Tomoyuki Akiyama1, Takuo Kubota2, Keiichi Ozono2, Toshimi Michigami3, Daisuke Kobayashi4, Shinji Takeyari2, Yuichiro Sugiyama5, Masahiro Noda6, Daisuke Harada7, Noriyuki Namba7, Atsushi Suzuki8, Maiko Utoyama9, Sachiko Kitanaka10, Mitsugu Uematsu11, Yusuke Mitani12, Kunihiro Matsunami13, Shigeru Takishima14, Erika Ogawa15, Katsuhiro Kobayashi16. 1. Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address: takiyama@okayama-u.ac.jp. 2. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. 3. Department of Bone and Mineral Research, Osaka Women's and Children's Hospital, Osaka, Japan. 4. Department of Food and Chemical Toxicology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan. 5. Department of Pediatrics, Nagoya University Graduate School of Medicine, Aichi, Japan. 6. Department of Pediatrics, Showa General Hospital, Tokyo, Japan. 7. Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization (JCHO), Osaka, Japan. 8. Department of Neonatology and Pediatrics, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. 9. Department of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 10. Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 11. Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan. 12. Department of Pediatrics, Kanazawa University Hospital, Ishikawa, Japan. 13. Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan. 14. Department of Pediatrics, Soka Municipal Hospital, Saitama, Japan. 15. Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan. 16. Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Abstract
OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.
OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.