Dr Nicole Van Bergen B Sc (Hon), PhD Senior Research Officer, Neurodevelopmental Genomics, Murdoch Children's Research Institute Honorary Fellow, Department of Paediatrics, The University of Melbourne Murdoch Children's Research Institute The Royal Children's Hospital Parkville, Victoria Australia

Hunt For Cause of New Genetic Brain Disorder in Young Children

MedicalResearch.com Interview with:

Dr Nicole Van Bergen B Sc (Hon), PhD Senior Research Officer, Neurodevelopmental Genomics, Murdoch Children's Research Institute Honorary Fellow, Department of Paediatrics, The University of Melbourne Murdoch Children's Research Institute The Royal Children's Hospital Parkville, Victoria Australia

Dr. Van Bergen

Dr Nicole Van Bergen B Sc (Hon), PhD
Senior Research Officer, Neurodevelopmental Genomics, Murdoch Children’s Research Institute
Honorary Fellow, Department of Paediatrics, The University of Melbourne
Murdoch Children’s Research Institute
The Royal Children’s Hospital
Parkville, Victoria Australia 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We are in an era when the price tag of genetic testing by next generation sequencing is becoming a cost-effective and rapid tool for medical diagnosis. The benefit to patients is often a more accurate and early diagnosis. Because we can do genetic analysis on blood or saliva, we don’t need to use more traditional invasive investigations such as biopsies, brain scans or other extensive imaging. We are reaching an unprecedented rate of discovery of new genes for rare disorders which will help solve the mystery for many previously undiagnosed conditions.

An incredibly talented international team of researchers, led by the Murdoch Children’s Research Institute (MCRI) identified the underlying cause of a rare brain disorder in children. Together they identified that pathogenic mutations in a gene called NAXD cause severe neurological damage in children after an episode of mild fever or illness. Only six cases have been recorded worldwide and all the children died soon after suffering either a fever or illness.

The 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.

MCRI lead laboratory researcher Nicole Van Bergen, said the research provides an excellent example of how new genetic testing technologies can be applied to solve the mystery of previously undiagnosed conditions.

“By coupling the genetic testing information with sophisticated functional genomic approaches in the laboratory, we were able to pinpoint the exact cause of this disorder,”Dr Van Bergan said. “We used skin cells from patients, as well as other laboratory tools, to work out the gene that caused the children’s early death.

“From this research we were able to end the diagnostic odyssey for a number of families Identification of the causative gene, as well as detailed clinical information can also assist in the diagnosis of other children with the same rare condition. After this research is published, this information will then be added into databases in genetic testing laboratories and assists in diagnosis of other children with similar clinical presentations. This information can also help restore reproductive confidence to these families.”

Dr Van Bergan said the international group of biologists and clinicians were able to link genetic mutations in the gene NAXD to an enzyme deficiency which leads to devastating effects in tissues such as the brain and the heart.

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

“Unfortunately, sometimes when the body is under stress (such as from a fever or infection) this process is not always working at 100 per cent efficiency. When this happens the cell’s metabolism can generate unwanted toxic side products, which can become harmful if they accumulate in cells. In order to prevent toxicity, cells have evolved an elegant metabolite repair system. Special enzymes, such as NAXD, will either repair or remove toxic metabolic side products from the cell. The concept of metabolite repair is relatively new, we don’t know much about it and we have only just begun to identify genetic disorders caused by faulty metabolite repair systems.”

MCRI Genetics Director and leader of the research team which made this discovery, Professor John Christodoulou, said NADHX is one example of an unwanted metabolic side product.

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

“These enzymes are found across all tissues in humans, and in many of other living species, highlighting their fundamental role in biological systems. “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. Head of the Enzymology and Metabolism research group at the University of Luxembourg, Dr Carole Linster was invited to take part in the research because of her expertise with the key enzyme.

In 2011 Dr Linster’s team discovered the molecular role of the enzyme NAXD. Using techniques developed in their laboratory, Dr Linster’s team of researchers were able to demonstrate that skin cells from the young patients described above accumulated toxic levels of the abnormal NADHX metabolite. Dr Linster’s team also used bacteria to model the genetic mutations in NAXD. They showed that mutant versions of NAXD were less efficient in repairing the toxic NADHX compound. Interestingly these mutations also induced thermolability – a decreased enzyme function at higher temperatures. This may in part explain why the disease onset in patients was often triggered after episodes of fever.

Together the results the international team of researchers generated have allowed NAXD deficiency to be classified as a new disorder due to mutations in the metabolite repair gene NAXD. This will have a direct effect on highly energetic tissues including the brain and the heart. 

MedicalResearch.com: What should readers take away from your report?

Response: This body of research has identified NAXD deficiency as a new 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 potential therapeutic strategies that could delay or prevent the onset of this devastating disease. Only a few metabolite repair disorders have been described to date. Given the rapid progress in this research field, more of this type of disorder are likely to be identified when clinicians and biochemists work together through similar international research collaborations focusing on mysterious rare diseases. This will benefit patients and their families by finally providing an answer to the rare disease. It will also help diagnose new cases, and in the future could lead to the development of new treatments.

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: The research findings provide the first description of pathogenic variants in NAXD, which is one of the two key enzymes needed for the repair of damaged NAD metabolites. It is perhaps not too surprising that the clinical features in these cases were very similar to those in children reported to have mutations in the other key repair gene, namely NAXE. The clinical deterioration in all these children was triggered by episodes of fever or stress, leading to a toxic accumulation of damaged NADHX metabolites, with devastating effects on tissues highly reliant on energy production.

Dr Van Bergen said that these research findings may help identify further cases of this disorder, and even perhaps allow for more rapid diagnosis or better manage the initial symptoms that triggered the rapid neurodegeneration of the patients. Identification of the genetic basis of the disorder ended the long and arduous diagnostic odyssey for these children, and for their parents restored their reproductive confidence.

“Now that we have worked out what was the genetic basis of this disorder in children, we are planning to tackle whether targeted treatments could be developed,” Dr Van Bergen said. “We are currently planning to make stem cell models and animal models so that we can better understand the basic biology of NAXD deficiency. We will be able to use these model systems to develop and test new treatments with the hope that we might be able to slow or even prevent disease progression in children with NAXD deficiency.

MedicalResearch.com: Is there anything else you would like to add? 

All of this research would not have been possible without the support of the families and our research funding sources. The research was supported may international funding organisations including:

The Crane and Perkins families

Lions International Club Esch-sur-Alzette

The Victorian Government’s Operational Infrastructure Support Program

Fonds National de la Recherche Luxembourg

Aevi Genomic Medicine Inc.

German Bundesministerium für Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders

E-Rare project GENOMIT

EU Horizon2020 Collaborative Research Project SOUND

Instituto de Salud Carlos III

Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón

Wellcome Centre for Mitochondrial Research

Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease

Mitochondrial Disease Patient Cohort

Lily Foundation

UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.


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, NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses, Brain, Volume 142, Issue 1, January 2019, Pages 50–58, https://doi.org/10.1093/brain/awy310

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Last Updated on October 14, 2019 by Marie Benz MD FAAD