King's College London

Research portal

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation

Research output: Contribution to journalArticle

Standard

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. / Chelban, Viorica; Wilson, Matthew P.; Warman Chardon, Jodi; Vandrovcova, Jana; Zanetti, M. Natalia; Zamba-papanicolaou, Eleni; Efthymiou, Stephanie; Pope, Simon; Conte, Maria R; Abis, Giancarlo; Liu, Yo-tsen; Tribollet, Eloise; Haridy, Nourelhoda A.; Botía, Juan A; Ryten, Mina; Nicolaou, Paschalis; Minaidou, Anna; Christodoulou, Kyproula; Kernohan, Kristin D.; Eaton, Alison; Osmond, Matthew; Ito, Yoko; Bourque, Pierre; Jepson, James E.C.; Bello, Oscar; Bremner, Fion; Cordivari, Carla; Reilly, Mary M.; Foiani, Martha; Heslegrave, Amanda; Zetterberg, Henrik; Heales, Simon J.R.; Wood, Nicholas W.; Rothman, James E.; Boycott, Kym M; Mills, Philippa B.; Clayton, Peter T.; Houlden, Henry.

In: Annals of Neurology, Vol. 86, No. 2, 01.08.2019, p. 225-240.

Research output: Contribution to journalArticle

Harvard

Chelban, V, Wilson, MP, Warman Chardon, J, Vandrovcova, J, Zanetti, MN, Zamba-papanicolaou, E, Efthymiou, S, Pope, S, Conte, MR, Abis, G, Liu, Y, Tribollet, E, Haridy, NA, Botía, JA, Ryten, M, Nicolaou, P, Minaidou, A, Christodoulou, K, Kernohan, KD, Eaton, A, Osmond, M, Ito, Y, Bourque, P, Jepson, JEC, Bello, O, Bremner, F, Cordivari, C, Reilly, MM, Foiani, M, Heslegrave, A, Zetterberg, H, Heales, SJR, Wood, NW, Rothman, JE, Boycott, KM, Mills, PB, Clayton, PT & Houlden, H 2019, 'PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation', Annals of Neurology, vol. 86, no. 2, pp. 225-240. https://doi.org/10.1002/ana.25524

APA

Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-papanicolaou, E., ... Houlden, H. (2019). PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. Annals of Neurology, 86(2), 225-240. https://doi.org/10.1002/ana.25524

Vancouver

Chelban V, Wilson MP, Warman Chardon J, Vandrovcova J, Zanetti MN, Zamba-papanicolaou E et al. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. Annals of Neurology. 2019 Aug 1;86(2):225-240. https://doi.org/10.1002/ana.25524

Author

Chelban, Viorica ; Wilson, Matthew P. ; Warman Chardon, Jodi ; Vandrovcova, Jana ; Zanetti, M. Natalia ; Zamba-papanicolaou, Eleni ; Efthymiou, Stephanie ; Pope, Simon ; Conte, Maria R ; Abis, Giancarlo ; Liu, Yo-tsen ; Tribollet, Eloise ; Haridy, Nourelhoda A. ; Botía, Juan A ; Ryten, Mina ; Nicolaou, Paschalis ; Minaidou, Anna ; Christodoulou, Kyproula ; Kernohan, Kristin D. ; Eaton, Alison ; Osmond, Matthew ; Ito, Yoko ; Bourque, Pierre ; Jepson, James E.C. ; Bello, Oscar ; Bremner, Fion ; Cordivari, Carla ; Reilly, Mary M. ; Foiani, Martha ; Heslegrave, Amanda ; Zetterberg, Henrik ; Heales, Simon J.R. ; Wood, Nicholas W. ; Rothman, James E. ; Boycott, Kym M ; Mills, Philippa B. ; Clayton, Peter T. ; Houlden, Henry. / PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. In: Annals of Neurology. 2019 ; Vol. 86, No. 2. pp. 225-240.

