Forskning ved Københavns Universitet - Københavns Universitet


Defining the phenotypic spectrum of SLC6A1 mutations

Publikation: Bidrag til tidsskriftTidsskriftartikel

  • 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 Choi
  • Jong 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
  • Heather C Mefford
  • Rikke S. Møller

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.

Udgave nummer2
Sider (fra-til)389-402
Antal sider14
StatusUdgivet - feb. 2018

ID: 190432916