(SALT LAKE CITY)—Alternating hemiplegia of childhood (AHC) is a rare disorder that usually begins in infancy, with intermittent episodes of paralysis and stiffness, 首先影响身体的一侧, 然后另一个. Symptoms mysteriously appear and disappear, 一次又一次, and affected children often experience dozens of episodes per week. 随着年龄的增长, children fall progressively behind their peers in both intellectual abilities and motor skills, 超过一半的人会患上癫痫. 不幸的是, 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.
研究ers 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 自然遗传学.
In a collaborative effort with the AHC Foundation, Kathryn J. Swoboda, M.D., 该研究的共同第一作者, associate professor of neurology and pediatrics, and director of the Pediatric Motor Disorders 研究 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,塔拉·纽科姆说, 基因顾问, University of Utah Department of Neurology, 也是这项研究的合著者. "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, 据马修·斯威尼说, M.D., an instructor in the U of U Departments of Neurology and Pediatrics and an epilepsy specialist at Primary Children's Hospital. "Families often present 一次又一次 to the emergency room, and children may undergo dozens of tests and invasive procedures,斯威尼说, 也是研究的合著者. “经常, 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, 快速发作的肌张力障碍帕金森症, and clinical testing for mutations in this gene is readily available through a blood test. "Having a means to confirm a diagnosis more quickly, 用一个简单的血液测试, will allow us to better care for our patients and provide them opportunities for early enrollment in clinical trials,斯沃博达说. "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,合著者Lynn Jorde说, 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.M . Sandra Reyna.D., from the Department of Neurology Pediatric Motor Disorders 研究 Program.
Whole genome sequencing was performed in collaboration with the Institute for Systems Biology.