March 31, 2011

Discovery Lecturer offers Rett syndrome insights

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Huda Zoghbi, M.D., discusses her research into Rett syndrome at last week’s Discovery Lecture. (photo by Joe Howell)

Discovery Lecturer offers Rett syndrome insights

During her first year of residency in pediatric neurology, Huda Zoghbi, M.D., saw two patients who shaped her career.

The year was 1983. Zoghbi had read a new report in the Annals of Neurology describing Rett syndrome, a progressive disorder of autism, dementia, ataxia (loss of control of body movements) and loss of purposeful hand use/hand-wringing in girls.

She walked into a clinic the same week she read the report and saw Ashley, who had been healthy and typically developing until she was 3 and began to lose her social skills, hand use and language skills.

A week later, Zoghbi saw another patient, a girl diagnosed with cerebral palsy, who was wringing her hands and had other symptoms of Rett syndrome.

“At that time no one had seen any Rett child in the United States. Nobody believed me about Ashley having Rett syndrome and yet here was another patient with the same symptoms,” Zoghbi, a professor of Molecular and Human Genetics at Baylor College of Medicine, told the crowd at last week's Discovery Lecture.

Zoghbi decided to dig deeper. She searched the clinic records for every girl with mental retardation and seizures (another symptom of Rett syndrome), came up with 35 charts, reviewed them and identified seven more girls with Rett syndrome.

“That's how within a span of a couple of weeks I became the U.S. expert on Rett syndrome,” she laughed.

A fascination with the syndrome and its effects pushed Zoghbi into research.

“As naïve as one can be, I decided this is a genetic disease, and it's got to be (a gene) on the X chromosome because there are only girls affected, and I'm going to clone the gene.”

Sixteen years later, she and her colleagues reported in Nature Genetics that mutations in the gene methyl-CpG-binding protein 2 gene (MECP2) cause Rett syndrome.

They have since established that MECP2 mutations cause a broad spectrum of phenotypes: females may present with isolated mental retardation, autism or milder forms of Rett; males with mutations that inactivate MECP2 die in infancy, while milder mutations can cause mental retardation, motor dysfunction or psychosis.

Zoghbi and her colleagues generated a mouse model that shows features of classic Rett syndrome in humans, including the hand-wringing motions, which they have used to explore the molecular mechanisms of Rett syndrome.

They are now using other mouse models with loss of MECP2 in specific brain regions to understand which brain regions mediate certain symptoms, with the goal of devising therapeutic strategies based on their findings.

Zoghbi's lecture was sponsored by the Department of Pediatrics and the Vanderbilt Kennedy Center. For a complete schedule of the Discovery Lecture series and archived video of previous lectures, go to