Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity.

Hypophosphatasia is a rare metabolic bone disease characterized biochemically by deficient enzymatic activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). All isoforms of TNSALP (e.g. bone and liver TNSALP), apparently differing only by posttranslational modifications, are affected. To explore the biochemical basis and extremely variable severity of hypophosphatasia, we used 2-site immunoradiometric assays that quantify in serum either 1) bone TNSALP (iBALP) alone, or 2) both bone and liver TNSALP (iTNSALP). Sera from 33 patients in 26 kindreds reflecting all 6 clinical types of the disorder were studied. In every patient, except the two with pseudohypophosphatasia, serum iBALP and iTNSALP levels were decreased compared to age-appropriate control ranges. The magnitude of the decrease in iBALP and iTNSALP levels correlated with clinical severity. The mean ratio of iBALP or iTNSALP level to total ALP activity was unremarkable for the mild childhood, adult, and odonto forms of hypophosphatasia. For the severe perinatal and infantile forms, the mean ratios were low. If our finding of reduced iBALP levels in the circulation reflects a similar abnormality in the skeleton, the pathogenesis of hypophosphatasia could involve decreased amounts of extracellular TNSALP in bone and cartilage. How TNSALP gene mutations affect the enzyme and cause skeletal disease requires further investigation.