Collaborating researchers at the University of Luxembourg, Murdoch Children’s Research Institute, the Children’s Hospital of Philadelphia, and the University of Exeter have made a genetic discovery, linking genetic mutation with a novel childhood disorder. The international group of biologists and clinicians were able to link genetic mutations to an enzyme deficiency, which leads to devastating effects in tissues such as the brain and the heart induced by fever.
Cells metabolise and produce unwanted toxic byproducts in the process. In healthy humans, the body’s evolved ability to remove these toxic products works via two enzymes, one of them called NAXD. This is called a metabolite repair enzyme.
The repercussions of these pathogenic genetic mutations are: impaired function of the mitochondria, less efficient metabolic repair and, most telling, decreased NAXD function at higher temperatures.
The researchers were able to demonstrate from patient skin cells, using the group’s previously developed methodologies, that the patients’ NAXD enzyme is inefficient.
The enzyme efficiency can cope with normal function demands, but when efficiency is reduced even further by the high temperatures of fever, the toxic byproducts accumulate and normal functioning of the cell is unmanageable due to toxicity.
In vitro studies were conducted that showed restoring the enzyme to normal levels in vitro, NADHX accumulation could be completely reversed. These experiments strongly support that NAXD mutations indeed cause the newly described neurological disorder.
When looking at the patients' genomic information with the results from their skin cells and in vitro studies, the generated results allowed them to classify NAXD deficiency as a novel metabolite repair disorder with a direct impact in key tissues, such as the brain and the heart.
Commenting on the findings Dr Carole Linster, LCSB head of the Enzymology and Metabolism research group said: “This is the first study to identify pathogenic mutations in NAXD.”
She continued on metabolite repair saying: “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.”
“Image from the RCSB PDB (www.rcsb.org) of PDB ID 3RQ2 (I.A. Shumilin, M.T. Cymborowski, O. Chertihin, K.N. Jha, J.C. Herr, S.A. Lesley, A.J. Joachimiak, W. Minor (2012) Crystal Structure of ADP/ATP-dependent NAD(P)H-hydrate dehydratase from Bacillus subtilis co-crystallized with ATP/Mg2+ and soaked with NADH Structure 20 1715-1725).”
