AHC is a very rare disorder that causes paralysis that freezes one side of the body and then the other in devastating bouts that arise at unpredictable intervals. Seizures, learning disabilities and difficulty walking are common among patients with this diagnosis.
AHC is almost always a sporadic disease, which means that typically no one else in the family has the disease, said Doctor Erin Heinzen, senior author of the study. "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 per cent 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. "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 Doctor David Goldstein, 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. "While there is considerably more work to do, our initial evaluation of the mutations suggests that they may alter the behaviour of the transporter pump as opposed to reducing its activity, as do other mutations in the gene that cause a less severe neurological disease."
MEDICA.de; Source: Duke University Medical Center