Rett syndrome - Areas of Research

Rett Syndrome is a rare neurodevelopmental disorder that occurs almost exclusively in females. Affected infants and children typically develop normally until about 7 to 18 months of age, when they may begin to lose previously acquired skills, such as purposeful hand movements and the ability to communicate. Other abnormalities typically include slowing of head growth; development of distinctive hand movements, such as hand clapping, rubbing, or "wringing"; and impaired control of walking. Affected children also typically develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, impairment of language development, and seizures. Rett syndrome is a major genetic cause of mental retardation in females.

It was investigators at Baylor College of Medicine who found that most cases of Rett syndrome are caused by mutations in the gene on the X chromosome that directs production of the protein MeCP2 (methyl-CpG-binding protein). One of the mechanisms used to control the expression of genes during development is the chemical modification by methylation of parts (cytosines) of the DNA (deoxyribonucleic acid) strand. MeCP2 is one of the proteins that will bind to such methylated DNA, thus slowing down or blocking production of messenger RNA (ribonucleic acid) from the gene that is methylated. If MeCP2 is defective, reduced in amount, or absent, then the controlled blocking of methylated genes in the central nervous system does not occur properly, and genes that should be repressed are instead expressed inappropriately.

Note: The abbreviation for the methyl-CpG-binding protein GENE is MECP2, and the abbreviation for the PROTEIN that is produced from the gene is MeCP2.

Ongoing research at the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center:

Further understanding of the disease
There is significant variation in the clinical severity of Rett syndrome, and also a variety of mutations that have been found in the MECP2 gene. One research goal of the Baylor College of Medicine group is to find correlations between different MECP2 mutations and the clinical consequences. Screening the MECP2 gene for mutations in a large number of females with learning disabilities, mental retardation, and autism, as well as atypical and classic Rett syndrome cases, will reveal whether MECP2 mutations are responsible for some cases of autism or mental deficiency for which the causes were previously not known. In the approximately 20% of Rett patients in whom an MECP2 mutation has not been found, they will look to see if there is a previously undetected genetic alteration that might explain disruption of MECP2 expression.

Investigators also wish to determine the mechanism of how MECP2 mutations cause Rett syndrome. To do this, they will perform studies with cells and tissues with mutated and normal MECP2 genes from animals, patients, and healthy controls.

The Baylor College of Medicine group has recently developed a mouse model for Rett syndrome, as a further tool for determining the mechanism of the disorder and for testing therapeutic options. In this mouse model, presence of an abnormally short MeCP2 protein causes symptoms that correspond well with the human Rett syndrome. Researchers are now characterizing the behavior, neural damage, and physiology of these mice, in addition to performing detailed studies of genes that are abnormally expressed. Identification of genes that would normally be suppressed by MeCP2 activity will be important for pinpointing genes that may be responsible for different aspects of the Rett syndrome, such as autistic behavior, seizures, or compulsive hand movements. These "downstream" genes may also become targets themselves of mental retardation research.

Work towards therapy
A benefit of the mouse model of Rett syndrome is the ability to test therapeutic strategies. Investigators will test the effectiveness of dietary supplementation with folate and betaine, which are known to supply methyl groups, and the effects of L-carnitine, which has been anecdotally reported to improve the well-being of Rett patients. The apparently normal period of early development in Rett syndrome patients is an encouragement in the search for a way to intervene early in treatment of the disorder.

Patient facilities at Baylor College of Medicine:

The Blue Bird Circle Rett Center at Baylor College of Medicine is one of the few centers in the United States that specializes in diagnosis and care of girls and women with Rett syndrome. Several physicians who serve the Blue Bird Circle Rett Clinic are also involved in research at Baylor College of Medicine.