In 1966, an Austrian neurologist named Andreas Rett first described more than 20 young female patients which shared similar characteristics, starting from the observation of identical stereotypic hand movements. In 1983, the Swedish pediatrician Bengt Hagberg gave for the first time the name of Rett syndrome (RTT) to the symptoms he detected in a group of young girls that presented, among other things, a progressive loss of speech and hand use.
Two years later, in 1985, a symposium in Vienna established eight clinical inclusion criteria to define the Rett syndrome and provide a guide for the professionals. At the same time, the first parent organization, the International Rett Syndrome Association, was constituted. As for every rare disease, the associations of patients and/or their families are fundamental for helping the knowledge on the disease to be spread as much as possible.
The Vienna criteria gave a reliable help for establishing the clinical diagnosis of the RTT until the end of the past century when the genetic revolution provided a great step forward through the understanding of the molecular basis of the disease.
The discovery of the MeCP2 gene
1999 marked a milestone in the scientific understanding of the RTT. In that year was discovered the relationship between the malfunction of the MeCP2 gene and the RTT. This gene codes a nuclear protein (MeCP2) involved in the regulation of the expression of various genes. The protein MeCP2 is particularly important in the neuronal cells, where it regulates the correct development of the brain during the early months/years of life.
Studies conducted in mice without the MeCP2 gene showed that the functionality of specific brain regions was compromised, and the animals showed some typical symptoms of RTT like motor and cognitive impairment.
The presumed role of the protein MeCP2 is to regulate the expression of many genes either by silencing or activating them. So, the MeCP2 interaction with other proteins hampers the finding of a drug able to cure the symptoms of the RTT, because many pathogenic pathways are involved and it is unlikely to discover a molecule with a reliable therapeutic effect.
Main clinical features of the RTT
Depending on the type of the mutations occurring in the MeCP2 gene, the clinical symptoms and the evolution of the RTT may vary. Two main groups of symptoms have been identified, thus originating the severe and the mild RTT phenotype.
The following symptoms are common to both the severe and the mild form, but in the severe form, they appear already in the first months of life and strongly hamper the social and family life of the young patients. Children with severe RTT:
– do not learn to walk;
– have serious difficulties in talking or do not talk;
– show hand stereotypic movements;
– lose the hand skills;
– have epilepsy (more than 60% of patients);
– have abnormal breathing patterns, either hyperventilation or breath-holding;
– present scoliosis (75% of patients);
– their sleep is disturbed.
Generally, the patients present some of the symptoms described above, but such symptoms appear later (however, always during the childhood) and do not compromise completely the social and family life of the girls. The patients can walk, maintain a certain use of the hands, learn the language and eat autonomously; they are also able to pronounce some words. Nevertheless, symptoms like sleep problems, speech delay and some difficult of movement – such as loss of balance – are present.
Therapeutic strategies and networking efforts
As mentioned above, because of the great number of metabolic pathways affected by the malfunction of MeCP2, the pharmaceutical approach does not cure the disease, just alleviates some symptom. The most used drugs belong to three areas, affecting the brain neurotransmitters, or the growth and development factors, or other cellular processes.
To date, the replacement of the impaired MeCP2 by gene therapy, or its activation on the inactive X chromosome, seem to have the potential to reverse the symptoms of the RTT. However, there is still the problem of the possible overexpression of the gene that could lead to developing RTT symptoms in the same way.
Finally, the networking efforts to collect data and to share experiences between the families of the patients are as important as the scientific studies. The first registries used to collect epidemiologic information on the RTT were the Texas registry and the Australian Rett Syndrome Database. InterRett provides information from clinicians and families based on questionnaires, as well as the Australian Paediatric Surveillance Unit and the Rare Disease Clinical Research Network for RTT (the latter based only on US patients).
Moreover, advocacy groups such as the International Rett Syndrome Association (IRSA) are active both in the funding of networking tools and in the research of RTT.
A long way has been carried out since the first observations of Andreas Rett. In the last 50 years, the combined efforts of scientists, physicians and families’ associations have been improving the expectancy and the quality of life of the patients, even if with discrepancies among the countries and the socioeconomic status, as the availability of therapies and/or the genetic screening are not for all the people. The great challenge for the future will be making effective the promising therapeutic strategies tested in the animal models, even if an effort of realism is also needed in the short run.
Leonard H. et al. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol. 2017 Jan;13(1):37-51.
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).