PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

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 bi

SUBMITTER: Chelban V 

PROVIDER: S-EPMC6772106 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature