Defining the phenotypic spectrum of SLC6A1 mutations

Area of Science:

• Genetics
• Neurology
• Epilepsy

Background:

• Pathogenic variants in the SLC6A1 gene have been associated with myoclonic atonic epilepsy (MAE) and intellectual disability (ID).
• The full phenotypic spectrum associated with SLC6A1 mutations requires further elucidation in a larger patient cohort.

Purpose of the Study:

• To define the phenotypic spectrum of pathogenic SLC6A1 variants in a larger cohort of affected individuals.
• To characterize the electroclinical features and cognitive outcomes in patients with SLC6A1-related disorders.

Main Methods:

• Reviewed electroclinical data from 34 subjects with pathogenic SLC6A1 variants, including 24 probands and 6 family members.
• Included 4 previously published cases for comprehensive electroclinical description.
• Analyzed cognitive development, epilepsy characteristics, EEG findings, and treatment responses.

Main Results:

• Intellectual disability (ID) was present in 97% of subjects, with language impairment being the most common feature.
• Epilepsy occurred in 31/34 cases, with MAE being diagnosed in 16 patients; absence, myoclonic, and atonic seizures were most frequent.
• Valproic acid was effective in achieving seizure freedom in 20/31 patients, though cognitive outcome did not clearly correlate with seizure control. EEG commonly showed diffuse spike-wave discharges.

Conclusions:

• Pathogenic SLC6A1 variants predominantly manifest as MAE with pre-epileptic language delay and mild/moderate ID.
• The spectrum can also include ID without epilepsy or ID associated with focal epilepsy.
• Understanding the SLC6A1 phenotypic spectrum is crucial for accurate diagnosis and management of these neurodevelopmental disorders.