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 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; Guido Rubboli; Heather C Mefford; Rikke S. Møller

doi:10.1111/epi.13986

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

Department of Clinical Medicine

33 Citations (Scopus)

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 language	English
Journal	Epilepsia
Volume	59
Issue number	2
Pages (from-to)	389-402
Number of pages	14
ISSN	0013-9580
DOIs	https://doi.org/10.1111/epi.13986
Publication status	Published - Feb 2018

Keywords

epilepsy
epilepsy genetics
MAE
SLC6A1

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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., Rodan, L. H., Tan, W. H., Bird, L. M., Nespeca, M., Gleeson, J. G., Yoo, Y., ... Møller, R. S. (2018). Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia, 59(2), 389-402. https://doi.org/10.1111/epi.13986

Johannesen, KM, Gardella, E, Linnankivi, T, Courage, C, de Saint Martin, A, Lehesjoki, AE, Mignot, C, Afenjar, A, Lesca, G, Abi-Warde, MT, Chelly, J, Piton, A, Merritt, JL, Rodan, LH, Tan, WH, Bird, LM, Nespeca, M, Gleeson, JG, Yoo, Y, Choi, M, Chae, JH, Czapansky-Beilman, D, Reichert, SC, Pendziwiat, M, Verhoeven, JS, Schelhaas, HJ, Devinsky, O, Christensen, J, Specchio, N, Trivisano, M, Weber, YG, Nava, C, Keren, B, Doummar, D, Schaefer, E, Hopkins, S, Dubbs, H, Shaw, JE, Pisani, L, Myers, CT, Tang, S, Tang, S, Pal, DK, Millichap, JJ, Carvill, GL, Helbig, KL, Mecarelli, O, Striano, P, Helbig, I, Rubboli, G, Mefford, HC & Møller, RS 2018, 'Defining the phenotypic spectrum of SLC6A1 mutations', Epilepsia, vol. 59, no. 2, pp. 389-402. https://doi.org/10.1111/epi.13986

@article{a7566f54d28e42a4b8b5f60549737eca,

title = "Defining the phenotypic spectrum of SLC6A1 mutations",

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.",

keywords = "epilepsy, epilepsy genetics, MAE, SLC6A1",

author = "Johannesen, {Katrine M.} and Elena Gardella and Tarja Linnankivi and Carolina Courage and {de Saint Martin}, Anne and Lehesjoki, {Anna Elina} and Cyril Mignot and Alexandra Afenjar and Gaetan Lesca and Abi-Warde, {Marie Th{\'e}r{\`e}se} and Jamel Chelly and Am{\'e}lie Piton and Merritt, {J. Lawrence} and Rodan, {Lance H.} and Tan, {Wen Hann} and Bird, {Lynne M.} and Mark Nespeca and Gleeson, {Joseph G.} and Yongjin Yoo and Murim Choi and Chae, {Jong Hee} and Desiree Czapansky-Beilman and Reichert, {Sara Chadwick} and Manuela Pendziwiat and Verhoeven, {Judith S.} and Schelhaas, {Helenius J.} and Orrin Devinsky and Jakob Christensen and Nicola Specchio and Marina Trivisano and Weber, {Yvonne G.} and Caroline Nava and Boris Keren and Diane Doummar and Elise Schaefer and Sarah Hopkins and Holly Dubbs and Shaw, {Jessica E.} and Laura Pisani and Myers, {Candace T.} and Sha Tang and Shan Tang and Pal, {Deb K.} and Millichap, {John J.} and Carvill, {Gemma L.} and Helbig, {Kathrine L.} and Oriano Mecarelli and Pasquale Striano and Ingo Helbig and Guido Rubboli and Mefford, {Heather C} and M{\o}ller, {Rikke S.}",

year = "2018",

month = feb,

doi = "10.1111/epi.13986",

language = "English",

volume = "59",

pages = "389--402",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

number = "2",

}

TY - JOUR

T1 - Defining the phenotypic spectrum of SLC6A1 mutations

AU - Johannesen, Katrine M.

AU - Gardella, Elena

AU - Linnankivi, Tarja

AU - Courage, Carolina

AU - de Saint Martin, Anne

AU - Lehesjoki, Anna Elina

AU - Mignot, Cyril

AU - Afenjar, Alexandra

AU - Lesca, Gaetan

AU - Abi-Warde, Marie Thérèse

AU - Chelly, Jamel

AU - Piton, Amélie

AU - Merritt, J. Lawrence

AU - Rodan, Lance H.

AU - Tan, Wen Hann

AU - Bird, Lynne M.

AU - Nespeca, Mark

AU - Gleeson, Joseph G.

AU - Yoo, Yongjin

AU - Choi, Murim

AU - Chae, Jong Hee

AU - Czapansky-Beilman, Desiree

AU - Reichert, Sara Chadwick

AU - Pendziwiat, Manuela

AU - Verhoeven, Judith S.

AU - Schelhaas, Helenius J.

AU - Devinsky, Orrin

AU - Christensen, Jakob

AU - Specchio, Nicola

AU - Trivisano, Marina

AU - Weber, Yvonne G.

AU - Nava, Caroline

AU - Keren, Boris

AU - Doummar, Diane

AU - Schaefer, Elise

AU - Hopkins, Sarah

AU - Dubbs, Holly

AU - Shaw, Jessica E.

AU - Pisani, Laura

AU - Myers, Candace T.

AU - Tang, Sha

AU - Tang, Shan

AU - Pal, Deb K.

AU - Millichap, John J.

AU - Carvill, Gemma L.

AU - Helbig, Kathrine L.

AU - Mecarelli, Oriano

AU - Striano, Pasquale

AU - Helbig, Ingo

AU - Rubboli, Guido

AU - Mefford, Heather C

AU - Møller, Rikke S.

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

KW - epilepsy

KW - epilepsy genetics

KW - MAE

KW - SLC6A1

U2 - 10.1111/epi.13986

DO - 10.1111/epi.13986

M3 - Journal article

C2 - 29315614

AN - SCOPUS:85041378864

SN - 0013-9580

VL - 59

SP - 389

EP - 402

JO - Epilepsia

JF - Epilepsia

IS - 2

ER -

Defining the phenotypic spectrum of SLC6A1 mutations

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Keywords

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