Defects in Metabolite Repair Lead to a Neurometabolic Disorder

Mutations in the body’s metabolite repair system involving two coenzymes cause a lethal neurometabolic disorder of early childhood. These are the findings of a study by scientists of Helmholtz Zentrum München and Technische Universität München which has been published in the American Journal of Human Genetics.

Neurometabolic Disorder
Source: Wikipedia

In recent years, researchers have focused intensively on damage to DNA molecules and proteins. Their repair has also been the subject of numerous publications. Now, Laura S. Kremer and Holger Prokisch have investigated damage to two coenzymes in a joint research project of the Institute of Human Genetics of Helmholtz Zentrum München and Technische Universität München.

Molecules without function

“Damage to molecules of the energy metabolism can either arise spontaneously or as byproducts in enzymatic reactions,” said Kremer. Altered chemical substances can have a toxic effect on cells. This also applies to the hydrated form of the coenzymes NADH and NADPH*:  NADHX and NADPHX: “While NADH and NADPH as redox equivalents are involved in many cellular processes, NADHX and NADPHX can no longer assume this role in electron transport,” added Prokisch. “On the contrary, they even inhibit important dehydrogenases and thus damage cells.”

Neurometabolic disorder caused by defective coenzymes

To prevent this toxic effect, an efficient NAD(P)HX repair system has developed in the cell consisting of two enzymes, NAXD und NAXE**. The clinical relevance of this repair system was unknown until now. Kremer: “By means of exome sequencing we found pathogenic mutations in NAXE in certain patients.” The affected children suffered from acute ataxia, myelopathy, skin lesions and cerebellar edema. Many died by the age of three. In their skin cells, highly elevated concentrations of the toxic metabolite cyclic-NADHX were measured, resulting from NAXE deficiency and thus a defective NAD(P)HX repair system.

Interestingly, skin lesions also occur in other diseases caused by an impaired NAD metabolism: for example in pellagra, which is caused by a chronic lack of nicotinic acid, a precursor of NAD and NADP, but also in other pellagra-like genetic diseases. “Since in these diseases the administration of nicotinic acid shows a therapeutic effect, the next step is to investigate whether this also applies to patients with NAXE deficiency,” said Prokisch.