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

for the Care4Rare Canada Consortium and the SYNaPS Study Group

Research output: Contribution to journalArticle

Abstract

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We 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 adenosine triphosphate (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. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 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 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We 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 etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.

Original languageEnglish
Pages (from-to)225-240
Number of pages16
JournalAnnals of Neurology
Volume86
Issue number2
DOIs
Publication statusPublished - Aug 1 2019

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Pyridoxal Phosphate
Polyneuropathies
Mutation
Optic Atrophy
Adenosine Triphosphate
Erythrocytes
Calorimetry
Wheelchairs
Aptitude
Electrophysiology
Enzyme Assays
Genetic Association Studies
Circular Dichroism
Natural History
Recombinant Proteins
Fatigue
Virulence
Mass Spectrometry
Fibroblasts
Genome

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. / for the Care4Rare Canada Consortium and the SYNaPS Study Group.

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

Research output: Contribution to journalArticle

for the Care4Rare Canada Consortium and the SYNaPS Study Group 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
for the Care4Rare Canada Consortium and the SYNaPS Study Group. / PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. In: Annals of Neurology. 2019 ; Vol. 86, No. 2. pp. 225-240.
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T1 - PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation

AU - for the Care4Rare Canada Consortium and the SYNaPS Study Group

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

AU - Kriouile, Yamna

AU - Khorassani, Mohamed El

AU - Aguennouz, Mhammed

AU - Veggiotti, Pierangelo

AU - Savasta, Salvatore

AU - Garavaglia, Barbara

AU - Borgione, Eugenia

AU - Portaro, Simona

AU - Scuderi, Carmela

AU - Borgione, Eugenia

AU - Striano, Pasquale

AU - Silvestri, Gabriella

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We 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 adenosine triphosphate (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. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 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 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We 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 etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.

AB - Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We 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 adenosine triphosphate (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. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 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 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We 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 etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.

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