Mild phenotype associated with SLC6A1 gene mutation: A case report with literature review

Abstract

A bstract The Solute Carrier Family 6 Member 1 ( SLC6A1 ) gene encodes the gamma-aminobutyric acid (GABA) transporter 1, which is one of the main GABA transporters. The clinical picture of SLC6A1 gene mutations is characterized by a broader spectrum including a mild-to-moderate intellectual disability, speech difficulties, behavioral problems, epilepsy (often with myoclonic-atonic and atypical absence seizures, characterizing a myoclonic-atonic epilepsy), and neurological signs. We describe a boy with an SLC6A1 mutation and a milder phenotype, characterized by a learning disorder without intellectual disability, nonspecific dysmorphisms, and an electroencephalogram picture closely resembling that of myoclonic-atonic epilepsy with brief absence seizures that have appeared during the follow-up, responsive to valproic acid.

Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1

“…Finally, focusing on the treatment to improve epilepsy in our patients, administration of VPA has given a good response. These results of the treatment with VPA are similar to those obtained in patients with other SLC6A1 variants [ 2 , 41 ].…”

A Reappraisal of GAT-1 Localization in Neocortex

“…After reports of SLC6A1 variants in patients with myoclonic atonic epilepsy (Dikow et al, 2014;Carvill et al, 2015;Mattison et al, 2018;Cai et al, 2019;Posar and Visconti, 2019), clinical, neurophysiological, and genetic examination of a relatively large cohort of subjects (n = 34) bearing SLC6A1 mutations demonstrated that 97% of them exhibited varying degrees of intellectual disability (ID) and that 91% had been diagnosed with epilepsy (absence, myoclonic, or atonic) based on EEG patterns characterized by irregular, high, ample, generalized spikes, and wave discharges (Johannesen et al, 2018). Notably, more than 60% of these subjects had suffered from moderate or significant ID before epilepsy onset, whereas in a limited number of cases, the ID was not accompanied by epilepsy.…”

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

“…Of the >100 GAT1 variants deposited in the ENSEMBL database, 45 point mutations (including 12 frameshift/truncating and 28 missense) are displayed in Fig. 3g and Table 3 ( Cai et al, 2019 ; Carvill et al, 2015 ; Halvorsen et al, 2015 ; Islam et al, 2018 ; Johannesen et al, 2018 ; Mattison et al, 2018 ; Palmer et al, 2016 ; Posar & Visconti, 2019 ; Rauch et al, 2012 ; Wang et al, 2020 ; Zech et al, 2017 ). The mutations are linked to impaired cognitive development, several epileptic seizure types and mild to moderate ID (mostly language impairment) in the afflicted individuals.…”