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UCSF-led team discovers cause of rare disease

Childhood disorder called PKD linked to genetic mutations

A large, international team of researchers led by scientists at the University of California, San Francisco has identified the gene that causes a rare childhood neurological disorder called PKD/IC, or "paroxysmal kinesigenic dyskinesia with infantile convulsions," a cause of epilepsy in babies and movement disorders in older children.

The study involved clinics in cities as far flung as Tokyo, New York, London and Istanbul and may improve the ability of doctors to diagnose PKD/IC, and it may shed light on other movement disorders, like Parkinson's disease.

The culprit behind the disease turns out to be a mysterious gene found in the brain called PRRT2. Nobody knows what this gene does, and it bears little resemblance to anything else in the human genome.

"This is both exciting and a little bit scary," said Louis Ptacek, MD, who led the research. Ptacek is the John C. Coleman Distinguished Professor of Neurology at UCSF and a Howard Hughes Medical Institute Investigator.

Discovering the gene that causes PKD/IC will help researchers understand how the disease works. It gives doctors a potential new way of definitively diagnosing the disease by looking for genetic mutations in the gene. The work may also shed light on other conditions that are characterized by movement disorders, including possibly Parkinson's disease.

"Understanding the underlying biology of this disease is absolutely going to help us understand movement disorders in general," Ptacek said.

About the Disease

PKD/IC strikes infants with epileptic seizures that generally disappear within a year or two. However, the disease often reemerges later in childhood as a movement disorder in which children suffer sudden, startling, involuntary jerks when they start to move. Even thinking about moving is enough to cause some of these children to jerk involuntarily.

The disease is rare, and Ptacek estimates strikes about one out of every 100,000 people in the United States. At the same time, the disease is classified as "idiopathic"—which is just another way of saying we don't really understand it, Ptacek said.

If you take an image of the brain by MRI, patients with the disease all look completely normal. There are no injuries, tumors or other obvious signs that account for the movements—as is often the case with movement disorders. Work with patients in the clinic had suggested a genetic cause, however.

"Sometimes we trace the family tree, and lo and behold, there is a history of it," said Ptacek. In the last several years, he and his colleagues have developed a large cohort of patients whose families have a history of the disease.

The new research was based on a cohort of 103 such families that included one or more members with the disease. Genetic testing of these families led to the researchers to mutations in the PRRT2 gene, which cause the proteins the gene encodes to shorten or disappear entirely in the brain and spinal cord, where they normally reside.

One possible explanation for the resulting neurological symptoms, the researchers found, relates to a loss of neuronal regulation. When the genetic mutations cause the gene products to go missing, the nerve cells where they normally appear may become overly excited, firing too frequently or strongly and leading to the involuntary movements.

The article, "Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions" by Hsien-Yang Lee, Yong Huang, Nadine Bruneau, Patrice Roll, Elisha D.O. Roberson, Mark Hermann, Emily Quinn, James Maas, Robert Edwards, Tetsuo Ashizawa, Betul Baykan, Kailash Bhatia, Susan Bressman, Michiko K. Bruno, Ewout R. Brunt, Roberto Caraballo, Bernard Echenne, Natalio Fejerman, Steve Frucht, Christina A. Gurnett, Edouard Hirsch, Henry Houlden, Joseph Jankovic, Wei-Ling Lee, David R. Lynch, Shehla Mohammed, Ulrich Meuller, Mark P. Nespeca, David Renner, Jacques Rochette, Gabrielle Rudolf, Shinji Saiki, Bing-Wen Soong, Kathryn J. Swoboda, Sam Tucker, Nicholas Wood, Michael Hanna, Anne M. Bowcock, Pierre Szepetowski, Ying-Hui Fu and Louis J. Ptacek appears in the January 26, 2012 issue of Cell Reports. The article can be accessed online at:

In addition to UCSF, authors on this study are affiliated with the Université de la Méditerranée in Marseille, France; Washington University School of Medicine in Saint Louis, MO; the University of Florida in Gainesville, FL; Istanbul University in Turkey; University College London; Beth Israel Medical Center in New York; the Queen's Medical Center in Honolulu, HI; the University of Groningen in the Netherlands; Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina; Hôpital Gui de Chauliac in Montpellier, France; Mount Sinai Medical Center in New York; Hôpitaux Universitaires de Strasbourg in France; Baylor College of Medicine in Houston; the National Neuroscience Institute in Singapore; Children's Hospital of Philadelphia; Guy's Hospital in London; Justus-Liebig-Universität in Giessen, Germany; Rady Children's Hospital in San Diego; the university of California, San Diego; the University of Utah in Salt Lake City; the Université de Picardie Jules Verne in Amiens, France; Kanazawa Medical University in Ishikawa, Japan; the National Yang-Ming University School of Medicine in Taipei, Taiwan; Taipei Veterans General Hospital in Taiwan; the International Paroxysmal Kinesigenic Dyskinesia/Infantile Convulsions Collaborative Working Group; and the Juntendo University School of Medicine in Tokyo.

This work was funded by the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia Parkinson Foundation, the National Institutes of Health, the Sandler Neurogenetics Fund, ANR, INSERM and the Howard Hughes Medical Institute.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Jason Socrates Bardi | EurekAlert!
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