NAXD Deficiency Associated with Perinatal Autoinflammation, Pancytopenia, Dermatitis, Colitis, and Cystic Encephalomalacia

Abstract

NAD(P)HX dehydratase (NAXD) catalyzes the recovery of toxic derivatives of nicotinamide adenine dinucleotides which play an essential role in mitochondrial metabolism. Mutations in NAXD were recently shown to cause early-onset neurodegeneration exacerbated by febrile illness. Here, we report a novel homozygous stop-gain variant in NAXD in an infant who presented with a fulminant course of autoinflammation, dermatitis, colitis, and cystic encephalomalacia beginning at 3 weeks of age. Our findings support the central role of NAXD-mediated metabolite repair for normal tissue function and implicate innate immune processes in the pathogenesis of NAXD deficiency.

Keywords

NAXD - mitochondria - cystic encephalomalacia

• References

• 1 Cantó C, Menzies KJ, Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 2015; 22 (01) 31-53
• 2 Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 2008; 10 (02) 179-206
• 3 Rafter GW, Chaykin S, Krebs EG. The action of glyceraldehyde-3-phosphate dehydrogenase on reduced diphosphopyridine nucleotide. J Biol Chem 1954; 208 (02) 799-811
• 4 Yoshida A, Dave V. Inhibition of NADP-dependent dehydrogenases by modified products of NADPH. Arch Biochem Biophys 1975; 169 (01) 298-303
• 5 Marbaix AY, Noël G, Detroux AM, Vertommen D, Van Schaftingen E, Linster CL. Extremely conserved ATP- or ADP-dependent enzymatic system for nicotinamide nucleotide repair. J Biol Chem 2011; 286 (48) 41246-41252
• 6 Houtkooper RH, Cantó C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev 2010; 31 (02) 194-223
• 7 Acheson SA, Kirkman HN, Wolfenden R. Equilibrium of 5,6-hydration of NADH and mechanism of ATP-dependent dehydration. Biochemistry 1988; 27 (19) 7371-7375
• 8 Kremer LS, Danhauser K, Herebian D. et al. NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood. Am J Hum Genet 2016; 99 (04) 894-902
• 9 Spiegel R, Shaag A, Shalev S, Elpeleg O. Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy. Neurogenetics 2016; 17 (03) 187-190
• 10 Van Bergen NJ, Guo Y, Rankin J. et al. NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. Brain 2019; 142 (01) 50-58
• 11 Zhou J, Li J, Stenton SL. et al. NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. Brain 2020; 143 (02) e8-e8
• 12 Feng X, Wu H, Grossman JM. et al. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum 2006; 54 (09) 2951-2962
• 13 Van Schaftingen E, Rzem R, Marbaix A, Collard F, Veiga-da-Cunha M, Linster CL. Metabolite proofreading, a neglected aspect of intermediary metabolism. J Inherit Metab Dis 2013; 36 (03) 427-434
• 14 Linster CL, Van Schaftingen E, Hanson AD. Metabolite damage and its repair or pre-emption. Nat Chem Biol 2013; 9 (02) 72-80
• 15 West AP, Khoury-Hanold W, Staron M. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 2015; 520 (7548): 553-557
• 16 Dhir A, Dhir S, Borowski LS. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 2018; 560 (7717): 238-242
• 17 Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol 2016; 16 (09) 566-580