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MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution
  1. F Laccone1,
  2. B Zoll1,
  3. P Huppke2,
  4. F Hanefeld2,
  5. W Pepinski3,
  6. R Trappe1
  1. 1Institute of Human Genetics, Göttingen, Germany
  2. 2Neuropaediatric Department, Göttingen, Germany
  3. 3Department of Forensic Medicine, Medical University, Bialystok, Poland
  1. Correspondence to:
 Dr F Laccone, Institute of Human Genetics, Heinrich-Düker Weg 12, 37073 Göttingen, Germany;
 flaccon{at}gwdg.de

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Rett syndrome (RTT) is one of the most frequent neurodevelopmental disorders affecting almost exclusively females. It is characterised by normal development until 6-18 months followed by a more or less rapid decline of acquired functions mainly of the higher brain functions, such as communicative speech and purposeful hand use. Mutations in the MECP2 gene have been described in RTT patients world wide.1–4 Along with classical RTT females, several RTT variants, like the preserved speech variant, congenital RTT, and a patient with an Angelman syndrome-like phenotype, have been reported to carry mutations in the MECP2 gene.4–8 RTT has been considered an X linked dominant disease lethal in males. This assumption was supported by the small number of affected RTT males and by a lethal knock out mouse model.9 Recently, however, two independent groups have shown that nullizygous male and heterozygous female knock out mice are viable.10,11 This finding strongly questions the hypothesis of male lethality of the RTT trait. Our recently published findings about a very high percentage of paternal origin of the mutation in the MECP2 gene in sporadic cases of RTT provide a simple explanation for the scarcity of affected males.12 Meanwhile, there has been a series of reports describing mutations in the MECP2 gene of males. The affected males can be divided into two groups according to the type of their mutation. The first group carries mutations in the MECP2 gene either already described in RTT females or mutations of unquestionable pathological value (frameshift mutations or nonsense mutations).5–16 All these patients are characterised by early onset of the disease and a severe encephalopathy. A subgroup are males with a 47,XXY karyotype who present with the typical RTT symptoms. The second group includes patients carrying mutations inherited from their …

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