Hypophosphatasia

Abstract

Hypophosphatasia (HPP) reveals a critical role for the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP) in skeletal mineralization. Its biochemical hallmark, subnormal serum ALP activity, results from loss-of-function mutation(s) within TNSALP, the gene that encodes TNSALP. HPP spans an extraordinary range of severity partly explained by autosomal recessive versus autosomal dominant or recessive transmission causing severe and mild HPP, respectively. Perinatal HPP is usually fatal due to profound skeletal hypomineralization. Infantile HPP presents before the age of 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia, craniosynostosis, or vitamin B6-responsive seizures. Respiratory failure and death often follow progressive chest deformity. Childhood HPP features loss of deciduous teeth from cementum hypoplasia, rickets, and weakness from static myopathy. Adult HPP causes osteomalacia with fractures and sometimes, inorganic pyrophosphate (PPi) deposition leading to arthropathy. Odonto-HPP refers to premature tooth loss alone. Discovery of phosphorethanolamine (PEA), PPi, and pyridoxal 5′-phosphate (PLP) accumulation in HPP demonstrated that TNSALP hydrolyzes several substrates of nanomolar or micromolar concentrations, and therefore is at much lower levels than the artificial substrates and pH of laboratory assays. Thus, “alkaline phosphatase” is a misnomer. Vitamin B6 disturbances in HPP reveal that TNSALP is a cell-surface enzyme. Membrane-impermeable PLP accumulates in plasma, but normal plasma concentrations of its hydrolysis product PL explain absence of symptoms of vitamin B6 deficiency or toxicity in all but the most severely affected HPP babies who can have vitamin B6-responsive seizures. PEA may derive from the GPI anchor for many cell-surface proteins. In HPP, hydroxyapatite (HA) crystals form normally in matrix vesicles (MVs) during “primary mineralization”, but excess PPi inhibits their growth after MVs rupture during “secondary mineralization” causing rickets or osteomalacia. Bone-targeted recombinant TNSALP therapy is emerging as an effective treatment.