Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder

Kalvakuntla, Sanjana; Lee, Minjae; Chung, Wendy K.; Demarest, Scott; Freed, Amber; Horning, Kyle J.; Bichell, Terry Jo; Iannaccone, Susan T.; Goodspeed, Kimberly

doi:10.3389/fnins.2023.1024388

Cited by 4 publications

(7 citation statements)

References 16 publications

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“…The finding that the S295L mouse displays SWDs with behavioral arrest is consistent with the diagnosis of absence epilepsy in the index patient. 6 Our findings provide additional supportive evidence that S295L is a pathogenic variant, and the GAT-1 S295L/+ mouse is a promising model for future mechanistic and translational studies.…”

Section: Gradient Of Epileptic Abnormalities With Progressive Gat-1 D...supporting

confidence: 72%

“…His language regressed 3 months after onset of speech and he subsequently recovered language approximately 6–12 months later. At 4 years and 6 months, he was speaking in simple‐phrased speech (previously reported by Kalvakuntla and colleagues 6 ). Episodes of staring began in infancy; however, electroencephalograms (EEGs) obtained prior to the age of 2 years were normal.…”

Section: Resultsmentioning

confidence: 63%

“…We report interval updates in the clinical characteristics of an individual with SLC6A1 ‐related disorder due to the S295L variant 4,6 . We reviewed lifetime medical records and data collected through a prospective natural history study of SLC6A1 ‐related disorder.…”

Section: Methodsmentioning

confidence: 99%

“…We report interval updates in the clinical characteristics of an individual with SLC6A1-related disorder due to the S295L variant. 4,6 We reviewed lifetime medical records and data collected through a prospective natural history study of SLC6A1-related disorder. Informed consent was obtained from the legal guardian of this participant, and the study was approved by the institutional review board of the study site, the University of Texas Southwestern Medical Center.…”

Section: Clinical Data Collection and Analysismentioning

confidence: 99%

“…A mouse model of SLC6A1 ‐related disorder has recently been generated by introducing a S295L missense mutation first identified in a child with developmental delay and hypotonia, 4 and who later developed absence epilepsy 6 . Cultured neurons and astrocytes differentiated from patient‐derived induced pluripotent stem cells with this mutation show reduced GABA uptake, reduced surface expression of GAT‐1, and accumulation of the mutant protein in the endoplasmic reticulum, 5,7 suggesting loss of function.…”

Section: Introductionmentioning

confidence: 99%

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Patient‐derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice

et al. 2023

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The solute carrier family 6 member 1 (SLC6A1) gene encodes GAT‐1, a γ‐aminobutyric acid transporter expressed on astrocytes and inhibitory neurons. Mutations in SLC6A1 are associated with epilepsy and developmental disorders, including motor and social impairments, but variant‐specific animal models are needed to elucidate mechanisms. Here, we report electrocorticographic (ECoG) recordings and clinical data from a patient with a variant in SLC6A1 that encodes GAT‐1 with a serine‐to‐leucine substitution at amino acid 295 (S295L), who was diagnosed with childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT‐1S295L/+) have spike‐and‐wave discharges with motor arrest consistent with absence‐type seizures, similar to GAT‐1+/− mice. GAT‐1S295L/+ and GAT‐1+/− mice follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide (200 mg/kg ip) and the GAT‐1 antagonist NO‐711 (10 mg/kg ip). By contrast, GAT‐1−/− mice were insensitive to both ethosuximide and NO‐711 at the doses tested. In conclusion, ECoG findings in GAT‐1S295L/+ mice phenocopy GAT‐1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations.

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Section: Gradient Of Epileptic Abnormalities With Progressive Gat-1 D...supporting

confidence: 72%

Section: Resultsmentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Clinical Data Collection and Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patient‐derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice

et al. 2023

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Beyond the Diagnosis: Evaluation of Quality-of-Life Measures and Family Functioning in SLC6A1-Related Neurodevelopmental Disorder

Dahshi,

Kalvakuntla,

Lee

et al. 2024

Pediatric Neurology

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

Trivisano,

Butera,

Quintavalle

et al. 2023

Front. Neurosci.

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IntroductionSLC6A1 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.MethodsWe 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.ResultsIn 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.DiscussionBased 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.

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Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder

Cited by 4 publications

References 16 publications

Patient‐derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice

Patient‐derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice

Beyond the Diagnosis: Evaluation of Quality-of-Life Measures and Family Functioning in SLC6A1-Related Neurodevelopmental Disorder

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

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