Defining the phenotypic spectrum of SLC6A1 mutations

Johannesen, K. M.; Gardella, E.; Linnankivi, T.; Courage, C.; de Saint Martin, A.; Lehesjoki, A. E.; Mignot, C.; Afenjar, A.; Lesca, G.; Abi-Warde, M. T.; Chelly, J.; Piton, A.; Merritt, J. L., 2nd; Rodan, L. H.; Tan, W. H.; Bird, L. M.; Nespeca, M.; Gleeson, J. G.; Yoo, Y.; Choi, M.; Chae, J. H.; Czapansky-Beilman, D.; Reichert, S. C.; Pendziwiat, M.; Verhoeven, J. S.; Schelhaas, H. J.; Devinsky, O.; Christensen, J.; Specchio, N.; Trivisano, M.; Weber, Y. G.; Nava, C.; Keren, B.; Doummar, D.; Schaefer, E.; Hopkins, S.; Dubbs, H.; Shaw, J. E.; Pisani, L.; Myers, C. T.; Tang, S.; Tang, S.; Pal, D. K.; Millichap, J. J.; Carvill, G. L.; Helbig, K. L.; Mecarelli, O.; Striano, P.; Helbig, I.; Rubboli, G.; Mefford, H. C.; Moller, R. S.

Epilepsia. 2018 Jan 10; 59(2):389-402


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.

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