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 language | English |
|---|---|
| Pages (from-to) | 225-240 |
| Number of pages | 16 |
| Journal | Annals of Neurology |
| Volume | 86 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 1 2019 |
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ASJC Scopus subject areas
- Neurology
- Clinical Neurology
Cite this
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 journal › Article
}
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85068354982&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068354982&partnerID=8YFLogxK
U2 - 10.1002/ana.25524
DO - 10.1002/ana.25524
M3 - Article
C2 - 31187503
AN - SCOPUS:85068354982
VL - 86
SP - 225
EP - 240
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 2
ER -