Hypophosphatasia is a rare disease characterized by low serum levels of tissue non-specific alkaline phosphatase (TNSALP) and a spectrum of skeletal disease varying from the severest form with death in utero to mild with no clinical abnormality in adults. Currently, the diagnosis of hypophosphatasia is made on the basis of clinical findings, radiography, low serum alkaline phosphatase levels and raised abnormal phosphorylated metabolites; there are elevations in serum pyridoxal 5′-phosphate, urinary phosphoethanolamine and inorganic pyrophosphate. In borderline cases the biochemical diagnosis remains uncertain. Prenatally, diagnosis is made using radiography and ultrasonography together with chorionic villus tissue biopsy, in which TNSALP levels are measured using an antibody-based assay. Since hypophosphatasia results from mutations in the TNSALP gene we have, for the first time in two U.K. families, undertaken restriction fragment length polymorphism (RFLP) analysis using three intragenic RFLPs for Bcl I and Msp I at the ALPL locus. One family was informative, and a mutant-allele-specific haplotype with respect to three RFLPs was defined. In the other family the disease was shown to segregate with one allele of the Bcl I RFLP, but the Msp I RFLPs were not informative. The disease segregated in the two families with different alleles of the Bcl I RFLP, suggesting that the mutations are likely to be different. We confirm that DNA analysis is likely to be the way ahead for diagnosing hypophosphatasia, and that standardized screening methods need to be developed for detecting mutations in these and other families.
1. Hypophosphatasia is a disorder characterized by low serum levels of alkaline phosphatase (ALP) and a range of skeletal deformities. The levels of a number of phosphorylated metabolites, namely phosphoethanolamine and pyrophosphate, are characteristically raised. Levels of pyridoxal-5′-phosphate (PLP) have also been reported to be raised. 2. Hypophosphatasia is a rare disease and experience of measuring PLP in patients is lacking. We have had the chance to look at PLP levels in four families with hypophosphatasia, specifically to examine the quantitative relationship between ALP and PLP which has not been described before. 3. We confirmed that PLP levels are raised in hypo-phosphatasia and related to the disease severity. A significant negative linear relationship was found between the log PLP and log ALP (log PLP = 5.99−2.76 log ALP; r = − 0.85, P < 0.001). 4. Measurement of PLP is simpler than some of the phosphorylated compounds, e.g. pyrophosphate. PLP may be a useful measure in patients with a suspected diagnosis of hypophosphatasia or for screening family members to detect potential heterozygotes and to monitor any response to therapy. 5. There did not appear to be any adverse clinical effects in relation to disturbed vitamin B 6 metabolism in hypophosphatasia. 6. Vitamin B 6 is used therapeutically in a number of conditions with monitoring of PLP levels. In these conditions PLP levels should be interpreted in conjunction with the prevailing serum ALP levels as the metabolism of these compounds is closely inter-related.