Bibtex Download

@article{2501d0564aaa4d639378535025625f91,
title = "PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation",
abstract = "ObjectiveTo identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.MethodsWe performed genome‐wide sequencing, homozygosity mapping and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on ATP‐binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient‐derived fibroblasts, plasma and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology and biochemical quantification.ResultsWe identified bi‐allelic mutations in PDXK in five individuals from two unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair‐bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP‐binding pocket. Low PDXK ATP‐binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'‐phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in one family, improvement in power, pain and fatigue contributing to patients regaining their ability to ambulate during the first year of PLP normalization.InterpretationWe show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown aetiology characterised by reduced PLP levels.",
author = "Viorica Chelban and Wilson, {Matthew P.} and {Warman Chardon}, Jodi and Jana Vandrovcova and Zanetti, {M. Natalia} and Eleni Zamba-papanicolaou and Stephanie Efthymiou and Simon Pope and Conte, {Maria R} and Giancarlo Abis and Yo-tsen Liu and Eloise Tribollet and Haridy, {Nourelhoda A.} and Bot{\'i}a, {Juan A} and Mina Ryten and Paschalis Nicolaou and Anna Minaidou and Kyproula Christodoulou and Kernohan, {Kristin D.} and Alison Eaton and Matthew Osmond and Yoko Ito and Pierre Bourque and Jepson, {James E.C.} and Oscar Bello and Fion Bremner and Carla Cordivari and Reilly, {Mary M.} and Martha Foiani and Amanda Heslegrave and Henrik Zetterberg and Heales, {Simon J.R.} and Wood, {Nicholas W.} and Rothman, {James E.} and Boycott, {Kym M} and Mills, {Philippa B.} and Clayton, {Peter T.} and Henry Houlden",
year = "2019",
month = "8",
day = "1",
doi = "10.1002/ana.25524",
language = "English",
volume = "86",
pages = "225--240",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation

AU - Chelban, Viorica

AU - Wilson, Matthew P.

AU - Warman Chardon, Jodi

AU - Vandrovcova, Jana

AU - Zanetti, M. Natalia

AU - Zamba-papanicolaou, Eleni

AU - Efthymiou, Stephanie

AU - Pope, Simon

AU - Conte, Maria R

AU - Abis, Giancarlo

AU - Liu, Yo-tsen

AU - Tribollet, Eloise

AU - Haridy, Nourelhoda A.

AU - Botía, Juan A

AU - Ryten, Mina

AU - Nicolaou, Paschalis

AU - Minaidou, Anna

AU - Christodoulou, Kyproula

AU - Kernohan, Kristin D.

AU - Eaton, Alison

AU - Osmond, Matthew

AU - Ito, Yoko

AU - Bourque, Pierre

AU - Jepson, James E.C.

AU - Bello, Oscar

AU - Bremner, Fion

AU - Cordivari, Carla

AU - Reilly, Mary M.

AU - Foiani, Martha

AU - Heslegrave, Amanda

AU - Zetterberg, Henrik

AU - Heales, Simon J.R.

AU - Wood, Nicholas W.

AU - Rothman, James E.

AU - Boycott, Kym M

AU - Mills, Philippa B.

AU - Clayton, Peter T.

AU - Houlden, Henry

PY - 2019/8/1

Y1 - 2019/8/1

N2 - ObjectiveTo identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.MethodsWe performed genome‐wide sequencing, homozygosity mapping and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on ATP‐binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient‐derived fibroblasts, plasma and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology and biochemical quantification.ResultsWe identified bi‐allelic mutations in PDXK in five individuals from two unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair‐bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP‐binding pocket. Low PDXK ATP‐binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'‐phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in one family, improvement in power, pain and fatigue contributing to patients regaining their ability to ambulate during the first year of PLP normalization.InterpretationWe show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown aetiology characterised by reduced PLP levels.

AB - ObjectiveTo identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.MethodsWe performed genome‐wide sequencing, homozygosity mapping and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on ATP‐binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient‐derived fibroblasts, plasma and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology and biochemical quantification.ResultsWe identified bi‐allelic mutations in PDXK in five individuals from two unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair‐bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP‐binding pocket. Low PDXK ATP‐binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'‐phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in one family, improvement in power, pain and fatigue contributing to patients regaining their ability to ambulate during the first year of PLP normalization.InterpretationWe show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown aetiology characterised by reduced PLP levels.

UR - http://www.scopus.com/inward/record.url?scp=85068354982&partnerID=8YFLogxK

U2 - 10.1002/ana.25524

DO - 10.1002/ana.25524

M3 - Article

VL - 86

SP - 225

EP - 240

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454