Devastating Neurological Disorder Caused by Single Gene Mutation

The affected child—almost always a girl—develops normally during the first five months of life. After the fifth month, head growth slows down and the child loses whatever purposeful hand movements she had developed during her first five months. After 30 months, the child frequently develops repetitive hand washing or hand wringing gestures; 50–80% of children with the disorder will eventually have seizures. Rett syndrome is also associated with varying degrees of mental retardation.

Rett syndrome is caused by the failure of the infant's brain to develop normally. This developmental failure is in turn associated with a mutation in the MECP2 gene, which resides on the far end of the longest arm of the X chromosome.

After failing to establish a cause and effect relationship between the MECP2 mutation and the large variety of symptoms displayed by Rett syndrome victims by studying overall gene function in the brain, investigators at Baylor College of Medicine (Houston, TX, USA) decided to focus their attention on the hypothalamus region of the brains of laboratory mice. They studied both Rett syndromes, where MECP2 fails to function, and a newly identified mutation where MECP2 is duplicated and its protein product overexpressed.

Results published in the May 30, 2008, issue of the journal Science revealed that both disorders changed the expression of about 2,500 genes. In the animals with Rett syndrome, 2,200 genes were less active than they were in normal mice, while the remainder showed increased activity. The numbers were precisely reversed in the duplication syndrome.

"From a practical viewpoint, knowing how the two syndromes behave on a molecular level is really important,” said senior author Dr. Huda Zoghbi, professor of molecular genetics at Baylor College of Medicine. "The duplication syndrome and Rett syndrome may share many clinical symptoms, but on the level of the neuron they are totally different, and so the treatment would be totally different.”

"Rett syndrome is a devastating disease,” said Dr. Zoghbi. "Think about what it takes to function normally: You have to be coordinated, you must be able to think, you have to be able to communicate, and you need to move smoothly and with balance. The symptoms of other neurological diseases affect some of these functions, but Rett syndrome affects them all. Rett syndrome is particularly heartbreaking, because it develops after the child has already learned to walk, and perhaps even say a few words. To lose all that, and gradually develop a symptom from almost every neurological disease in the book is quite mind-boggling.”


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Baylor College of Medicine