NAD(P)HX dehydratase (NAXD) deficiency

a novel neurodegenerative disorder exacerbated by febrile illnesses

Nicole J. Van Bergen, Yiran Guo, Julia Rankin, Nicole Paczia, Julia Becker-Kettern, Laura S. Kremer, Angela Pyle, Jean François Conrotte, Carolyn Ellaway, Peter Procopis, Kristina Prelog, Tessa Homfray, Júlia Baptista, Emma Baple, Matthew Wakeling, Sean Massey, Daniel P. Kay, Anju Shukla, Katta M. Girisha, Leslie E.S. Lewis & 15 others Saikat Santra, Rachel Power, Piers Daubeney, Julio Montoya, Eduardo Ruiz-Pesini, Reka Kovacs-Nagy, Martin Pritsch, Uwe Ahting, David R. Thorburn, Holger Prokisch, Robert W. Taylor, John Christodoulou, Carole L. Linster, Sian Ellard, Hakon Hakonarson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

Original languageEnglish
Pages (from-to)50-58
Number of pages9
JournalBrain : a journal of neurology
Volume142
Issue number1
DOIs
Publication statusPublished - 01-01-2019

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Hydro-Lyases
Neurodegenerative Diseases
NAD
Fever
Fibroblasts
Exome
Physiological Stress
Niacinamide
Azides
Poisons
Galactose
Recombinant Proteins
Computer Simulation
Reverse Transcription
6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide
Reactive Oxygen Species
Nucleotides
Heart Failure
Adenosine Triphosphate
Genome

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Van Bergen, N. J., Guo, Y., Rankin, J., Paczia, N., Becker-Kettern, J., Kremer, L. S., ... Hakonarson, H. (2019). NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. Brain : a journal of neurology, 142(1), 50-58. https://doi.org/10.1093/brain/awy310
Van Bergen, Nicole J. ; Guo, Yiran ; Rankin, Julia ; Paczia, Nicole ; Becker-Kettern, Julia ; Kremer, Laura S. ; Pyle, Angela ; Conrotte, Jean François ; Ellaway, Carolyn ; Procopis, Peter ; Prelog, Kristina ; Homfray, Tessa ; Baptista, Júlia ; Baple, Emma ; Wakeling, Matthew ; Massey, Sean ; Kay, Daniel P. ; Shukla, Anju ; Girisha, Katta M. ; Lewis, Leslie E.S. ; Santra, Saikat ; Power, Rachel ; Daubeney, Piers ; Montoya, Julio ; Ruiz-Pesini, Eduardo ; Kovacs-Nagy, Reka ; Pritsch, Martin ; Ahting, Uwe ; Thorburn, David R. ; Prokisch, Holger ; Taylor, Robert W. ; Christodoulou, John ; Linster, Carole L. ; Ellard, Sian ; Hakonarson, Hakon. / NAD(P)HX dehydratase (NAXD) deficiency : a novel neurodegenerative disorder exacerbated by febrile illnesses. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 1. pp. 50-58.
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abstract = "Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.",
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Van Bergen, NJ, Guo, Y, Rankin, J, Paczia, N, Becker-Kettern, J, Kremer, LS, Pyle, A, Conrotte, JF, Ellaway, C, Procopis, P, Prelog, K, Homfray, T, Baptista, J, Baple, E, Wakeling, M, Massey, S, Kay, DP, Shukla, A, Girisha, KM, Lewis, LES, Santra, S, Power, R, Daubeney, P, Montoya, J, Ruiz-Pesini, E, Kovacs-Nagy, R, Pritsch, M, Ahting, U, Thorburn, DR, Prokisch, H, Taylor, RW, Christodoulou, J, Linster, CL, Ellard, S & Hakonarson, H 2019, 'NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses', Brain : a journal of neurology, vol. 142, no. 1, pp. 50-58. https://doi.org/10.1093/brain/awy310

NAD(P)HX dehydratase (NAXD) deficiency : a novel neurodegenerative disorder exacerbated by febrile illnesses. / Van Bergen, Nicole J.; Guo, Yiran; Rankin, Julia; Paczia, Nicole; Becker-Kettern, Julia; Kremer, Laura S.; Pyle, Angela; Conrotte, Jean François; Ellaway, Carolyn; Procopis, Peter; Prelog, Kristina; Homfray, Tessa; Baptista, Júlia; Baple, Emma; Wakeling, Matthew; Massey, Sean; Kay, Daniel P.; Shukla, Anju; Girisha, Katta M.; Lewis, Leslie E.S.; Santra, Saikat; Power, Rachel; Daubeney, Piers; Montoya, Julio; Ruiz-Pesini, Eduardo; Kovacs-Nagy, Reka; Pritsch, Martin; Ahting, Uwe; Thorburn, David R.; Prokisch, Holger; Taylor, Robert W.; Christodoulou, John; Linster, Carole L.; Ellard, Sian; Hakonarson, Hakon.

In: Brain : a journal of neurology, Vol. 142, No. 1, 01.01.2019, p. 50-58.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NAD(P)HX dehydratase (NAXD) deficiency

T2 - a novel neurodegenerative disorder exacerbated by febrile illnesses

AU - Van Bergen, Nicole J.

AU - Guo, Yiran

AU - Rankin, Julia

AU - Paczia, Nicole

AU - Becker-Kettern, Julia

AU - Kremer, Laura S.

AU - Pyle, Angela

AU - Conrotte, Jean François

AU - Ellaway, Carolyn

AU - Procopis, Peter

AU - Prelog, Kristina

AU - Homfray, Tessa

AU - Baptista, Júlia

AU - Baple, Emma

AU - Wakeling, Matthew

AU - Massey, Sean

AU - Kay, Daniel P.

AU - Shukla, Anju

AU - Girisha, Katta M.

AU - Lewis, Leslie E.S.

AU - Santra, Saikat

AU - Power, Rachel

AU - Daubeney, Piers

AU - Montoya, Julio

AU - Ruiz-Pesini, Eduardo

AU - Kovacs-Nagy, Reka

AU - Pritsch, Martin

AU - Ahting, Uwe

AU - Thorburn, David R.

AU - Prokisch, Holger

AU - Taylor, Robert W.

AU - Christodoulou, John

AU - Linster, Carole L.

AU - Ellard, Sian

AU - Hakonarson, Hakon

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

AB - Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

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