Epilepsy in Rett syndrome--lessons from the Rett networked database

Andreea Nissenkorn; Rachel S Levy-Drummer; Ori Bondi; Alessandra Renieri; Laurent Villard; Francesca Mari; Maria A Mencarelli; Caterina Lo Rizzo; Ilaria Meloni; Mercedes Pineda; Judith Armstrong; Angus Clarke; Nadia Bahi-Buisson; Bosnjak Vlatka Mejaski; Milena Djuric; Dana Craiu; Alexsandra Djukic; Giorgio Pini; Anne-Marie Bisgaard; Bela Melegh; Aglaia Vignoli; Silvia Russo; Cristina Anghelescu; Edvige Veneselli; Joussef Hayek; Bruria Ben-Zeev

doi:10.1111/epi.12941

Epilepsy in Rett syndrome--lessons from the Rett networked database

Andreea Nissenkorn, Rachel S Levy-Drummer, Ori Bondi, Alessandra Renieri, Laurent Villard, Francesca Mari, Maria A Mencarelli, Caterina Lo Rizzo, Ilaria Meloni, Mercedes Pineda, Judith Armstrong, Angus Clarke, Nadia Bahi-Buisson, Bosnjak Vlatka Mejaski, Milena Djuric, Dana Craiu, Alexsandra Djukic, Giorgio Pini, Anne-Marie Bisgaard, Bela MeleghAglaia Vignoli, Silvia Russo, Cristina Anghelescu, Edvige Veneselli, Joussef Hayek, Bruria Ben-Zeev

Afdeling for Genetik

44 Citationer (Scopus)

Abstract

OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming.

METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves.

RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence.

SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.

Originalsprog	Engelsk
Tidsskrift	Epilepsia
Vol/bind	56
Udgave nummer	4
Sider (fra-til)	569-76
Antal sider	8
ISSN	0013-9580
DOI	https://doi.org/10.1111/epi.12941
Status	Udgivet - apr. 2015

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10.1111/epi.12941

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Nissenkorn, A., Levy-Drummer, R. S., Bondi, O., Renieri, A., Villard, L., Mari, F., Mencarelli, M. A., Lo Rizzo, C., Meloni, I., Pineda, M., Armstrong, J., Clarke, A., Bahi-Buisson, N., Mejaski, B. V., Djuric, M., Craiu, D., Djukic, A., Pini, G., Bisgaard, A.-M., ... Ben-Zeev, B. (2015). Epilepsy in Rett syndrome--lessons from the Rett networked database. Epilepsia, 56(4), 569-76. https://doi.org/10.1111/epi.12941

Nissenkorn, A, Levy-Drummer, RS, Bondi, O, Renieri, A, Villard, L, Mari, F, Mencarelli, MA, Lo Rizzo, C, Meloni, I, Pineda, M, Armstrong, J, Clarke, A, Bahi-Buisson, N, Mejaski, BV, Djuric, M, Craiu, D, Djukic, A, Pini, G, Bisgaard, A-M, Melegh, B, Vignoli, A, Russo, S, Anghelescu, C, Veneselli, E, Hayek, J & Ben-Zeev, B 2015, 'Epilepsy in Rett syndrome--lessons from the Rett networked database', Epilepsia, bind 56, nr. 4, s. 569-76. https://doi.org/10.1111/epi.12941

@article{9de5c118432b4b96b24633144c9cd9d8,

title = "Epilepsy in Rett syndrome--lessons from the Rett networked database",

abstract = "OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.",

keywords = "Adolescent, Child, Child, Preschool, Databases, Factual, Epilepsy, Female, Genetic Association Studies, Humans, Infant, Male, Methyl-CpG-Binding Protein 2, Rett Syndrome, Young Adult",

author = "Andreea Nissenkorn and Levy-Drummer, {Rachel S} and Ori Bondi and Alessandra Renieri and Laurent Villard and Francesca Mari and Mencarelli, {Maria A} and {Lo Rizzo}, Caterina and Ilaria Meloni and Mercedes Pineda and Judith Armstrong and Angus Clarke and Nadia Bahi-Buisson and Mejaski, {Bosnjak Vlatka} and Milena Djuric and Dana Craiu and Alexsandra Djukic and Giorgio Pini and Anne-Marie Bisgaard and Bela Melegh and Aglaia Vignoli and Silvia Russo and Cristina Anghelescu and Edvige Veneselli and Joussef Hayek and Bruria Ben-Zeev",

note = "Wiley Periodicals, Inc. {\textcopyright} 2015 International League Against Epilepsy.",

year = "2015",

month = apr,

doi = "10.1111/epi.12941",

language = "English",

volume = "56",

pages = "569--76",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell Publishing, Inc",

number = "4",

}

TY - JOUR

T1 - Epilepsy in Rett syndrome--lessons from the Rett networked database

AU - Nissenkorn, Andreea

AU - Levy-Drummer, Rachel S

AU - Bondi, Ori

AU - Renieri, Alessandra

AU - Villard, Laurent

AU - Mari, Francesca

AU - Mencarelli, Maria A

AU - Lo Rizzo, Caterina

AU - Meloni, Ilaria

AU - Pineda, Mercedes

AU - Armstrong, Judith

AU - Clarke, Angus

AU - Bahi-Buisson, Nadia

AU - Mejaski, Bosnjak Vlatka

AU - Djuric, Milena

AU - Craiu, Dana

AU - Djukic, Alexsandra

AU - Pini, Giorgio

AU - Bisgaard, Anne-Marie

AU - Melegh, Bela

AU - Vignoli, Aglaia

AU - Russo, Silvia

AU - Anghelescu, Cristina

AU - Veneselli, Edvige

AU - Hayek, Joussef

AU - Ben-Zeev, Bruria

PY - 2015/4

Y1 - 2015/4

N2 - OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.

AB - OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.

KW - Adolescent

KW - Child

KW - Child, Preschool

KW - Databases, Factual

KW - Epilepsy

KW - Female

KW - Genetic Association Studies

KW - Humans

KW - Infant

KW - Male

KW - Methyl-CpG-Binding Protein 2

KW - Rett Syndrome

KW - Young Adult

U2 - 10.1111/epi.12941

DO - 10.1111/epi.12941

M3 - Journal article

C2 - 25789914

SN - 0013-9580

VL - 56

SP - 569

EP - 576

JO - Epilepsia

JF - Epilepsia

IS - 4

ER -

Epilepsy in Rett syndrome--lessons from the Rett networked database

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