MedWire News: Researchers have identified de novo mutations in the ATP1A3 gene that they believe are responsible for a sporadic childhood paralysis known as alternating hemiplegia of childhood (AHC).
The team compared genomic data from seven affected children and their unaffected parents to isolate potential causative mutations and candidate genes.
"When we found new mutations in all seven children in the same gene we knew we had found the cause of this disease," lead study author Erin Heinzen (Duke University School of Medicine, North Carolina, USA) told the press.
In a replication study in 98 patients ATP1A3 mutations were present and thought to be causative in 74% of cases. Most of the patients with AHC who were genotyped had one of seven ATP1A3 mutations.
Writing in Nature Genetics, the authors explain that AHC patients have episodes of intermittent hemiplegia on alternating sides of the body, as well as developmental delay, dystonia, and choreoathetosis from infancy.
As AHC is largely a spontaneously occurring disease that is not inherited, the genetics of the condition have been difficult to analyze using traditional genetic methods.
"This kind of discovery really brings home just what the human genome project and next-generation sequencing have made possible," said study co-author David Goldstein, also from Duke University, in a press statement.
He added: "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."
ATP1A3 encodes the sodium-potassium ATPase α3 subunit. Mutations in this gene have also been shown to cause rapid-onset dystonia-parkinsonism (DYT12). Further research by the investigators suggests that the mutations likely to be responsible for AHC influence the activity of the sodium-potassium ATPase pump activity, whereas those responsible for DYT12 exert hypomorphic effects on the pump.
"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," commented Goldstein.
Another study author Mohamad Mikati, also from Duke University, concluded: "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."
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