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

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Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

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.

Originalsprog	Engelsk
Sider (fra-til)	389-402
Antal sider	14
Tidsskrift	Epilepsia
Vol/bind	59
Udgave nummer	2
DOI	https://doi.org/10.1111/epi.13986
Status	Udgivet - feb. 2018

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10.1111/epi.13986

Citationsformater

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

@article{b32f94a9401141d28fc36104348dd8ac,

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 = "Adolescent, Adult, Anticonvulsants/therapeutic use, Ataxia/complications, Child, Child, Preschool, Cohort Studies, Electroencephalography, Epilepsies, Myoclonic/complications, Epilepsies, Partial/complications, Epilepsy, Generalized/complications, Female, GABA Plasma Membrane Transport Proteins/genetics, Genetic Association Studies, Humans, Intellectual Disability/complications, Language Development Disorders/complications, Male, Mutation, Mutation, Missense, Neurodevelopmental Disorders/complications, Phenotype, Treatment Outcome, Valproic Acid/therapeutic use, Young Adult",

author = "Johannesen, {Katrine M} and Elena Gardella and Tarja Linnankivi and Carolina Courage and {de Saint Martin}, Anne and Anna-Elina Lehesjoki and Cyril Mignot and Alexandra Afenjar and Gaetan Lesca and Marie-Th{\'e}r{\`e}se Abi-Warde and Jamel Chelly and Am{\'e}lie Piton and Merritt, {J Lawrence} and Rodan, {Lance H} and Wen-Hann Tan and Bird, {Lynne M} and Mark Nespeca and Gleeson, {Joseph G} and Yongjin Yoo and Murim Choi and Jong-Hee Chae 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}",

note = "Wiley Periodicals, Inc. {\textcopyright} 2018 International League Against Epilepsy.",

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",

}

Johannesen, KM , 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, JL, Rodan, LH, Tan, W-H, Bird, LM, Nespeca, M, Gleeson, JG, Yoo, Y, Choi, M, Chae, J-H, 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, bind 59, nr. 2, s. 389-402. https://doi.org/10.1111/epi.13986

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 - Adolescent

KW - Adult

KW - Anticonvulsants/therapeutic use

KW - Ataxia/complications

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Electroencephalography

KW - Epilepsies, Myoclonic/complications

KW - Epilepsies, Partial/complications

KW - Epilepsy, Generalized/complications

KW - Female

KW - GABA Plasma Membrane Transport Proteins/genetics

KW - Genetic Association Studies

KW - Humans

KW - Intellectual Disability/complications

KW - Language Development Disorders/complications

KW - Male

KW - Mutation

KW - Mutation, Missense

KW - Neurodevelopmental Disorders/complications

KW - Phenotype

KW - Treatment Outcome

KW - Valproic Acid/therapeutic use

KW - Young Adult

U2 - 10.1111/epi.13986

DO - 10.1111/epi.13986

M3 - Article

C2 - 29315614

SN - 0013-9580

VL - 59

SP - 389

EP - 402

JO - Epilepsia

JF - Epilepsia

IS - 2

ER -

Defining the phenotypic spectrum of SLC6A1 mutations

Abstract

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