Researchers at Duke University Medical Center have now discovered that mutations in one gene cause the disease in the majority of patients with a diagnosis of AHC, and because of the root problem they discovered, a treatment may become possible.
The study was published online on July 29 in Nature Genetics.
AHC is almost always a sporadic disease, which means that typically no one else in the family has the disease, said Erin Heinzen, Ph.D., co-author of the study and Assistant Professor of Medicine in the Section of Medical Genetics. "Knowing that we were looking for genetic mutations in children with this disease that were absent in the healthy parents, we carefully compared the genomes of seven AHC patients and their unaffected parents. When we found new mutations in all seven children in the same gene we knew we had found the cause of this disease."
All of the mutations were found in a gene that encodes ATP1A3, 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.
In a remarkably broad international collaborative effort, the authors partnered with three family foundations (USA, Italy and France), including scientists from 13 different countries, to study an additional 95 patients and showed over 75 percent had disease-causing mutations in the gene for ATP1A3.
"This study is an excellent example of how genetic research conducted on a world-wide scale really can make a difference for such a rare disorder as AHC," said Arn van den Maagdenberg, Ph.D., and co-author on the study and geneticist from Leiden University Medical Centre in the Netherlands. "It truly was an effort from many research groups that led to this remarkable discovery."
"This kind of discovery really brings home just what the human genome project and next-generation sequencing have made possible," said David Goldstein, Ph.D., Director of the Duke Center for Human Genome Variation and co-senior author on the study. "For a disease like this one with virtually no large families to study, it would have been very difficult to find the gene before next-generation sequencing."
"Ideally what you want from a study like this is a clear indication of how the mutations change protein function so you know how to screen for drugs that will restore normal function or compensate for the dysfunction," said Goldstein, who is also a Professor in Duke Molecular Genetics and Microbiology. "While there is considerably more work to do, our initial evaluation of the mutations suggests that they may alter the behavior of the transporter pump as opposed to reducing its activity, as do other mutations in the gene that cause a less severe neurological disease."
Co-senior author Mohamad Mikati, M.D., Professor of Pediatrics and of Neurobiology, and Chief of Pediatric Neurology at Duke, said, "Many years ago my work with other collaborators on a family with this disease proved that AHC can be caused by genetic factors, but until now we did not know the underlying gene abnormality.
"The finding that ATP1A3 mutations cause AHC will increase awareness of the disease and the ability to accurately diagnose patients," Mikati said. "While it may take a while for novel drugs to be developed to better treat this disease, we will see an immediate impact through specific testing for mutations in this gene when we suspect a case of AHC. This direct testing will prevent misdiagnoses that too often have caused patients to be treated with inappropriate medications."
Other authors worked at the University of Utah, Salt Lake City; Università Cattolica Sacro Cuore, Rome; UPMC Univ Paris, INSERM, CNRS and Groupe Hospitalier de la Pitié-Salpêtrière, in Paris; Leiden University Medical Centre, Leiden, The Netherlands; University of Melbourne, Melbourne, Australia; University Hospitals of Lyon, France; University of Chicago, Illinois; University of California, San Francisco; Rijnland Hospital, Leiderdorp, The Netherlands; Sydney Children's Hospital, Randwick, and University of Sydney, New South Wales, Australia; Royal Hobart Hospital, Hobart, Australia; Our Lady's Children's Hospital, Crumlin, and the Childrens University Hospital, Dublin, Ireland; Rigshospitalet, University of Copenhagen; CRNL, CNRS INSERM, in Lyon, France; and UCL Institute of Neurology, London.
The study was funded by the Center for Human Genome Variation, the Alternating Hemiplegia of Childhood Foundation, the ENRAH for SMEs Consortium grant of the European Commission Research Programme, Association Française de l'Hémiplégie Alternante, A.I.S.EA Onlus, CMSB within the Netherlands Genomics Initiative, the Wellcome Trust, and the University of Utah.
Mary Jane Gore | EurekAlert!
New technique for in-cell distance determination
19.03.2019 | Universität Konstanz
Dalian Coherent Light Source reveals hydroxyl super rotors from water photochemistry
19.03.2019 | Chinese Academy of Sciences Headquarters
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock
Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...
Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
19.03.2019 | Physics and Astronomy
19.03.2019 | Life Sciences
19.03.2019 | Physics and Astronomy