SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures

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• 作者：Samantha Palmer ; BA^a ; Meghan C. Towne ; MS ; LGC^a ; ^b ; Phillip L. Pearl ; MD^c ; Renee C. Pelletier ; BA^a ; ^b ; Casie A. Genetti ; MS ; CGC^a ; ^b ; Jiahai Shi ; PhD^d ; Alan H. Beggs ; PhD^a ; ^b ; Pankaj B. Agrawal ; MD ; MMSC^a ; ^b ; ^e ; Catherine A. Brownstein ; MPH ; PhD^a ; ^b ; ^{Catherine.brownstein@childrens.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：epilepsy with myoclonic-atonic seizures ; myoclonic-astatic epilepsy ; Doose syndrome ; ketogenic diet ; GABA ; SLC6A1 ; ketosis
• 刊名：Pediatric Neurology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：64
• 期：Complete
• 页码：77-79
• 全文大小：500 K

文摘

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.

Methods

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.

Results

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.

Conclusion

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.