Genetic mutation behind rare childhood paralysis

A genetic biomarker for the very rare and severe form of paralysis in children--alternating hemiplegia of childhood--could help speed up correct diagnosis, prevent misdiagnosis and inappropriate treatment, and may even lead to new therapeutics for this currently incurable disability. The mutated gene was found by a team including researchers from Duke University Medical Center.

Alternating hemiplegia of childhood, only fully characterized in the early 1970s, causes attacks of weakness and paralysis on one or both sides of the body, along with epilepsy, learning disabilities and problems with walking. There is no cure, and diagnosis is often delayed, partly because the condition is so rare, affecting as few as one in a million.

The researchers sequenced the exomes (the coding regions of genes) of children with alternating hemiplegia of childhood and their parents, and all 7 children had mutations in the same gene, called ATP1A3. There were no other cases in the family, suggesting that this was a spontaneous mutation.

The team collaborated with three family foundations in the U.S., Italy and France, and looked at the genomes of 98 children with the disorder. In around three-quarters of the cases, there were mutations in the same gene, which forms part of a protein that helps to regulate brain activity.

"This kind of discovery really brings home just what the human genome project and next-generation sequencing have made possible," said David Goldstein, director of the Duke Center for Human Genome Variation. "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."

The next step will be to work out how the mutation changes protein function, and then to screen for drugs that could either restore normal function or compensate for the dysfunction. While there are only a small number of potential patients, correct diagnoses and effective treatments would make a major difference to affected families.

- read the press release
- see the abstract in Nature Genetics

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