Yonsei Med J.  2012 May;53(3):495-500. 10.3349/ymj.2012.53.3.495.

Genetic and Epileptic Features in Rett Syndrome

• Kim HJ
• Kim SH
• Kim HD
• Lee JS
• Lee YM
• Koo KY
• Lee JS
• Kang HC

• KMID: 1776982
• DOI: http://doi.org/10.3349/ymj.2012.53.3.495

Abstract

PURPOSE
Rett syndrome is a severe neurodevelopmental disorder in females. Most have mutations in the methyl-CpG-binding protein 2 (MECP2) gene (80-90%). Epilepsy is a significant commonly accompanied feature in Rett syndrome. Our study was aimed at comprehensive analysis of genetic and clinical features in Rett syndrome patients, especially in regards to epileptic features.
MATERIALS AND METHODS
We retrospectively reviewed 20 patients who were diagnosed with MECP2 mutations at Severance Children's Hospital between January 1995 and July 2010. All patients met clinical criteria for Rett syndrome. Evaluations included clinical features, epilepsy classification, electroencephalography analysis, and treatment of seizures.
RESULTS
Ages ranged from 3.6 to 14.3 years (7.7+/-2.6). Fourteen different types of MECP2 mutations were found, including a novel in-frame mutation (1153-1188 del36). Fourteen of these patients (70.0%) had epilepsy, and the average age of seizure onset was 3.0+/-1.8 years. Epilepsy was diverse, including partial seizure in four patients (28.5%), secondarily generalized seizure in six (42.8%), generalized tonic seizure in two (14.3%), Lennox-Gastaut syndrome in one (7.1%), and myoclonic status in non-progressive encephalopathy in one (7.1%). Motor functions were delayed so that only 10 patients (50.0%) were able to walk independently: five (35.8%) in the epilepsy group and five (83.3%) in the non-epilepsy group. Average developmental scale was 33.5+/-32.8 in the epilepsy group and 44.4+/-21.2 in the non-epilepsy group. A clear genotype-phenotype correlation was not found.
CONCLUSION
There is a tendency for more serious motor impairment and cognitive deterioration in Rett syndrome patients with epilepsy.

Keyword

Rett syndrome; epilepsy; MECP2 mutation

MeSH Terms

Adolescent
Child
Child, Preschool
Epilepsy/*genetics/*pathology
Female
Genotype
Humans
Male
Methyl-CpG-Binding Protein 2/*genetics
Mutation
Phenotype
Retrospective Studies
Rett Syndrome/*genetics/*pathology

Reference

1. Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol. 2002. 6:293–297.

2. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999. 23:185–188.

3. Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008. 70:1313–1321.

4. Aber KM, Nori P, MacDonald SM, Bibat G, Jarrar MH, Kaufmann WE. Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. Neuroscience. 2003. 116:77–80.

5. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003. 302:885–889.

6. Engel J Jr. Report of the ILAE classification core group. Epilepsia. 2006. 47:1558–1568.

7. Synek VM. Prognostically important EEG coma patterns in diffuse anoxic and traumatic encephalopathies in adults. J Clin Neurophysiol. 1988. 5:161–174.

8. Ben Zeev Ghidoni B. Rett syndrome. Child Adolesc Psychiatr Clin N Am. 2007. 16:723–743.

9. Glaze DG, Percy AK, Skinner S, Motil KJ, Neul JL, Barrish JO, et al. Epilepsy and the natural history of Rett syndrome. Neurology. 2010. 74:909–912.

10. Nissenkorn A, Gak E, Vecsler M, Reznik H, Menascu S, Ben Zeev B. Epilepsy in Rett syndrome---the experience of a National Rett Center. Epilepsia. 2010. 51:1252–1258.

11. Jian L, Nagarajan L, de Klerk N, Ravine D, Christodoulou J, Leonard H. Seizures in Rett syndrome: an overview from a one-year calendar study. Eur J Paediatr Neurol. 2007. 11:310–317.

12. Steffenburg U, Hagberg G, Hagberg B. Epilepsy in a representative series of Rett syndrome. Acta Paediatr. 2001. 90:34–39.

13. Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett's syndrome. Correlation of electroencephalographic characteristics with clinical staging. Arch Neurol. 1987. 44:1053–1056.

14. Verma NP, Chheda RL, Nigro MA, Hart ZH. Electroencephalographic findings in Rett syndrome. Electroencephalogr Clin Neurophysiol. 1986. 64:394–401.

15. Niedermeyer E, Rett A, Renner H, Murphy M, Naidu S. Rett syndrome and the electroencephalogram. Am J Med Genet Suppl. 1986. 1:195–199.

16. Trauner DA, Haas RH. Electroencephalographic abnormalities in Rett syndrome. Pediatr Neurol. 1987. 3:331–334.

17. Caraballo RH, Cersósimo RO, Espeche A, Arroyo HA, Fejerman N. Myoclonic status in nonprogressive encephalopathies: study of 29 cases. Epilepsia. 2007. 48:107–113.

18. Elia M. Myoclonic status in nonprogressive encephalopathies: an update. Epilepsia. 2009. 50:Suppl 5. 41–44.

19. Fukuda T, Yamashita Y, Nagamitsu S, Miyamoto K, Jin JJ, Ohmori I, et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005. 27:211–217.

20. Pan H, Wang YP, Bao XH, Meng HD, Zhang Y, Wu XR, et al. MECP2 gene mutation analysis in Chinese patients with Rett syndrome. Eur J Hum Genet. 2002. 10:484–486.

21. Chae JH, Hwang YS, Kim KJ. Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome. J Child Neurol. 2002. 17:33–36.