Download PDF
Journal of Pediatric Neurology 2021; 19(02): 105-108
DOI: 10.1055/s-0040-1713682
Case Report

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

Nadja Lucas 
1   Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Gregor Dückers
2   Helios Children's Hospital, Krefeld, Germany
,
Carsten Speckmann
3   Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
4   Center for Chronic Immunodeficiency, Institute for Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Stephan Ehl
4   Center for Chronic Immunodeficiency, Institute for Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Norbert Utz
2   Helios Children's Hospital, Krefeld, Germany
,
Bochen Cheng
5   BGI-Shenzhen and China National GeneBank, Shenzhen, China
,
Mingyan Fang
5   BGI-Shenzhen and China National GeneBank, Shenzhen, China
,
Tim Niehues
2   Helios Children's Hospital, Krefeld, Germany
,
Min Ae Lee-Kirsch 
1   Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
› Author Affiliations Funding This study was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation), under grant LU2342/1-1 to N.L. and grant 369799452/404459235 to M.L.K., and by the Shenzhen Municipal Government of China, under grant JCYJ20170817145536203 to M.F.
› Further Information
Also available at
    Permissions and Reprints

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

Supplementary Material



Publication History

Received: 28 February 2020

Accepted: 18 May 2020

Article published online:
20 July 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 4 Yoshida A, Dave V. Inhibition of NADP-dependent dehydrogenases by modified products of NADPH. Arch Biochem Biophys 1975; 169 (01) 298-303
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 14 Linster CL, Van Schaftingen E, Hanson AD. Metabolite damage and its repair or pre-emption. Nat Chem Biol 2013; 9 (02) 72-80
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 16 Dhir A, Dhir S, Borowski LS. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 2018; 560 (7717): 238-242
    CrossrefPubMedGoogle Scholar
  • 17 Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol 2016; 16 (09) 566-580
    CrossrefPubMedGoogle Scholar