Hypophosphatasia (HPP) is an inherited systemic bone disease caused by the deficiency of tissue-nonspecific alkaline phosphatase (TNAP). HPP is classified into six forms and the symptoms of HPP vary depending on the form. The pathophysiology of HPP is basically due to a defect of bone mineralization. TNAP is encoded by the ALPL gene, and the TNAP protein expressed in bone, kidney, liver, and neuronal cells and is linked to the cell membrane via a glycosylphosphatidylinositol anchor. TNAP is an ectoenzyme hydrolyzing phosphate compound such as inorganic pyrophosphate. TNAP plays an important role in mineralization of hard tissues. Defect of mineralization process causes hypomineralization of hard tissues, which leads to rickets or osteomalacia and dental manifestations. In addition, hypomineralization of the ribs results in respiratory failure in the severe forms, which is the main cause of death. Inheritance of HPP is autosomal recessive, but autosomal dominant cases have been reported in the milder forms. To date, a total of 335 mutations in the ALPL gene have been reported, and mutation sites are scattered throughout the gene. Recent development of enzyme replacement therapy has opened up a new vista on the treatment of this previously untreatable disease.
Part of the book: Pathophysiology