Hypophosphatasia: Nature's Window on Alkaline Phosphatase Function in Humans

Hypophosphatasia (HPP) features defective skeletal mineralization that manifests as rickets in newborns, infants, children, and adolescents, and as osteomalacia in adults. This chapter reviews the documentation beginning in 1988, which states that HPP is caused by loss-of-function mutations in tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP), the gene that encodes the TNSALP isoenzyme. However, the pathogenesis of the defective skeletal mineralization in HPP seems primarily to result from deficient TNSALP hydrolysis of inorganic pyrophosphate, an inhibitor of mineralization. It provides a brief history of the proposed function of alkaline phosphatase (ALP) in humans, and reviews the molecular and biological chemistry of human ALPs. Furthermore, it deals with HPP in detail. Based on this understanding, it discusses the insights gained from this experiment-of-nature. Furthermore, it summarizes the refinements concerning the role of TNSALP obtained from knockout mouse studies. Subsequently, it states that prenatal diagnosis of HPP is possible. During the second trimester, fetal ultrasonography or radiography has proven helpful for perinatal HPP. From the first trimester, chorionic villus samples have been used successfully for TNSALP mutation detection. However, the considerable number and variety of TNSALP mutations, as well as the influence of other factors on the HPP phenotype, makes prognostication difficult. However, there is no established medical treatment for HPP.