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Rett Syndrome

Ola Skjeldal gives a detailed overview of Rett syndrome, including a definition of the syndrome, the clinical features and a genetic background.

What is Rett syndrome?

Rett syndrome (RTT) is a neurodevelopmental disorder first described by the Austrian paediatrician Andreas Rett in 1968. However, the syndrome was not internationally known until 1983 when Professor Bengt Hagberg, a child neurologist in Gothenburg, described a group of patients with exactly the same clinical patterns as published by Rett. Since then the condition has been known worldwide as one of the pervasive neurodevelopmental disorders. It seems to occur in all countries and in all ethnic groups. The condition is one of the most frequent genetic causes of neurological disability. Most of the epidemiological surveys which have been done reveal the prevalence to be about 1 in 10,000 females.


Ola Skjeldal

Clinical features

RTT is a severe neurodevelopmental disorder, mostly affecting females. However, there are also rare cases of boys and adult males with RTT (1). The most important clinical signs are impairment in cognition, motor control and communication skills. The so-called classical form of RTT is characterised by an apparently normal development the first 6-18 months of life followed by regressive loss of abilities alongside autistic behaviour, at least in the early phases. Furthermore, loss of motor skills, loss of other acquired skills such as purposeful hand function, deceleration of head growth and later the appearance of stereotypic hand movements and respiratory dysfunction are all very common clinical features. A majority of those affected also suffer from epilepsy. In many cases the epilepsy is complicated and difficult to treat. Dysfunction in the autonomic nervous system is also common.

The diagnosis of classical RTT was originally based upon eight mandatory and eight supportive clinical criteria (2). These criteria were revised in 2010 (3) and were limited to the obligatory presence of a period of regression and four main criteria: Partial or complete loss of acquired purposeful hand skills and speech, gait abnormalities and stereotypic hand movements.

In recent years a substantial number of RTT cases have been published and the phenotypic spectrum of RTT has evolved. As early as 1994, the diagnosis included both classical RTT and so-called RTT variants. (4). In the last decade, the term RTT-like disorders has been used for individuals sharing many of the clinical characteristics with RTT, but not fulfilling all the diagnostic criteria. In contrast to classical and atypical RTT, the term RTT-like disorders is not clearly defined (5). This has created confusion and discussions about the concept of diagnosis and RTT.

Genetic background

The main genetic cause of RTT was identified in 1999 (6). It was then clear that the causative mutations were localised in the MECP2 gene, which encodes for methyl-CpG-binding protein (MECP2). This protein seems to have many important functions. Among other things MECP2 helps to regulate gene activity (expression) by modifying chromatin, the complex of DNA and protein that packages DNA into chromosomes. In the brain, the MECP2 protein is also important for the function of several types of cells, including the neurons. The protein likely plays an important role in maintaining synapses between neurons. This makes RTT a strong candidate for being grouped with the “synaptogenic disorders”, much like many other variants of autism spectrum disorders. Furthermore, it seems likely that MECP2 is also able to activate other so-called target genes.

Mutations in the MECP2 gene are found in about 97% of cases with classical RTT. Interestingly though, in atypical cases identified, mutations are found in only 50-70%. Furthermore, MECP2 mutations can occur in patients without any RTT phenotype at all. In the last 2-3 years mutations in genes other than MECP2 have been found in females with both classical RTT and RTT-like phenotypes. In fact, almost 100 genes which are claimed to be associated with RTT phenotype have been published. Although there is no doubt that most of the RTT is due to mutations in MECP2 it seems that mutations in a substantial number of other genes can be associated with RTT. The reason for this is still unclear. However, this shows us that RTT must be a clinical diagnosis, based on clear diagnostic criteria.

1. Chahil G., Yelam A. and Bollu PC. Rett syndrome in Males. Cureus, 2018, 10(10): e3414
2. Hagberg B., Hanefeld F., Percy A. and Skjeldal O. Un 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(5): 293 - 297
3. (Neul JL., Kaufmann WE., Glaze DG. Et al. Rett syndrome: revised diagnostic criteria and nomenclature. Annals of neurology 2010, 68(6): 944-950)
4. Hagberg BA, Skjeldal OH: Rett variants: a suggested model for inclusion criteria. Pediatric neurology, 1994, 11(1): 5-11
5. Schonewolf-Greuich B., Bisgaard AM., Moller RS. et al. Clinician`s guide to genes associated with Rettlike phenotypes-investigation of a Danish cohort and review of the literature. Clinical genetics, 2017++
6. Amir RE., Van den Veyver IB., Wan M. Et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999, 23: 185-188
7. Tillotson R. and Bird A. The molecular basis of MeCP2 function in the Brain. J Mol Biol 2017, Epub ahead of print