Gene mutations linked to most cases of rare disorder -- Alternating Hemoplegia of Childhood

(Press-News.org) (SALT LAKE CITY)—Alternating hemiplegia of childhood (AHC) is a rare disorder that usually begins in infancy, with intermittent episodes of paralysis and stiffness, first affecting one side of the body, then the other. Symptoms mysteriously appear and disappear, again and again, and affected children often experience dozens of episodes per week. As they get older, children fall progressively behind their peers in both intellectual abilities and motor skills, and more than half develop epilepsy. Unfortunately, medications that work for epilepsy have been unsuccessful in controlling the recurrent attacks of paralysis, leaving parents and physicians with few options, and significantly disabling those affected.

Researchers at the University of Utah Departments of Neurology and Human Genetics, in collaboration with researchers at Duke University Medical Center, have discovered that mutations in the ATP1A3 gene cause the disease in the majority of patients with a diagnosis of AHC. The study was published online on Sunday, July 29, 2012, in Nature Genetics.

In a collaborative effort with the AHC Foundation, Kathryn J. Swoboda, M.D., co-first author on the study, associate professor of neurology and pediatrics, and director of the Pediatric Motor Disorders Research Program at the University of Utah, established an international database of patients with AHC from around the world, starting with a single family nearly 14 years ago. This database now includes 200 affected individuals from more than a dozen countries. Access to clinical information and DNA samples from this database were critical to the success of the international collaboration that helped to identify the first gene causing AHC in a significant percentage of patients.

"AHC is almost always a sporadic disease, which means that there is no family history of the disorder," says Tara Newcomb, genetic counselor, University of Utah Department of Neurology, and a co-author of the study. "The rarity of the disease and the almost exclusively sporadic inheritance made AHC an ideal candidate for next-generation sequencing."

The mysterious and intermittent nature of the neurologic symptoms, which range from unusual eye movements to seizure-like episodes, to partial and/or full body paralysis often results in a prolonged diagnostic odyssey for parents and children, according to Matthew Sweney, M.D., an instructor in the U of U Departments of Neurology and Pediatrics and an epilepsy specialist at Primary Children's Medical Center. "Families often present again and again to the emergency room, and children may undergo dozens of tests and invasive procedures," says Sweney, also a study co-author. "Often, it is only after the spells fail to respond to antiepileptic medications that the diagnosis is considered."

The ATP1A3 gene encodes one piece of a key transporter molecule that normally would move sodium and potassium ions across a channel between neurons (nerve cells) to regulate brain activity. Mutations in this gene are already known to cause another rare movement disorder, rapid onset dystonia parkinsonism, and clinical testing for mutations in this gene is readily available through a blood test. "Having a means to confirm a diagnosis more quickly, using a simple blood test, will allow us to better care for our patients and provide them opportunities for early enrollment in clinical trials," Swoboda says. "The identification of the gene provides scientists with the opportunity to identify specifically targeted and truly effective therapies."

In a broad international collaborative effort, the initial collaboration between the University of Utah and Duke investigators expanded to involve more than three dozen researchers from 13 countries. "This discovery is a testament to the power of the next-generation sequencing technologies, which are becoming increasingly available as a result of the Human Genome Project," says co-author Lynn Jorde, Ph.D., professor and chair of the U of U Department of Human Genetics. "These technologies are rapidly revolutionizing our ability to diagnose rare disorders, and provide hope for hundreds of families of children with rare disorders about which little is known and no targeted treatments currently exist."

### Funding for the work at the University of Utah was provided by a grant from the Alternating Hemiplegia of Childhood Foundation (AHCkids.org). The Utah team also included former postdoctoral fellow Chad Huff, Ph.D., from the Department of Human Genetics, and Louis Viollet, M.D., Ph.D., and Sandra Reyna, M.D., from the Department of Neurology Pediatric Motor Disorders Research Program (https://medicine.utah.edu/neurology/research/swoboda).

Whole genome sequencing was performed in collaboration with the Institute for Systems Biology.