A rare disease a day: Rett syndrome


In honor of rare disease day later this week, I am raising awareness of some of the rare diseases as brief posts. Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease, Batten disease , Hurler Syndrome, Charcot-Marie-Tooth, Fibromuscular dysplasia, Huntington’s disease,  Giant Axonal Neuropathy (GAN). Neuroendocrine tumor, Amyloidosis, Lowe syndrome and now its the turn of Rett Syndrome.


Rett syndrome  is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. Onset occurs between 6 and 18 months of age. Clinical features are small hands and feet, deceleration of the rate of head growth (including microcephaly), repetitive stereotyped hand movements (such as wringing and/or repeatedly putting hands into the mouth), gastrointestinal disorders,  seizures, no verbal skills, 50%  do not walk, Scoliosis, growth failure, and constipation are also common. These features are confused with those of Angelman syndrome, cerebral palsy and autism. Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy. Females can live up to 40 years or more.


Rett syndrome is caused by mutations in the gene MECP2. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. In some very rare cases, no known mutated gene can be found suggesting changes in MECP2 that are not identified by presently used techniques or mutations in other genes that may result in clinical similarities. Currently there is no cure for Rett syndrome. Mice with induced Rett Syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MeCP2 gene back when they are adults. One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse signs in MeCP2 mutant mice. Another area research is to counter the neuroexcitotoxic effect of increased spinal fluid levels glutamate and increased NMDA receptors in the brain by the use of NMDA antagonists. GABAA receptor antagonists may also offer a possible therapeutic target for the treatment of MECP2 duplication syndrome. The clinically approved drug sarizotan was recently shown as an effective treatment for respiratory disorders in mouse models of Rett syndrome. Cholesterol homeostasis is a potential target for the treatment of patients with Rett syndrome. Statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice.  Acetyl-L-carnitine treatment from birth was associated with an almost complete rescue of hippocampal dendritic morphology abnormalities with no discernable side effects in  mutant mice. Mice lacking Mecp2 show decreased levels of brain-derived neurotrophic factor (BDNF), and fingolimod administration  partially rescues these levels as well as the size of the striatum. 


Links to a large number of patient and support groups and foundations can be found at Rare Connect.




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