, a later onset epilepsy in his female sibling had a less expected course leading to SUDEP within the first year of seizure onset. Seizures in the female sibling is presumably related to the same allele with incomplete gene penetration or X chromosome inactivation. This case highlights the importance of genetic counseling and early testing in siblings of patients with cryptogenic epilepsy and/or developmental or intellectual delays. Treatment with anti-seizure medications may mitigate mortality in at risk patients. Investigating the link between genetic epilepsies and SUDEP can help identify high-risk individuals, inform preventive strategies, and may uncover targets for future therapeutic interventions.

Funding: Authors report no funding or conflict related to this study. SC is a neurology resident, and HU is an epilepsy fellow at University of California San Diego. Authors wish to thank Dr. Ali Torkamani (Scripps Research Translational Institute, La Jolla, CA).