Abstracts

Rationale: SLC6A1-related disorder (SRD) was initially described in patients with epilepsy with myoclonic atonic seizures and is rapidly becoming one of the leading genetic causes of epilepsy and autism spectrum disorder. However, little is known of the full spectrum of disease severity. Haploinsufficiency of SLC6A1 leads to impaired function of the GABA-transporter type 1 that is responsible for reuptake of GABA from the synaptic cleft. Patients typically present with developmental delay, hypotonia, and seizures. Here we present EEG findings and seizure semiologies from our specialty clinic for SRD and prospective natural history study.

Methods: We reviewed records from patients with confirmed SRD by clinical genetic testing from our SRD Specialty Clinic. Clinical EEG reports from historical medical records were reviewed and frequency of abnormalities were recorded if reported at least once. A subset enrolled in the prospective natural history study and completed a 4-hour video EEG.

Results: We reviewed 86 EEG reports from our SRD clinic patients (n=25) and eighteen 4-hr EEGs from our prospective natural history study. There was an even gender distribution (M13:F12) and median age at initial clinical EEG was 2-years. The age range for all clinical EEGs reviewed was 6-months to 23-years. Missense genetic variants were the most prevalent variant type (21 missense, 4 nonsense), and there were 5 recurrent variants in our cohort (1 sibling pair). There was no genotype-phenotype correlation among individuals with recurrent variants. All but one had delayed developmental milestones and 8/25 had regression. The mean age of seizure onset was 24-months, and the most prevalent reported seizure semiologies included absence, myoclonic, and atonic seizures. Intermittent rhythmic delta activity (IRDA) was prevalent on both study-related and clinical EEGs, while generalized slowing and generalized spike wave discharges were more prevalent on clinical EEGs, Figure 1. Review of clinical EEGs demonstrates that EEGs obtained before 2-years of age were more likely to be normal (8/17, 47%), while only two EEGs from individuals 2-years and up were normal. There was a higher prevalence of seizures captured on clinical EEGs including absence (7/11), myoclonic (3/11), atonic (2/11), subclinical (2/11), generalized tonic clonic (1/11), and electrographic status epilepticus of sleep (1/11). Levetiracetam, valproic acid, and clobazam are the most frequently used anti-seizure medications, but a high proportion of patients had discontinuation of levetiracetam due to behavioral side effects (10/13).

Conclusions: This is the first prospective observational study of SRD. We demonstrated that generalized abnormalities on EEG were more common than focal features. Further, absence epilepsy was more prevalent than myoclonic atonic seizures, and IRDA on EEG was common. Absence seizures and IRDA are features that overlap with childhood absence epilepsy (CAE). Evaluation for SLC6A1 haploinsufficiency may be considered in patients with CAE in certain clinical scenarios.

Funding: SLC6A1 Connect