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!
Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex
New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center
Russian researchers together with their French colleagues discovered that a genuine feature of superconductors -- quantum Abrikosov vortices of supercurrent -- can also exist in an ordinary nonsuperconducting metal put into contact with a superconductor. The observation of these vortices provides direct evidence of induced quantum coherence. The pioneering experimental observation was supported by a first-ever numerical model that describes the induced vortices in finer detail.
These fundamental results, published in the journal Nature Communications, enable a better understanding and description of the processes occurring at the...
In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.
Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
25.06.2018 | Physics and Astronomy
25.06.2018 | Earth Sciences
25.06.2018 | Power and Electrical Engineering