SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures.
Epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy or Doose syndrome, has been recently linked to variants in the SLC6A1 gene. Epilepsy with myoclonic-atonic seizures is often refractory to antiepileptic drugs, and the ketogenic diet is known for treating medically intractable seizures, although the mechanism of action is largely unknown. We report a novel SLC6A1 variant in a patient with epilepsy with myoclonic-atonic seizures, analyze its effects, and suggest a mechanism of action for the ketogenic diet.



We describe a ten-year-old girl with epilepsy with myoclonic-atonic seizures and a de novo SLC6A1 mutation who responded well to the ketogenic diet. She carried a c.491G>A mutation predicted to cause p.Cys164Tyr amino acid change, which was identified using whole exome sequencing and confirmed by Sanger sequencing. High-resolution structural modeling was used to analyze the likely effects of the mutation.



The SLC6A1 gene encodes a transporter that removes gamma-aminobutyric acid from the synaptic cleft. Mutations in SLC6A1 are known to disrupt the gamma-aminobutyric acid transporter protein 1, affecting gamma-aminobutyric acid levels and causing seizures. The p.Cys164Tyr variant found in our study has not been previously reported, expanding on the variants linked to epilepsy with myoclonic-atonic seizures.



A 10-year-old girl with a novel SLC6A1 mutation and epilepsy with myoclonic-atonic seizures had an excellent clinical response to the ketogenic diet. An effect of the diet on gamma-aminobutyric acid reuptake mediated by gamma-aminobutyric acid transporter protein 1 is suggested. A personalized approach to epilepsy with myoclonic-atonic seizures patients carrying SLC6A1 mutation and a relationship between epilepsy with myoclonic-atonic seizures due to SLC6A1 mutations, GABAergic drugs, and the ketogenic diet warrants further exploration.
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Samantha
S
Palmer
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Meghan C
MC
Towne
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Phillip L
PL
Pearl
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Renee C
RC
Pelletier
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Casie A
CA
Genetti
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR.
Jiahai
J
Shi
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Alan H
AH
Beggs
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Pankaj B
PB
Agrawal
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: Catherine.brownstein@childrens.harvard.edu.
Catherine A
CA
Brownstein
D002648:Child; D055423:Diet, Ketogenic; D004831:Epilepsies, Myoclonic / Q000178:diet therapy* / Q000235:genetics*; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation
D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human
Doose syndrome; GABA; SLC6A1; epilepsy with myoclonic-atonic seizures; ketogenic diet; ketosis; myoclonic-astatic epilepsy