Hypophosphatasia: Vitamin B6 status of affected children and adults

• Published in: Bone (New York, N.Y.) Vol. 154; p. 116204
• Main Authors: Whyte, Michael P., Zhang, Fan, Wenkert, Deborah, Mack, Karen E., Bijanki, Vinieth N., Ericson, Karen L., Coburn, Stephen P.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.01.2022
• Subjects: 4-Pyridoxic acid; Alkaline phosphatase; Cerebrospinal fluid; Enzymopathy; Hypervitaminosis B6; Hypovitaminosis B6; Inborn error; Inorganic pyrophosphate; L-tryptophan challenge; Metabolic bone disease; Neuropathy; Osteomalacia; Pyridoxal; Pyridoxal 5′-phosphate; Pyridoxamine; Pyridoxine; Rickets; Vitamin B6-dependent seizures; Alkaline phosphatase; Pyridoxal; Pyridoxine; Cerebrospinal fluid; Neuropathy; Enzymopathy; Hypovitaminosis B6; Metabolic bone disease; L-tryptophan challenge; Rickets; Hypervitaminosis B6; Vitamin B6-dependent seizures; Inorganic pyrophosphate; Pyridoxal 5′-phosphate; Osteomalacia; Pyridoxamine; Inborn error; 4-Pyridoxic acid
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2021.116204

Hypophosphatasia (HPP) is the heritable dento-osseous disease caused by loss-of-function mutation(s) of the gene ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphomonoester phosphohydrolase expressed in healthy people especially in the skeleton, liver, kidneys, and developing teeth. In HPP, diminished TNSALP activity leads to extracellular accumulation of its natural substrates including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′-phosphate (PLP), the principal circulating form of vitamin B6 (B6). Autosomal dominant and autosomal recessive inheritance involving >450 usually missense defects scattered throughout ALPL largely explains the remarkably broad-ranging severity of this inborn-error-of-metabolism. In 1985 when we identified elevated plasma PLP as a biochemical hallmark of HPP, all 14 investigated affected children and adults had markedly increased PLP levels. However, pyridoxal (PL), the dephosphorylated form of PLP that enters cells to cofactor many enzymatic reactions, was not low but often inexplicably elevated. Levels of pyridoxic acid (PA), the B6 degradation product quantified to assess B6 sufficiency, were unremarkable. Canonical signs or symptoms of B6 deficiency or toxicity were absent. B6-dependent seizures in infants with life-threatening HPP were later explained by their profound deficiency of TNSALP activity blocking PLP dephosphorylation to PL and diminishing gamma-aminobutyric acid synthesis in the brain. Now, there is speculation that altered B6 metabolism causes further clinical complications in HPP. Herein, we assessed the plasma PL and PA levels accompanying previously reported elevated plasma PLP concentrations in 150 children and adolescents with HPP. Their mean (SD) plasma PL level was nearly double the mean for our healthy pediatric controls: 66.7 (59.0) nM versus 37.1 (22.2) nM (P < 0.0001), respectively. Their PA levels were broader than our pediatric control range, but their mean value was normal; 40.2 (25.1) nM versus 39.3 (9.9) nM (P = 0.7793), respectively. In contrast, adults with HPP often had plasma PL and PA levels suggestive of dietary B6 insufficiency. We discuss why the B6 levels of our pediatric patients with HPP would not cause B6 toxicity or deficiency, whereas in affected adults dietary B6 insufficiency can develop. •Hypophosphatasia (HPP) denotes heritable alkaline phosphatase (ALP) deficiency•Pyridoxal 5′-phosphate, an ALP substrate, accumulates extracellularly in HPP•HPP children average elevated pyridoxal and normal pyridoxic acid levels in plasma•Neither B6 deficiency nor toxicity characterize HPP in children•Adults with HPP often have plasma B6 levels indicative of dietary B6 insufficiency