Insights into cognitive and behavioral comorbidities of SLC6A1-related epilepsy: five new cases and literature review

Marina Trivisano; Ambra Butera; Chiara Quintavalle; Angela De Dominicis; Costanza Calabrese; Simona Cappelletti; Federico Vigevano; Antonio Novelli; Nicola Specchio

doi:10.3389/fnins.2023.1215684

Insights into cognitive and behavioral comorbidities of SLC6A1-related epilepsy: five new cases and literature review

Front Neurosci. 2023 Aug 28:17:1215684. doi: 10.3389/fnins.2023.1215684. eCollection 2023.

Authors

Affiliations

¹ Clinical and Experimental Neurology, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.
² Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental age "Gaetano Barresi", University of Messina, Messina, Italy.
³ PROMISE Department, School of Child Neurology and Psychiatry, University of Palermo, Palermo, Italy.
⁴ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Abstract

Introduction: SLC6A1 pathogenic variants have been associated with epilepsy and neurodevelopmental disorders. The clinical phenotype includes different seizure types, intellectual disability, and psychiatric symptoms affecting mood and behavior. Few data regarding neuropsychological features have been described, and details on cognitive profiles are often missing due to the lack of standardized tests.

Methods: We retrospectively reviewed the neuropsychological assessments of five subjects carrying heterozygous missense genetic variants in SLC6A1. We also collected data on epileptic features, EEGs, and brain MRIs. Additionally, we reviewed neuropsychological data from 204 previously reported patients with SLC6A1 pathogenic variants.

Results: In our series, at the last evaluation (median 12.6 years), three patients had borderline intellectual functioning, one patient had mild cognitive impairment, and one patient presented with a moderate cognitive disability. Three out of five patients underwent at least two neuropsychological evaluations, which revealed a worsening of cognitive functions over time. We detected attention deficits in all patients. In addition, we observed anxiety, disruptive behavior disorder, emotional instability, and hetero aggressiveness. We also performed a literature review that highlighted that most of the patients with SLC6A1 pathogenic variants have mild-to-moderate intellectual disability and that one-third of cases have autistic traits.

Discussion: Based on the literature review and the detailed description of our cases, we conclude that patients with SLC6A1-related epilepsy mostly present with mild-to-moderate intellectual disability, often associated with attention disorders. Such symptoms may worsen over time. Periodic standardized neuropsychological tests may be useful tools to follow development over time, and patient-specific rehabilitation programs could be tailored consistently.

Keywords: SLC6A1; autism spectrum disorder; developmental and epileptic encephalopathy; genetic epilepsy; neuropsychological features.