The Puzzle of Rett Syndrome
By Laura Bonetta

A disease can be a difficult puzzle to doctors and scientists until a breakthrough starts to bring a few of the pieces together.

Imagine facing a three-year-old girl who cannot speak or pick up and hold things. She has abnormal breathing and she keeps moving her hands as though she is washing them. Her parents say she was a perfectly healthy baby until sometime after her first birthday. These are the telltale signs of Rett syndrome, a severe neurological disease that strikes mostly girls. But a diagnosis is difficult. There is no test for Rett syndrome, and many of its symptoms are similar to those of cerebral palsy and autism. Even with a proper diagnosis, no one knows what causes the disease or how to treat it.

For many years, this was the picture of Rett syndrome. Then Ruthie Amir in the laboratory of HHMI investigator Huda Zoghbi discovered a gene that, when mutated, causes the disease. Scientists have since developed a test to accurately diagnose patients. They have also engineered mice to model the human disease—an invaluable tool to start understanding how the disease develops and to find ways to treat it.

Finding the Gene

Zoghbi faced a formidable challenge in searching for the gene responsible for Rett syndrome. "Gene hunters" rely on families with several members suffering from a disease to trace the inheritance of the responsible gene and home in on its location in the genome. But when Zoghbi started to work on Rett syndrome in the early 1980s, there were only two known families with two affected girls in each—all other cases of Rett syndrome were isolated patients. With the help of two additional small families and collaborations with other scientists, Zoghbi's group finally found the Rett syndrome gene in 1999. This was the breakthrough everyone had been waiting for.

The gene instructs all cells in the body to make a protein called methyl-CpG-binding protein 2, or MeCP2 for short. Scientists think that the protein's normal function is to turn off several genes at certain times during the maturation of the central nervous system. In Rett syndrome, the MECP2 gene is mutated so that the protein it makes cannot keep these genes silent at the appropriate times. Although scientists have not yet figured out how, the inappropriate activity of these genes in the brain causes the brain to malfunction.

A Gene on the X Chromosome

The MECP2 gene is located on the X chromosome, one of the two sex chromosomes. This location explains why the disease primarily affects girls. Males have only one X chromosome and one copy of the MECP2 gene. Mutations that wipe out this gene tend to be lethal to young infants. Females, on the other hand, have two copies of the X chromosome, but in each cell only one copy is active. If in a sufficient number of cells the X chromosome with the normal MECP2 gene is active, these cells can compensate for the ones with the faulty gene on the active X. In such cases, girls will survive, albeit with great disabilities.

Most girls with Rett syndrome have no family history of the disease. This means that the mutation in the MECP2 gene arose in only one of the mother's eggs or father's sperm, or in the embryo itself, and is not transmitted to other children in the same family. But in the few cases where the disease runs in the family, the faulty gene is carried on one of the X chromosomes in all the mother's cells. As a result, half of her children inherit the X chromosome with the mutated gene.

Whether or not the girls who inherit the mutant gene develop Rett syndrome or a milder disease or even show any symptoms of disease at all seems to depend on the proportion of cells in which the mutant gene is on the active X chromosome and on the nature of the mutation.

A Gene with Many Faces

After doctors started testing suspected Rett syndrome patients for a mutated copy of the MECP2 gene, they were surprised to find that mutations in this gene also cause other diseases that affect brain synaptic plasticity—the characteristic of the brain that determines, for example, whether you are a fast or slow learner. Diseases such as infantile encephalopathy, Angelman syndrome, mental retardation, autism, and learning disabilities can all be caused by mutations in MECP2, as well as by mutations in other genes. How can mutations in a single gene cause so many different physical manifestations—or, as geneticists would say, so many "phenotypes"?

The phenotype of a MECP2 mutation depends in part on the pattern of X inactivation. For example, if 80 percent of cells in the brain have inactivated the X chromosome with the mutant MECP2 gene, the patient might have mild mental retardation. If, on the other hand, only 50 percent of cells have the mutated gene on the inactive X chromosome, the patient might develop Rett syndrome. Scientists don't yet understand how X inactivation is controlled and why the pattern differs from one person to another.

But there is an additional layer of complexity. The phenotype of a MECP2 mutation is also determined by the precise nature of the mutation itself. For example, mutations that completely eradicate the MeCP2 protein cause more severe symptoms than ones that result in a protein that is partially inactivated.

Prospects for Treating the Disease

Perhaps one of the most crucial pieces of the puzzle that scientists are still trying to find is how the faulty gene affects the brain. To find clues, two groups of researchers, one at the Massachusetts Institute of Technology in Cambridge and the other at the University of Edinburgh in Scotland, engineered mice that lack Mecp2. Regardless of whether the gene is removed when mice are embryos or after the mice are born, the mice develop a progressive neurological syndrome. This means that, at least in the mouse, Rett syndrome results from the lack of the Mecp2 protein in the brain and not from a problem that occurs while the brain is developing in the embryo. It may therefore be possible to treat the disease by restoring the functions of the MeCP2 protein in the brain, even after birth.

Zoghbi's group is currently testing this possibility. The scientists have created their own mouse model of the disease. Instead of lacking the Mecp2 gene, the mice have a mutated gene that makes a partially functional protein—a situation that is similar to what occurs in a large number of Rett syndrome patients. These mice faithfully reproduce many of the features observed in patients. The researchers are now doing experiments to put back the normal Mecp2 gene in the brains of the mutant mice at different times before and after birth. If the scientists are able to correct the neurological defects in their mouse model, they will know that the damage caused by Mecp2 mutations is not permanent. This will be good news for patients and their families. It may someday be possible to develop drugs to reverse at least some of the symptoms of the disease.

Several pieces of the puzzle are still missing, but four short years after Zoghbi and her colleagues found the responsible gene, the picture of Rett syndrome is becoming clearer.

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