Rett Syndrome Study

Approximately 1 in 10 000 - 15 000 girls are affected by Rett syndrome. The National Institute of Neurological Disorders and Stroke has useful info on Rett syndrome here. Here is a small excerpt from that site:

Rett syndrome is a childhood neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. It affects females almost exclusively.

....The course of Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Before the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. The onset of this period of regression is sometimes sudden.

More information about Rett syndrome can also be found on the International Rett Syndrome Association webpage here.

The latest issue of Science brings some encouraging news to those who suffer from Rett syndrome. This news report notes that researchers have been able to reverse some of the dramatic neurological problems of Rett syndrome in an experimental mouse model. Here is a snippet from the news piece:

Some of the dramatic neurological problems of Rett syndrome can be reversed in an experimental mouse model, researchers have found. Although the work does not have direct therapeutic applications, scientists studying the devastating genetic disorder hail the findings as a sign that treatments are at least possible in principle. "This is very exciting," says Huda Zoghbi, a geneticist at Baylor College of Medicine in Houston, Texas. "It gives us researchers and the families and patients hope that, as we uncover [biochemical] pathways that could be safely manipulated, we can recover some function in these girls."

....Mutations in a gene called MECP2 are to blame....

Jacky Guy and Adrian Bird of the University of Edinburgh, U.K., and colleagues created mice with a genetic roadblock--a string of DNA--inserted into Mecp2 (the mouse version of the human gene) that prevented cells from reading the gene to make the protein it encodes. Female mice with the blocked Mecp2 developed normally for 4 to 12 months before showing Rett-like symptoms, including impaired mobility, an abnormal gait, tremors, and breathing difficulties.

Then the researchers turned Mecp2 back on, exploiting another gene they'd bestowed on the mice. This gene encoded a hybrid protein: a DNA-splicing enzyme fused to an estrogen receptor. The enzyme can recognize and remove the roadblock in Mecp2, but the attached estrogen receptor prevented it from entering the cell nucleus. By injecting the mice with tamoxifen, a drug that binds estrogen receptors, the researchers sent the hybrid protein scuttling into the nucleus to snip out the roadblock and restore Mecp2.

After the mice had received five weekly tamoxifen injections, the Rett-like symptoms all but disappeared. A few of the rodents continued to walk with their hindlimbs abnormally far apart, but otherwise they were hard to distinguish from their genetically normal relatives. It was a pleasant surprise, because researchers had feared that the developmental loss of Mecp2 led to missing or permanently disabled neural connections. "The general perception is that once the brain has missed out big time on some ingredient of normal development, it's never going to be able to recover," Bird says. "We thought maybe we'd get amelioration of the symptoms, but we didn't anticipate that things would be reversed on the scale that we found."

The actual report can be downloaded here (subscription needed). Here is the abstract:

Reversal of Neurological Defects in a Mouse Model of Rett Syndrome
By Jacky Guy, Jian Gan, Jim Selfridge, Stuart Cobb, Adrian Bird

Abstract: Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. Neuronal death is absent, suggesting that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.

Cheers,
Colin