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Rett syndrome

Tuesday 14 October 2003

Definition: Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2.

The syndrome of brain atrophy in girls described by Andreas Rett in 1966. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. Locus: Xq28.

Rett syndrome is a progressive neurological disorder. The symptoms of this disorder are easily confused with those of autism and cerebral palsy. It is recesive inherited and can be carried in a weak form for generations dormant with symptoms of learning disorder and total disability to socialize. The clinical diagnosis includes small head, hands, and feet. Stereotypical repetitive hand movements such as mouthing or wringing are also included. Girls are very prone to seizures, GI disorders, and are typically nonverbal. About 50% of the girls/women are ambulatory.

Rett syndrome (symbolized RTT) is X-linked dominant, affecting almost exclusively girls. Development is normal until 1 year of age, when language and motor milestones regress and acquired microcephaly is seen. Hand wringing and sighing are characteristic, and they develop autistic behavior.


- germline mutations in the Xq28 gene MECP2 encoding Methyl-CpG-binding protein 2

- germline mutations in CDKL5

  • CDKL5 Belongs to the Same Molecular Pathway of MeCP2 and it is Responsible for the Early Seizure Variant of Rett Syndrome (15917271).

- FOXG1-truncating mutations in a congenital variant of Rett syndrome.

  • FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization. (18571142)


- Rett syndrome is usually caused by a mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2). MECP2 is found on chromosome band Xq28, near the long end of the X chromosome.

- Rett syndrome can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects 1 in every 12,500 female live births.

- Most individuals with Rett syndrome are female. One explanation given for this was that the genetic defect that caused Rett syndrome in females caused embryonic lethality in males (that is, males with pathogenic MECP2 mutations died before they were born). While a plausible hypothesis, more recent research has contradicted this explanation.

- Most males with a pathogenic MECP2 mutation suffer from neonatal encephalopathy and die within a year or so of birth. Males who have two X chromosomes and a Y chromosome (often called Klinefelter syndrome), one with a mutated MECP2 gene, follow a similar development path to females with Rett syndrome. Males who have somatic mosaicism also have symptoms like females with Rett syndrome. Some researchers have reported cases of males with Rett syndrome who have a pathogenic MECP2 mutation but do not have a somatic mosaicism or an extra chromosome.

- Unlike most genetic diseases, many cases of Rett syndrome involve spontaneous mutations in one of the parent’s gonads. It has been argued that one cause of the majority of Rett syndrome individuals being female is that mutations to MECP2 are possibly more common in male gonads than female gonads, and only females can inherit a mutated MECP2 gene from fathers (males inherit a Y chromosome from fathers, which does not contain a copy of MECP2).


- Mouse model of Rett syndrome

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- Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, Pollazzon M, Buoni S, Spiga O, Ricciardi S, Meloni I, Longo I, Mari F, Broccoli V, Zappella M, Renieri A. FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome. Am J Hum Genet. 2008 Jun 18. PMID: 18571142


- Bienvenu T, Chelly J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat Rev Genet. 2006 Jun;7(6):415-26. PMID: 16708070

- Caballero IM, Hendrich B. MeCP2 in neurons: closing in on the causes of Rett syndrome. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R19-26. PMID: 15809268

- Kriaucionis S, Bird A. DNA methylation and Rett syndrome. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R221-7. Epub 2003 Aug 19. PMID: 12928486

- Dragich J, Houwink-Manville I, Schanen C. Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000 Oct;9(16):2365-75. PMID: 11005791