Hypophosphatasia (McKusick 146300, 241500, 241510) is a metabolic bone disease that establishes a critical (but as yet undefined) role for alkaline phosphatase (ALP) in skeletal mineralization in humans. Subnormal activity of ALP in serum (hypophosphatasemia) is the biochemical hallmark and reflects a generalized deficiency of activity of the tissue-nonspecific -liver/bone/kidney- ALP isoenzyme (TNSALP). Catalysis by the tissue-specific ALP isoenzymes—intestinal, placental, and germ-cell (placental-like) ALP—is not diminished.
TNSALP is a zinc metalloglycoprotein that is catalytically active as a multimer of identical subunits. The bone and liver isoforms differ by post-translational modification. TNSALP is attached to the extracellular surface of plasma membranes by glycosylphosphatidylinositol linkage. The TNSALP gene is greater than 50 kb and localized on chromosome 1p36.1-34 (McKusick 171760). The tissue-specific ALP isoenzymes, perhaps including a fetal form of intestinal ALP, are encoded by a family of smaller genes on chromosome 2q34-37 (McKusick 171740, 171750, 171800, 171810).
Hypophosphatasia causes defective skeletal mineralization that manifests clinically as rickets in infants and children and as osteomalacia in adults. Expressivity is remarkably variable. Stillbirth can follow in utero disease in the perinatal (“lethal”) form, which is apparent in newborns and is associated with the most severe skeletal hypomineralization and deformity. The infantile form presents as a developmental disorder by age 6 months. It can result in craniosynostosis and nephrocalcinosis from hypercalcemia and hypercalciuria and is often fatal. Premature loss of deciduous teeth, rickets, and myopathy are the cardinal clinical features of childhood hypophosphatasia. Adult hypophosphatasia typically causes recurrent metatarsal stress fractures and pseudofractures in long bones and occasionally produces arthritis from calcium pyrophosphate dihydrate (CPPD) and calcium phosphate crystal deposition. Odontohypophosphatasia refers to mildly affected individuals who have dental but no skeletal manifestations. Pseudohypophosphatasia is an extremely rare severe variant in which serum ALP activity is normal in clinical laboratory assays.
Three phosphocompounds (phosphoethanolamine [PEA], inorganic pyrophosphate [PPi], and pyridoxal 5′-phosphate [PLP]) accumulate endogenously in hypophosphatasia and are inferred to be natural substrates for TNSALP. PLP, a cofactor form of vitamin B6, collects extracellularly, but a variety of evidence shows that levels of PLP within cells are normal. This observation explains the usual absence of symptoms of deficiency or toxicity of vitamin B6 in patients and indicates that TNSALP functions as an ectoenzyme. Extracellular accumulation of PPi, which at low concentrations promotes calcium phosphate deposition but at high concentrations acts as an inhibitor of hydroxyapatite crystal growth, seems to account for the associated CPPD deposition, and perhaps calcific periarthritis, and the defective mineralization of bones and teeth.
Perinatal and infantile hypophosphatasia are transmitted as autosomal recessive traits and can be due to homozygosity or compound heterozygosity for a considerable number and variety of mutations in the TNSALP gene. Defective regulation of TNSALP gene expression or TNSALP biosynthesis may explain especially rare cases. Patients with childhood, adult, or odonto forms of hypophosphatasia can also be compound heterozygotes for TNSALP gene mutations. In some kindreds, however, mild forms of hypophosphatasia manifest with autosomal dominant inheritance. The TNSALP gene knock-out mouse is an excellent model for infantile hypophosphatasia, but prominently features lethal seizures that can be controlled with vitamin B6 supplementation.
There is no established medical treatment. Enzyme replacement by intravenous infusion of ALP from various tissue sources has generally not been clinically helpful. Clinical and radiographic improvement occurred, despite persistent biochemical abnormalities, in the one severely affected infant treated by bone marrow and stromal cell transplantation.
Prenatal diagnosis of perinatal hypophosphatasia has been achieved during the second trimester with ultrasonography, radiography, and assay of ALP activity in amniocytes. During the first trimester, chorionic villus samples have been used for RFLP and TNSALP gene mutation analysis and for TNSALP activity assay. Prenatal diagnosis of the infantile form requires molecular techniques.