NAXE Mutations Disrupt the Cellular NAD(P)HX Repair System and Cause a Lethal Neurometabolic Disorder of Early Childhood

Abstract

To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States

“…A genome-wide meta-analysis identified APOA1BP (the gene encoding the AIBP protein) as a susceptibility locus for migraine (Anttila et al, 2013). A recent human study reports that APOA1BP variants leading to the loss of AIBP expression were found in a lethal neurometabolic disorder of early childhood (Kremer et al, 2016). Further studies are needed to explore the endogenous AIBP function.…”

Clinical, biochemical, and genetic features associated with VARS2 -related mitochondrial disease

“…WES on genomic DNA from affected individual P3 was performed at the Institute of Human Genetics (Munich, Germany) using the SureSelect Human All Exon 50 Mb kit (Agilent, Santa Clara, CA, USA) for in‐solution enrichment followed by sequencing as 75 bp paired‐end runs on a HiSeq2500 (Illumina) as described previously [Haack et al., ; Kremer et al., ]. This achieved an average of 143‐fold coverage with 97.7% of the exome covered at least 20‐fold.…”

AIBP, NAXE, and Angiogenesis

“…5 In the absence of NAXE protein there is an increase in cyclic-NADHX that has been shown to inhibit cellular NADH dehydrogenases. 6–8 Two splice variants of AIBP are synthesized with the longer form predicted to reside in the mitochondria and the shorter form remaining in the cytosol. 7 As an indication of its importance mutations in the APOA1BP gene are associated with lethal neurometabolic disorders of childhood.…”

“…7 As an indication of its importance mutations in the APOA1BP gene are associated with lethal neurometabolic disorders of childhood. 6, 9 There is controversy regarding whether AIBP is exclusively intracellular or secreted, with Ritter et al (2002) demonstrating its presence in urine, cerebrospinal fluid, and in the serum of some septic patients, but not in the serum of healthy patients. 10 HepG2 cells were also reported to secrete small amounts of AIBP.…”