Long Island scientists have moved a tantalizing step forward in efforts to better understand -- and alleviate -- some of the devastating symptoms of Rett Syndrome, a rare, incurable, neurodevelopmental condition that primarily strikes girls.
The syndrome shares key symptoms associated with autism spectrum disorders but has many symptoms that are unique, including an underlying genetic mutation, said biochemist Nicholas Tonks of Cold Spring Harbor Laboratory.
Writing in the current issue of the Journal of Clinical Investigation, Tonks and colleagues report on a possible -- but still distant -- drug intervention.
"When you do classical academic research that has the opportunity to help real patients, it's a reason to get out of bed in the morning," Tonks said. "It is a very exciting time."
Tonks and research associate Navasona Krishnan have found that their so-called small-molecule -- an experimental drug candidate -- extends life expectancy in mouse models bred to develop Rett Syndrome. Tonks hopes eventually to move forward with human clinical trials of the approach. Currently, there are no drugs available to address symptoms associated with the neurodevelopmental disorder.
Tonks' strategy involves inhibiting the activity of an enzyme called PTP1B, which he discovered a 25 years ago. The enzyme goes awry in Rett Syndrome, as it does in certain cancers and some metabolic disorders. Controlling it, he and his team found, relieved syndrome-related symptoms in the humanized mice.
Tonks and colleagues found, for example, that PTP1B levels are extremely high in the afflicted mice. But when the enzyme was inhibited, cell communication processes flowed normally.
Now, he wants to know whether inhibition with his candidate molecule will do the same in people and is collaborating with scientists at Case Western Reserve University in Cleveland.
Rett Syndrome usually appears in toddlers after a normal period of development during infancy. Scientists have found that mutations in the MECP2 gene, which resides on the X chromosome, cause the condition.
Because males with Rett Syndrome have only one X chromosome, they usually die as infants. Females with the syndrome, however, can survive into middle age, experts say.
But afflicted girls and women have a constellation of problems: breathing difficulties, Parkinson's-like tremors, small head size, mental retardation, poor muscle development and an inability to speak. People with Rett Syndrome require lifelong, round-the-clock care.
Advocates for children and adults with the syndrome call it the most physically disabling of disorders linked to the autism spectrum.
"Historically it was considered an autism spectrum disorder," said Monica Coenraads, executive director the Rett Syndrome Research Trust in Connecticut and the mother of an 18-year-old daughter with the syndrome.
"Now that there is a gene associated with it, it's no longer included in the DSM-V," Coenraads said of the Diagnostic and Statistical Manual, Fifth Edition. The volume is considered the bible of psychiatry.
Nevertheless, she added, many people still refer to Rett Syndrome as an autism spectrum disorder. An estimated 16,000 people are affected in this country, with 350,000 worldwide.
Dr. David Katz, professor of neurosciences and psychiatry in the School of Medicine at Case Western, said the work at Cold Spring Harbor Laboratory is on an intriguing track. "These are promising results, encouraging results," said Katz, who has studied Rett Syndrome for years. "This is what we call early stage findings where there are encouraging results in a mouse model."
What has yet to be discovered, Katz said, is whether the experimental drug candidate can be given over a long period of time. It also is important to know whether there are side effects or other safety concerns.
Katz added that other laboratories in this country and abroad are investigating additional possible strategies.
Coenraads welcomes Tonks' work as well as that by other scientists.
"It's a very exciting time," she said of the collective Rett syndrome research. "We are very optimistic."
CORRECTION: An earlier version of this story misstated the first name of Cold Spring Harbor Laboratory biochemist Nicholas Tonks.