Today February 29th is celebrated worldwide the Rare Disease Day. This year’ slogan is “Join us in making the voice of rare diseases heard”. So this is my small contribution to such campaign, essential nowadays to increase support to all the people suffering those disorders and to their families. Because rare is the disorder but not them, is necessary to increase our awareness of what are a “rare disease” (that term, by the way, would be much more accurate if it would be “infrequent disease”). Thanks to all that, maybe pharma industry will give more attention to the research performed in thousands of labs trying to find cures for such devastating disorders. Here, today, I will try to explain briefly one of this rare diseases, the Rett syndrome.
Rett syndrome (RTT; incidence 1:10.000-15.000) is a rare brain disorder with devastating impact both on patients and their family’s lives, with no cure at the present. The disease accounts for approximately 3% of all cases of severe intellectual disability of genetic origin and represents the second most common genetic cause of intellectual disability in women. Girls affected by the disorder exhibit a seemingly normal postnatal development followed by a sudden deceleration in growth associated with progressive loss of acquired motor and language skills, stereotypic hand movements, muscle hypotonia, autonomic dysfunction and severe cognitive impairment. These symptoms appear normally during the second year of life and the most characteristic ones are the verbal and non-verbal communication deficits and loss of motor skills, especially hand use. Are also quite common the respiratory problems, gastrointestinal dysfunction, and seizures or epilepsy.
In more than 95% of typical RTT cases, the disorder is caused by mutations in an X chromosome-linked gene called methyl CpG-binding protein 2 (MECP2)1. MECP2 gene generates a multifunctional protein whose exact role is still controversial. Overall, different mutations in the MECP2 gene result in a suite of rare neurological disorders characterized by a clinical picture ranging from mild intellectual disability and autism to much more severe impairments in cognition, motor, and autonomic function. Globally, MECP2 mutations affect 30,000 new patients each year worldwide (1 case every 20 minutes).
Given that almost all RTT cases are sporadic, genetic counselling is not possible and the prevalence of these diseases is unlikely to decrease in the future. Until recently, MeCP2 was thought to act selectively as a transcriptional repressor. Recent data have provided evidence that MeCP2 also possesses transcriptional activating properties and hence indicate that the role of this protein should be better described by that of a transcriptional regulator. Although widely expressed, MeCP2 is found at the highest levels in mature neurons of the central nervous system. The nature of the RTT cognitive impairments in patients is still not fully understood. To this has contributed the difficulty in addressing cognition when communication and motor capacities are compromised, as it precludes most neuropsychological testing. Insight comes from studies in Mecp2-mutant mouse models that show learning and memory impairments in cognitive domains that include spatial memory and contextual and cued fear conditioning2.
Although the specific role of MeCP2 is still unclear, the effects of the malfunction of that protein and the major brain areas/circuits affected are better defined. RTT is not a neurodegenerative disorder and thus, there is no irreversible neuronal death. However, MeCP2 dysfunction causes a reversible atrophy of the dendritic tree of the neurons3 and a reduction of the brain levels of several neurotransmitters such dopamine and acetylcholine. 4. But even if we still lack a lot of knowledge about the mechanistic of the disease, recent discoveries suggest that the effects of MeCP2 deficiency are not purely developmental. This is supported by the striking findings from Guy and co-workers who showed that restoration of neuronal function is possible upon late protein expression in Mecp2-null animals5. Other labs have also described recently that the RTT phenotype is reversible in mice 6. By using pharmacological treatment with Levodopa and a Dopa-Decarboxylase inhibitor, it has been demonstrated that some of the phenotypes associated with RTT can be rescued and that the dopaminergic system is involved in the pathophysiology of RTT. Altogether, the data suggest that the RTT phenotype can be reversed, positioning RTT on a priority list of disorders for which further research urges.
Altogether, RTT patients and families need the maximum of help and support and for that scientific/pharma community must increase the effort into elucidating MeCP2 function and impact of the mutations occurring in the gene. The information gathered could explain the life-long consequences of MeCP2 malfunction in RTT patients and will help to detect novel and specific therapeutic targets to provide answers to RTT, with the aim of bridging the gap between bench and bedside. Translational knowledge of the molecular consequences and clinical severity of specific mutations will allow for the design of targeted therapies and will hopefully open up personalized treatment options for RTT patients.
- Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23, 185–188 (1999). ↩
- Pelka, G. J. et al. Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain 129, 887–898 (2006). ↩
- Armstrong, D. D. Neuropathology of Rett Syndrome. J Child Neurol 20, 747–753 (2005). ↩
- Wenk, G. L., Naidu, S., Casanova, M. F., Kitt, C. A. & Moser, H. Altered neurochemical markers in Rett’s syndrome. Neurology 41, 1753–1753 (1991). ↩
- Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007). ↩
- Szczesna, K. et al. Improvement of the Rett syndrome phenotype in a MeCP2 mouse model upon treatment with levodopa and a dopa-decarboxylase inhibitor. Neuropsychopharmacology 39, 2846–2856 (2014). ↩