NEW YORK (GenomeWeb News) – Mutations in a gene called ATP1A3, which codes for a component of an ion transporter pump important to nerve cell function, are behind most cases of a sporadic neurological condition known as alternating hemiplegia of childhood, or AHC, according to a new Nature Genetics study.
"The finding that ATP1A3 mutations cause AHC will increase awareness of the disease and the ability to accurately diagnose patients," co-senior author Mohamad Mikati, a neurobiology researcher at Duke University and chief of its pediatric neurology division, said in a statement.
"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," he added. "This direct testing will prevent misdiagnoses that too often have caused patients to be treated with inappropriate medications."
Along with David Goldstein, director of Duke's Center for Human Genome Variation, Mikati led an international team that sequenced the genomes or exomes of individuals from seven parent-child trios, searching for mutations in the affected child's protein-coding sequences that were missing in both of his or her unaffected parents. The group did similar sequencing experiments on three more AHC cases for which parental samples were not available.
In eight of the 10 affected individuals, the search led to alterations affecting ATP1A3, with follow-up testing in almost 100 more cases hinting that de novo mutations in the gene account for around three quarters of AHC cases.
The ability to diagnose AHC has improved in the four decades or so since it was first described, the researchers explained. But there is still relatively little known about the genetic glitches that can cause the rare neurological condition, characterized by paralysis that switches from one side of the body to the other and by other features that include developmental delays, learning and/or motility problems, and seizures.
Because the disease usually occurs sporadically, showing up in children with no family history of the disease, Mikati, Goldstein, and their colleagues decided to scour sequences from parent-child trios, when possible, to try and hunt down AHC-causing mutations.
For individuals from each of trios, along with three independent AHC cases, the researchers either did genome sequencing with Illumina GAIIx or HiSeq 2000 instruments or used the Agilent All Exon capture system to nab coding sequences in the genomes prior to the sequencing step.
Based on its analyses of these exomes (sequenced to an average depth of 90-fold) or genomes (sequenced to at least 25-fold coverage), the team tracked down rare mutations predicted to affect the function of the ATP1A3 gene's protein product in eight of the 10 individuals with AHC. These included all seven children from the parent-child trios and involved five different mutations to the gene.
When researchers did targeted sequencing of the ATP1A3 gene in 95 more AHC cases, they found alterations in the gene in 74 more individuals with the conditions.
Corresponding parental samples were not available for all of the individuals in this follow-up screen. But based on genetic patterns in parental samples that it could get its hands on, the team estimated that de novo APT1A3 mutations were the culprit in at least 74 percent of AHC cases tested.
Though the analysis uncovered many different ATP1A3 mutations in individuals with AHC, these alterations are generally predicted to affect the function of an ATPase pump that moves sodium and potassium across the cell membrane, producing gradient of these ions that's important to nerve cell communication.
In that respect, researchers explained, AHC may be genetically related to rare movement condition called dystonia-parkinsonism that has also been traced back to modified sodium/potassium ATPase transporter function.
"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," Goldstein said in a statement.