Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.

Abstract

Abstract"Perinatal" hypophosphatasia is the most severe form of this inborn error of metabolism, which is characterized by deficient activity of the tissue-nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP) (TNSALP). We report that autopsy tissue from three affected subjects, which was profoundly low in ALP activity, had essentially unremarkable levels of pyridoxal-5'-phosphate (PLP), pyridoxal, and total vitamin B6 content despite markedly elevated plasma PLP levels (5,800, 14,500, and 98,500 nM; adult norm, 5-109 nM).Our findings help to explain the general absence of symptoms of vitamin B6 excess or deficiency in hypophosphatasia, and provide evidence that TNSALP acts as an ectoenzyme to regulate extracellular rather than intracellular concentrations of PLP (the cofactor form of vitamin B6) and perhaps other phosphate compounds.

Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate. Substrate accumulation in carriers of hypophosphatasia corrects during pregnancy.

“…Subject A delivered a boy whose cord serum revealed hypophosphatasemia (total ALP activity 15 IU/liter) and an elevated plasma PLP concentration of 1,989 nM (previously, we had assayed cord blood from two newborn controls [mothers presumably receiving vitamins] whose serum total ALP activities were 109 and 135 IU/liter, and plasma PLP concentrations were 180 and 275 nM [25]). Now, 7 yr old, like his affected older brother, he has had premature loss of deciduous teeth and has subtle rachitic changes on skeletal radiographs.…”

Integrative Physiology and Functional Genomics of Epithelial Function in a Genetic Model Organism

“…There is also some evidence of hypomineralization in teeth (240). At least one human case has been reported with similar symptoms (244). However, the enigmatic renal role of alkaline phosphatase might be addressed in Drosophila, as the P-element insertions in Aph4 both disrupt expression and cause a transport phenotype (Fig.…”

Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia

“…Hypercalcemia and hyperphosphatemia can develop in severely affected patients. 1 The deranged vitamin B 6 metabolism shows that TNSALP functions as a cell-surface enzyme 6 and explains why pyridoxine-responsive seizures may occur when TNSALP deficiency is profound. 7 The manifestations of hypophosphatasia range from neonatal death with almost no skeletal mineralization to dental problems in adults without any bone symptoms.…”