• developmental delay
• methyl binding genes
• Rett syndrome
• MECP2

The report by Amir et al¹ that Rett syndrome (RS) is associated with mutations in the MECP2 gene permitted laboratory diagnosis of this devastating yet common neurodevelopmental disorder. Hitherto the paucity of familial cases of the syndrome and the failure to identify the syndrome in males despite fairly wide clinical criteria had defined it as an X linked dominant disorder with male lethality.² Soon, however, reports from the few families in which RS is segregating showed that male family members who inherited the same mutation in the MECP2 gene as their affected female relatives did sometimes survive to birth and beyond, but they did not, as the females did, develop Rett syndrome but were subject to an entirely different syndrome of severe male encephalopathy.^3,4 In the meantime, attempts were being made to relate the severity of the clinical picture presented by girls with RS (ranging from “classical” to “forme fruste”)² with the individual mutations. No correlations were observed either with the type of mutation or with its position within the MECP2 gene save that N-terminal changes tended to be more severe than those located further downstream.⁵ The gene is divided into a methyl binding domain (MBD), a transcription repression domain (TRD), and a proline rich C-terminal domain. Mutations cause loss of function by interfering either with DNA binding or with the downstream association of MeCP2 with its transcriptional corepressors Sin3A and HDAC.⁶ To date, >200 different mutations have been detected in girls with RS, >95% are de novo, and they are found in all of the domains. Those in the MBD are predominantly missense while those in the TRD tend to be nonsense or truncating mutations. Downstream C-terminal mutations may be individual and are often of the insertion or deletion type. Despite the …