Rare genetic brain disorder identified

Researchers have identified a rare genetic brain disorder that causes severe neurological damage in children after a mild fever or illness.

Only six cases have been recorded worldwide and all the children died soon after suffering either a fever or illness.

“An international group of biologists and clinicians*, was able to link genetic mutations to an enzyme deficiency which leads to devastating effects in tissues such as the brain and the heart,” said lead researcher Nicole Van Bergen from the Murdoch Children’s Research Institute (MCRI).

Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case.

Dr Van Bergen, who also holds an an honorary position at the University of Melbourne, said that given the underlying genetic basis of the disorder is now understood, future research will investigate whether treatment for the condition is possible.

The disorder was identified by an international team of researchers, led by MCRI.

“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,” Dr Van Bergen said.

“Cells are constantly carrying out thousands of chemical reactions which are collectively called the cell’s metabolism,” she said.

“Metabolism generates unwanted side products, which can become harmful if they accumulate in cells.”

She said to prevent toxicity, cells have evolved what are called metabolite repair systems: enzymes whose role is to repair or remove metabolic side products and metabolite repair is a relatively new concept and related disorders have only just started to be identified.

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

Professor John Christodoulou said 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.”

Prof Christodoulou said the MCRI team worked closely with the Luxembourg Centre for Systems Biomedicine at the University of Luxembourg.

The Head of the Enzymology and Metabolism research group at the University of Luxembourg, Dr Carole Linster, said her group was contacted because of their expertise with the key enzyme.

“We discovered the molecular role of NAXD in 2011 — and provided key results about the functional consequences of the mutations,” Dr Linster said.

“Using methodologies previously developed by the group, the researchers were able to demonstrate that, in skin cells derived from the young patients and containing mutations in the NAXD gene, the abnormal NADHX compound accumulates.”

The researchers found evidence of impaired function of the mitochondria (the cell’s energy factories) in patient cells and showed that mutant versions of the NAXD enzyme were less efficient in repairing the unwanted side product.

Dr Linster said it was especially interesting that the mutations induced thermolability — a decreased enzyme function at higher temperatures.

“This observation may at least in part explain why the disease onset in the patients coincided with episodes of fever,” she said.

“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.

“Only few metabolite repair disorders have been described to date.”

The researchers said that given the rapid progress in genomic sequencing, more mysterious rare diseases are likely to be identified through international collaborations of clinicians and research scientists collaborating internationally.

The findings have been published in a research paper titled ‘NAD(P)HX Dehydratase (NAXD) Deficiency: A Novel Neurodegenerative Disorder Exacerbated By Febrile Illnesses’ in the journal Brain.

*Key researchers came from MCRI, the University of Luxembourg, the Children’s Hospital of Philadelphia, the University of Exeter Medical School, Royal Brompton and St George’s University Hospital, Technische Universität München and Siegen’s DRK-Childrens-Hospital, the Kasturba Medical College and Hospital and the Wellcome Centre for Mitochondrial Research.

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