Defining the phenotypic spectrum of SLC6A1 mutations

Katrine M. Johannesen, Elena Gardella*, Tarja Linnankivi, Carolina Courage, Anne de Saint Martin, Anna Elina Lehesjoki, Cyril Mignot, Alexandra Afenjar, Gaetan Lesca, Marie Thérèse Abi-Warde, Jamel Chelly, Amélie Piton, J. Lawrence Merritt, Lance H. Rodan, Wen Hann Tan, Lynne M. Bird, Mark Nespeca, Joseph G. Gleeson, Yongjin Yoo, Murim ChoiJong Hee Chae, Desiree Czapansky-Beilman, Sara Chadwick Reichert, Manuela Pendziwiat, Judith S. Verhoeven, Helenius J. Schelhaas, Orrin Devinsky, Jakob Christensen, Nicola Specchio, Marina Trivisano, Yvonne G. Weber, Caroline Nava, Boris Keren, Diane Doummar, Elise Schaefer, Sarah Hopkins, Holly Dubbs, Jessica E. Shaw, Laura Pisani, Candace T. Myers, Sha Tang, Shan Tang, Deb K. Pal, John J. Millichap, Gemma L. Carvill, Kathrine L. Helbig, Oriano Mecarelli, Pasquale Striano, Ingo Helbig, Guido Rubboli, Heather C. Mefford, Rikke S. Møller

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Objective: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. Methods: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. Results: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty 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. 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 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). Significance: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

Original languageEnglish (US)
Pages (from-to)389-402
Number of pages14
JournalEpilepsia
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2018

Keywords

  • MAE
  • SLC6A1
  • epilepsy
  • epilepsy genetics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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