Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome

Vishnu Anand Cuddapah, Rajesh B. Pillai, Kiran V. Shekar, Jane B. Lane, Kathleen J. Motil, Steven A. Skinner, Daniel Charles Tarquinio, Daniel G. Glaze, Gerald McGwin, Walter E. Kaufmann, Alan K. Percy, Jeffrey L. Neul, Michelle L. Olsen

Research output: Contribution to journalArticle

Abstract

Background: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Methods: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time. Results: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p. Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p. Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity. Conclusions: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

Original languageEnglish (US)
Pages (from-to)152-158
Number of pages7
JournalJournal of Medical Genetics
Volume51
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Methyl-CpG-Binding Protein 2
Rett Syndrome
Mutation
Aptitude
Age of Onset
Point Mutation
Walking
Hand
Communication
Databases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cuddapah, V. A., Pillai, R. B., Shekar, K. V., Lane, J. B., Motil, K. J., Skinner, S. A., ... Olsen, M. L. (2014). Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome. Journal of Medical Genetics, 51(3), 152-158. https://doi.org/10.1136/jmedgenet-2013-102113

Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome. / Cuddapah, Vishnu Anand; Pillai, Rajesh B.; Shekar, Kiran V.; Lane, Jane B.; Motil, Kathleen J.; Skinner, Steven A.; Tarquinio, Daniel Charles; Glaze, Daniel G.; McGwin, Gerald; Kaufmann, Walter E.; Percy, Alan K.; Neul, Jeffrey L.; Olsen, Michelle L.

In: Journal of Medical Genetics, Vol. 51, No. 3, 2014, p. 152-158.

Research output: Contribution to journalArticle

Cuddapah, VA, Pillai, RB, Shekar, KV, Lane, JB, Motil, KJ, Skinner, SA, Tarquinio, DC, Glaze, DG, McGwin, G, Kaufmann, WE, Percy, AK, Neul, JL & Olsen, ML 2014, 'Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome', Journal of Medical Genetics, vol. 51, no. 3, pp. 152-158. https://doi.org/10.1136/jmedgenet-2013-102113
Cuddapah, Vishnu Anand ; Pillai, Rajesh B. ; Shekar, Kiran V. ; Lane, Jane B. ; Motil, Kathleen J. ; Skinner, Steven A. ; Tarquinio, Daniel Charles ; Glaze, Daniel G. ; McGwin, Gerald ; Kaufmann, Walter E. ; Percy, Alan K. ; Neul, Jeffrey L. ; Olsen, Michelle L. / Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome. In: Journal of Medical Genetics. 2014 ; Vol. 51, No. 3. pp. 152-158.
@article{eb69b26ebd3f48deba5572d73086aa49,
title = "Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome",
abstract = "Background: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95{\%} of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Methods: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time. Results: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p. Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p. Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity. Conclusions: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.",
author = "Cuddapah, {Vishnu Anand} and Pillai, {Rajesh B.} and Shekar, {Kiran V.} and Lane, {Jane B.} and Motil, {Kathleen J.} and Skinner, {Steven A.} and Tarquinio, {Daniel Charles} and Glaze, {Daniel G.} and Gerald McGwin and Kaufmann, {Walter E.} and Percy, {Alan K.} and Neul, {Jeffrey L.} and Olsen, {Michelle L.}",
year = "2014",
doi = "10.1136/jmedgenet-2013-102113",
language = "English (US)",
volume = "51",
pages = "152--158",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "3",

}

TY - JOUR

T1 - Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in rett syndrome

AU - Cuddapah, Vishnu Anand

AU - Pillai, Rajesh B.

AU - Shekar, Kiran V.

AU - Lane, Jane B.

AU - Motil, Kathleen J.

AU - Skinner, Steven A.

AU - Tarquinio, Daniel Charles

AU - Glaze, Daniel G.

AU - McGwin, Gerald

AU - Kaufmann, Walter E.

AU - Percy, Alan K.

AU - Neul, Jeffrey L.

AU - Olsen, Michelle L.

PY - 2014

Y1 - 2014

N2 - Background: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Methods: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time. Results: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p. Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p. Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity. Conclusions: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

AB - Background: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. Methods: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time. Results: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p. Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p. Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity. Conclusions: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

UR - http://www.scopus.com/inward/record.url?scp=84894438035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894438035&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2013-102113

DO - 10.1136/jmedgenet-2013-102113

M3 - Article

C2 - 24399845

AN - SCOPUS:84894438035

VL - 51

SP - 152

EP - 158

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 3

ER -