NORD gratefully acknowledges Eduardo Pérez Palma, PhD, Cologne Center for Genomics, University of Cologne, Germany; Dennis Lal, PhD, Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, USA; Katrine M. Johannesen, MD, The Danish Epilepsy Center Filadelfia, Dianalund, Denmark, and SLC6A1 Connect for the preparation of this report.
SLC6A1 epileptic encephalopathy is an autosomal dominant genetic disorder characterized by the loss-of-function of one copy of the human SLC6A1 gene. Clinical manifestation of SLC6A1 epileptic encephalopathy is characterized by early onset seizures (mean onset 3.7 years) and mild to severe intellectual disability. Seizure types include absences, myoclonic and atonic seizures. Language impairment and behavioral problems have also been observed. Some patients have shown intellectual disability without seizures or associated with focal epilepsy.
Given the limited number of patients available for characterization, the full extent of symptoms is yet to be described. The most common features observed include absence seizures, myoclonic-atonic epilepsy (onset from 7 months to 6 years, mean 3.7 years) and mild-to-moderate intellectual disability. Speech difficulties and behavioral problems have been described. The most common EEG pattern observed comprises irregular, high ample, and generalized spike-and-waves. To date, the most extensive patient collection was published by Johannesen et al5 and includes 34 patients. In this cohort, cognitive development was impaired in 33/34 (97%) subjects; 28/34 (82%) had mild to moderate intellectual disability, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 patients with a mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24). Two patients had speech delay only, and 1 had severe intellectual disability. After epilepsy onset, cognition declined in 46% (11 out of 24) of patients. The most common seizure types were absences, myoclonic, and atonic seizures. Sixteen patients (47%) fulfilled the diagnostic criteria for myoclonic-atonic epilepsy. Seven additional patients had different forms of generalized epilepsy, and two had focal epilepsy. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7 out of 34 patients (21%).
SLC6A1 epileptic encephalopathy is caused by a change (mutation) in one copy of the SLC6A1 gene that prevents the gene from working properly.
Two types of SLC6A1 gene variants have been observed in patients: 1) protein truncating variants that stop the protein production for one of the two SLC6A1 genes inherited from parents and 2) point mutations in critical regions of the protein such as GABA binding sites and transmembrane domains, which lead to loss-of-function of mutated proteins. Thus, the expected molecular pathomechanism of SLC6A1 disorders is haploinsufficiency; a single functional copy of the gene is not enough. The disease-mode is supported by experiments in GAT-1 knockout mice as well as mice administered with GAT-1 inhibitor. In these experiments, the mice show spontaneous spike-wave discharges typical of absence seizures, the predominant seizure type seen in individuals with SLC6A1 mutations. Recently, experimental evidence showed that SLC6A1 variants identified in epilepsy patients reduce GABA transport6 in vitro.
The SLC6A1 gene encodes for the voltage-dependent c-aminobutyric acid (GABA) transporter 1 (GAT-1) protein, one of the major GABA transporters of the human central nervous system. SLC6A1 is primarily expressed in the brain, specifically, in GABAergic neurons and astrocytes. The primary function of SLC6A1 is the reuptake of the GABA neurotransmitter from the extracellular space in the synapsys1. The SLC6A1 gene is located in the short arm of chromosome 3 (GRCh38 genomic coordinates: 3:10,992,733-11,039,248), contains 15 exons and is approximately 25 kb long. Genetic variation affecting the coding sequence of the gene in the general population is extremely rare2. Thus, the SLC6A1 gene is highly intolerant to variation. Patient variants in SLC6A1 were first described by Carvill et al. in 20153 (Online Mendelian Inheritance in Man database (OMIM) 137165)4 and were associated with early onset myoclonic-atonic epilepsy and intellectual disability. Later, with the collection of more patients, the phenotypic spectrum of SLC6A1-related disorders was expanded to include several types of seizures and different degrees of developmental delay. Notably, almost all of the genetic variants reported to date were not present in the parents (they arose ‘de novo’) and have not been observed in the general population.
SLC6A1 epileptic encephalopathy is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
This is an extremely rare disorder. To date, only 34 patients have been characterized in the literature5. Patients are from families with various ethnic backgrounds from the USA, Canada and European countries. The SLC6A1 gene was until recently not screened in diagnostic sequencing and it is likely that many more patients will be reported with inclusion of this gene on gene panels.
In order to diagnose a SLC6A1 epileptic encephalopathy, DNA sequencing is required. Depending on the available resources, whole genome and whole exome sequencing can be performed. However, targeted gene panel sequencing is often faster, less expensive and easier to reimburse by insurance. The SLC6A1 gene is included in a variety of current epilepsy-oriented gene panels. Independently of the sequencing method used, variants found in the SLC6A1 genes should be interpreted carefully. The American College of Medical Genetics (ACMG) guidelines should be followed to assign the variants found a disease-causing state8.
Currently, the number of patients and clinical data available is limited. Treatment may require interdisciplinary efforts including neurologists, developmental pediatricians, speech therapy and/or other health care professionals to systematically and comprehensively plan the treatment of an affected child. Data on drug treatment is not conclusive. However, valproic acid by itself or in combination with other antiepileptic drugs has shown positive results. Johannesen et al5 shows that ten out of 15 patients treated with valproic acid became seizure-free, and the remaining 5 showed a partial benefit. Valproic acid is thought to have a positive effect on the GABA system, possibly by increasing the GABA concentration in the human brain9. Overall, 20 out of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome.
SLC6A1 Connect is partnering with Dr. Steven Gray from UT Southwestern to develop a gene replacement therapy to treat SLC6A1 mutations. Pre-clinical and experimental work is currently underway aiming to produce a custom adeno-associated virus (AAV) suitable for SLC6A1 treatment.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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1. Scimemi, A. Structure, function, and plasticity of GABA transporters. Frontiers in Cellular Neuroscience 2014; 8: 161.
2. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536: 285-291.
3. Carvill GL, McMahon JM, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. AJHG 2015; 96: 808-815.
4. Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, and Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM), an online catalog of human genes and genetic disorders. Nucleic Acids Research 2015; 43: D789-798.
5. Johannesen KM, Gardella E, Linnankivi T, et al. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia 2018;59: 389-402.
6. Mattison KA, Butler KM, Inglis GAS, et al. SLC6A1 variants identified in epilepsy patients reduce gamma-aminobutyric acid transport. Epilepsia 2018;59: e135-e141.
7. Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Research 2016; 44, D862-868.
8. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015;17: 405-424.
9. Chateauvieux S, Morceau F, Dicato M, and Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. Journal of Biomedicine & Biotechnology 2010; Published online Jul 29.
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