Hypophosphatasia: A Developmental Anomaly of Alkaline Phosphatase?

Abstract

This report deals with quantitative and qualitative investigations of alkaline phosphatase in two unrelated infants with the severe infantile form of hypophosphatasia. Both affected infants had no detectable leukocyte alkaline phosphatase activities and both sets of parents and one sibling tended to have low but variable leukocyte enzyme activities. Normal duodenal juice alkaline phosphatase activity was present in the one patient in whom it was measured and a wide range of variation in enzymic activity was observed in the stools. There was no significant difference in the stool enzyme activity between both patients with hypophosphatasia (42.01 +/- 9.77 U) and control infants (40.55 +/- 6.29 U). However, the heterozygous parents had values significantly lower than the control adults (2.10 +/- 0.47 as compared with 19.10 +/- 4.44 U). Intestinal bacteria did not contribute significantly to the stool alkaline phosphatase activity. Enzyme activity was present in the bile of one of the patients and nearly absent in that of the other. Three "inducers" of alkaline phosphatase were given to both patients (phenobarbital, vitamin A, and corticosteroid). No clinical improvement or rise in serum alkaline phosphatase activity was observed during the trial of therapy with these agents. However, a significant increase in the activity of serum acid phosphatase was demonstrated during the course of vitamin A administration, suggesting an in vivo action of vitamin A on the lysosomes through decreasing the stability of the membrane and releasing acid phosphatase to the serum. Quantitative determination of tissue alkaline phosphatases from autopsy tissues was highly variable: no activity was found in bone, lungs, or spleen of either infant; there was a discrepancy in liver and kidney alkaline phosphatase values (zero in one patient and present in the other) and activity was present in the intestinal mucosa of both. Qualitative analysis of kidney, liver, and intestinal alkaline phosphatase revealed some differences between the patients and control subjects in heat inactivation and phenylalanine inhibition (Table 3). Starch gel electrophoresis of the liver preparation of one patient disclosed a single band which had greater mobility than that of six control subjects matched for age. Liver extracts from a premature and from full term newborns showed two bands. The single band of the patient's liver enzyme corresponded to the newborn's fast moving component. In addition, the intestinal enzyme prepared from the same patient had an extra band when compared with age-matched control subjects.

Histologic and ultrastructural studies on the mineralization process in hypophosphatasia

“…The hypophosphatasias are a group of hereditary skeletal dy splasias that are characterized by reduced chondroosseous mineralization and very low levels of alkaline phosphatase in blood and various tissues, including cartilage and bone [Fraser, 1957;Goldfisher et al, 1976;Kousseff and Mulivor, 1981;Teree and Klein, 1968;Warshaw et al, 19711. There are three clinically recognizable forms of hypophosphatasia: infantile with onset in utero, childhood, and adulthood, depending on the age of onset of demonstrable bone disease.…”

Vitamin D Metabolism in Hypophosphatasia

“…Although the peak concentration of alkaline phosphatase was far below the levels usually found in children with vitamin D deficiency, it is nevertheless noteworthy that the rickets provoked a marked rise in the serum level of the enzyme, since therapeutic trials with known inducers of alkaline phosphatase such as phenobarbital, corticosteroids and vitamin A have failed to increase the serum alkaline phosphatase activity in patients with hypophosphatasia (19).…”

Properties of human alkaline phosphatase and prenatal diagnosis of hypophosphatasia

“…This familial disease is associated with a deficiency of alkaline phosphatase (EC 3.1.3.1). The activities are low in bone, plasma, kidney and liver (Sobel et al, 1953 ;Gorodischer et aL, 1976); however, in intestine and placenta the activities are similar to the control values (Gorodischer et al, 1976;Danovitsch et al, 1968). Alkaline phosphatase can be divided into three major isoenzyme groups by immunological studies (Boyer, 1963): group I, the isoenzyme in bone, liver and spleen; group II, the isoenzyme in intestine; and group III, the isoenzyme in placenta.…”