Vitamin B6 Status in Hypophosphatasia: Association With Clinical Severity, Diagnostic Utility, and Effects on Vitamin B6 Metabolism by Supplementation and Enzyme Replacement Therapy

This study reports the concentrations of major vitamin B6 (VB6) vitamers (pyridoxal 5′-phospate [PLP], pyridoxal [PL], and 4-pyridoxic acid [PA]) in over 100 hypophosphatasia (HPP) cases to explore clues for clinical severity, to improve diagnostic sensitivity, and to examine VB6 changes by supplementation and enzyme replacement therapy. Serum samples were collected from HPP and non-HPP patients. When available, cerebrospinal fluid (CSF) samples were also analyzed to determine PLP, PL, and PA concentrations. Serum PLP concentrations, PLP-to-PL ratios, and PLP-to-PA ratios were higher in untreated HPP patients compared to non-HPP patients and reflected clinical severity. Perinatal severe HPP showed lower PL concentrations than perinatal benign HPP and the lowest PA concentrations among all clinical forms. Combining PLP-to-PL ratios with PLP concentrations improved diagnostic sensitivity. Under VB6 therapy, PLP concentrations and PLP-to-PL ratios remained higher in HPP patients than in non-HPP patients. VB6 changes produced by ERT were most clearly reflected by the reduction of PLP-to-PL ratios. CSF PLP concentrations and PLP-to-PL ratios were higher in untreated HPP patients than in non-HPP patients, while CSF PL concentrations were higher in patients on ERT compared to those not on ERT. Co-evaluation of serum PLP, PL, and PA concentrations may help understand clinical severity, can improve diagnostic sensitivity, and can demonstrate the effect of ERT on VB6 metabolism more effectively than the assay of PLP concentrations alone. Altered VB6 status in the CSF suggests that tissue-nonspecific alkaline phosphatase plays a key role in VB6 transport from peripheral blood to the brain via the blood–CSF barrier.