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Researchers identify genetic mutations causing a childhood disorder

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Published on Thursday, 10 January 2019

In a collaborative effort, researchers identified the genetic cause of a severe novel childhood disease. 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.

The international group of biologists and clinicians, including researchers from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg, and investigators at the Murdoch Children’s Research Institute, the Children's Hospital of Philadelphia and the University of Exeter Medical School, was able to link genetic mutations to an enzyme deficiency which leads to devastating effects in tissues such as the brain and the heart. The results were recently published in the scientific journal Brain.

A metabolic disease

Cells are constantly carrying out thousands of chemical reactions which are collectively called the cell’s metabolism. Metabolism generates unwanted side products, which can become harmful if they accumulate in cells. To prevent toxicity, cells have evolved what is called metabolite repair systems: enzymes whose role is to repair or remove metabolic side products. Metabolite repair is a relatively young concept and related disorders only start to be identified.

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, but they are also conserved in the great majority of other living species, indicating their fundamental role in biological systems.

Identification of the pathogenic mutations

“This is the first study to identify pathogenic mutations in NAXD, the most crucial enzyme in the repair system,” explains Dr Carole Linster, head of the Enzymology and Metabolism research group at the LCSB. The mutations were identified by sequencing the genome of six children who suffered neurodegeneration or cardiac failure induced by episodes of fever. Dr Linster and her team were contacted because of their expertise with the enzyme involved - they discovered the molecular role of NAXD in 2011 – and they provided key results about the functional consequences of the mutations.

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. Furthermore, by restoring the enzyme function to its normal level in vitro, NADHX accumulation could be completely reversed. These experiments strongly support that NAXD mutations indeed cause the newly described neurological disorder.

Devastating effects triggered by fever

The mutations have several consequences. 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. An especially interesting result was the fact that the mutations induced thermolability, i.e. 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.

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 study also forms a solid basis to investigate therapeutic strategies that could delay or prevent the onset of this terrible disease. “Only few metabolite repair disorders have been described to date,” stresses Carole Linster. “Given the rapid progress in this research field, more of this type of disorders are likely to be identified when clinicians and biochemists work hand in hand through similar international research collaborations focusing on mysterious rare diseases.”


To know more about the study, have a look at the video abstract:



Reference: NAD(P)HX Dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses, Nicole J Van Bergen, Yiran Guo, Julia Rankin, Nicole Paczia, Julia Becker-Kettern, Laura S Kremer, Angela Pyle, Jean-François Conrotte, Carolyn Ellaway, Peter Procopis, Kristina Prelog, Tessa Homfray, Júlia Baptista, Emma Baple, Matthew Wakeling, Sean Massey, Daniel P Kay, Anju Shukla, Katta M Girisha, Leslie E. S. Lewis, Saikat Santra, Rachel Power, Piers Daubeney, Julio Montoya, Eduardo Ruiz-Pesini, Reka Kovacs-Nagy, Martin Pritsch, Uwe Ahting, David R Thorburn, Holger Prokisch, Robert W Taylor, John Christodoulou, Carole L Linster, Sian Ellard, Hakon Hakonarson, Brain, 2019 Jan 1;142(1):50-58. DOI 10.1093/brain/awy310

Funding: In Luxembourg, this study was supported by a donation of the Lions International Club Esch-sur-Alzette. Julia Becker-Kettern and Nicole Paczia were supported by an AFR-PhD grant (4044610) and a CORE junior grant (C16/BM/11339953) of the Luxembourg National Research Fund (FNR), respectively.

© Image from the RCSB PDB (www.rcsb.org) of PDB ID 3RQ2.