Rare genetic disorder causes severe neurological damage after mild fever


29 Jan 2019

A rare genetic brain disorder – NAXD deficiency – that causes severe neurological damage in children after a mild fever or illness has been identified by an international team of researchers, led by Murdoch Children’s Research Institute, Victoria.

Only six cases of the condition NAD(P)HX Dehydratase (NAXD) Deficiency have been recorded worldwide and all the children died soon after episodes of febrile illness-induced neurodegeneration or cardiac failure.

“Affected children typically suffered from episodes of neurological regression triggered by mild fever or infection, neurodegeneration, and skin lesions, eventually leading to early childhood death,” said lead researcher Dr Nicole Van Bergen (PhD) MCRI’s Brain and Mitochondrial Group.

Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. The research team also found evidence of impaired mitochondrial function and higher sensitivity to metabolic stress in patient cells,  and showed that mutant versions of the NAXD enzyme were associated with deficient repair functions

Dr Van Bergen said that given the underlying genetic basis of the disorder is now understood, future research will investigate whether treatment for the condition is possible.

MCRI Genetics Director Professor John Christodoulou said NADHX is one example of an unwanted metabolic side product.

In healthy cells, the levels of this molecule are kept very low through detoxification by a metabolite repair system that consists of two partner enzymes, NAXE and NAXD.

“These enzymes are found across all tissues in humans, and in many of other living species, highlighting their fundamental role in biological systems,” Prof Christodoulou said. “This is the first study to identify pathogenic mutations in NAXD, the most crucial enzyme in the cell repair system.”

The mutations induced thermolability, decreased enzyme function at higher temperatures, which may at least in part explain why the disease onset in the patients coincided with episodes of fever.

“Taken together, the generated results allow to classify NAXD deficiency as a novel metabolite repair disorder with a direct impact in key tissues, such as the brain and the heart,” the researchers said.

Their research paper, ‘NAD(P)HX Dehydratase (NAXD) Deficiency: A Novel Neurodegenerative Disorder Exacerbated By Febrile Illnesses’ is published in the latest edition of the journal, Brain.

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