International Team Of Researchers Identify Gene Mutation Linked To Severe Neurological Disorder

Main Category: Neurology / Neuroscience
Article Date: 25 Jul 2004 - 0:00 PDT

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In an important breakthrough against a rare but devastating genetic disease, researchers have pinpointed the gene involved in rapid-onset dystonia-parkinsonism (RDP). People with RDP suffer from the symptoms of both dystonia (involuntary, irregular contortions of the muscles) and Parkinson's disease (tremors and muscle rigidity).

The international research team, led by Dr. Laurie Ozelius of the Albert Einstein College of Medicine and Dr. Allison Brashear of the Indiana University School of Medicine, found that six different mutations in this single gene accounted for RDP in seven unrelated families. Their study was reported in the July 21 issue of the journal Neuron.

Parkinson's disease afflicts about one million people in North America and dystonia about 300,000. RDP is a rare form of dystonia. Until this study, very little was known about RDP except that it has a rapid onset, with people often developing the disease over a period of just a few days or even hours.

Dr. Ozelius, an associate professor of molecular genetics at Einstein, analyzed DNA samples from the seven RDP families that were studied. She found six different mutations that all affected the same gene, known as ATP1A3. "The ATP1A3 gene codes for a protein that plays a role in the cellular 'pumps' that regulate the transit--both into and out of cells--of sodium and potassium, which are necessary for proper nerve signaling throughout the body," explains Dr. Ozelius. "The mutations in ATP1A3 appear to compromise the encoded protein's function and disrupt nerve signaling."

For people who have one of these mutations-either by inheriting it from a parent or developing it spontaneously-the "trigger" for bringing on RDP is usually some form of severe stress such as a very high fever or extreme physical exertion. RDP can strike over a broad age range: People as young as 4 and as old as 58 have developed the disorder.

"I've been hopeful they would find the genes responsible and that such a discovery would lead to better treatments," says Elizabeth Gay of Cincinnati, Ohio, whose family was involved in the study. Three of her five children and one grandchild suffer from RDP. It took 16 years and consultations with numerous specialists across the country before the disease was correctly diagnosed in her family members.

For Mrs. Gay's children--Sheila Gay, 49, Carolyn Sparks, 47, and Michael Gay, 39-RDP has meant being dependent on a motorized wheelchair. All of their motor skills are challenged, and even chewing food is difficult. The most disturbing handicap for all three is a severe speech impediment, says Mrs. Gay. "People think if you can't talk you are mentally incompetent or deaf. It's heartbreaking."

Dr. Susan Bressman, professor of neurology at Einstein and director of the Movement Disorder Research Center at Beth Israel Medical Center, made the eventual diagnosis of RDP in the Gays. Dr. Bressman noticed that the clinical features of RDP in the three siblings resembled those first noted by Indiana University's Dr. Brashear in a paper describing another family.

"I contacted Dr. Brashear and told her how symptoms of the patients I had seen mirrored those she had described in her paper," says Dr. Bressman. "At the time, there was a lot of skepticism that RDP was a distinct disorder with its own unique genetic cause."

After the two researchers compared notes and videos of their patients, "The similarities seemed clear," adds Dr. Brashear, who is an associate professor of neurology and vice-chairman of clinical practice and practice development at Indiana University School of Medicine. "We then got DNA samples from family members so that Dr. Ozelius could explore the genetic implications. With her discovery of the mutation of ATP1A3 among the families studied, and the prevalence of RDP that we've observed within these families, the link between RDP and a single gene has now been firmly established."

"There's so much more we can learn through the study of this gene and its mutations," adds Dr. Ozelius. "It's particularly exciting because it opens further avenues for examining different mutations in this gene that might shed light on the causes of more common neurological disorders that have similar symptoms, such as Parkinson's and epilepsy."

Other researchers of the international team involved in the study are from Massachusetts General Hospital and Harvard Medical School; the University of Chicago; the Federal University of Sao Paulo, Brazil; the Institute of Psychiatry and Neurology, Warsaw, Poland; Centro de Neurologia-Neurocirugia and Clinica Quiron, San Sebastian, Spain; Universitaire de Nice, France; and the Academic Medical Centre of the University of Amsterdam, The Netherlands. The research was supported by grants from the Dystonia Medical Research Foundation, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the National Heart, Lung, and Blood Institute, the National Institute of General Medical Sciences, and the CAPES Foundation. CONTACTS:

Karen Gardner
Albert Einstein College of Medicine
(718) 430-3101
kgardner@aecom.yu.edu

Mary Hardin
Indiana University School of Medicine
(317) 274-7722
mhardin@iupui.edu

Michelle Pipia-Stiles
Beth Israel Medical Center
(212) 523-4044
mstiles@chpnet.org