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GENATLAS PHENOTYPE
last update : 13-01-2010
Symbol RTT
Location Xq28
Name Rett syndrome
Corresponding gene MECP2
related resource Rett Syndrome at GeneDis
Other symbol(s) RETT
Main clinical features
  • affecting almost exclusively the females (for the males see RTTM)
  • characterized by a period of normal development for the first 6 to 18 months followed by a progressive deterioration leading to microcephaly, dementia, autism, loss of purposeful use of hands, jerky truncal ataxia, growth retardation and cardiac dysfunction, associated to bulbar dysfunction (hyperventilation episodes, abnormal thermal regulation)
  • five atypical forms : infantile seizure onset variant with seizure onset before regression ; congenital variant lacking the normal perinatal period ; the "forme fruste" with a milder and incomplete clinical course, the milder Zappella variant (Z-RTT) ; the late regression variant and the preserved speech variant (PVS)
    • Genetic determination sex linked
    Prevalence 1/10000 female birth by the age of 12 years
    Related entries . including some mild forms in females with motor coordination problems, mild learning disability and skewed X inactivation and in males a congenital encephalopathy, severe mental retardation and progressive spasticity, also including cases presenting with the main features of Angelman syndrome . including cases of non fetal, non progressive severe encephalopathy in males and females
    Function/system disorder neurology
    psychiatric disorder
    Type disease
    Gene product
    Name MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides flanked by AT-rich segments and recruits a co-repressor complex
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    various types     missense or nonsense mutations in exon 2-4 account for 80p100 of classic RTT, 50p100 of PSV and a lower percentage of other variants
    deletion     large deletions are a common cause of classic Rett syndrome and are less frequent in atypical cases
    Remark(s)
  • introduction of quantitative studies allow an overall MECP2 mutation detection rate of 90percent in classic RTT ; on the contrary the low fraction of deletions in RTT variants suggest genetic heterogeneity ; X-inactivation pattern may influence the phenotype severity
  • dysregulation of an activity-dependent EGR2/MECP2 pathway in RTT and autism (PMID: 19000991))
  • mutations arising in regions of DNA involved in the regulation of MECP2 expression levels (promoter, enhancers etc.) or in genes encoding regulatory factors of MECP2 could may be cause early to mid-gestation miscarriages (PMID: 20203171))
  • 60p100 of MeCP2 mutations in RTT are nonsense mutations
  • despite residing in the MBD C terminus, the T158M mutation surprisingly affects conformational dynamics spanning portions well into the N-terminal folded portion of the MBD (PMID: 21467044))
  • large deletion associated to severe phenotype with motor skills particularly affected (PMID: 22473088))
    • Genotype/Phenotype correlations
  • individuals with late truncating mutations (in C-terminus) had a less severe outcome than cases with missense and early truncating mutations
  • nonsense mutation R270X associated with reduced survival
  • 11 bp deletion in exon 1 in one subject with a milder phenotype