title: Clinical Forms and Animal Models of Hypophosphatasia.
abstract: Hypophosphatasia (HPP) is due to mutations of the tissue non-specific alkaline phosphatase (TNAP) gene expressed in the liver, kidney, and bone. TNAP substrates include inorganic pyrophosphate cleaved into inorganic phosphate (Pi) in bone, pyridoxal-5'-phosphate (PLP), the circulating form of vitamin B6, and phosphoethanolamine (PEA). As an autosomal recessive or dominant disease, HPP results in a range of clinical forms. Its hallmarks are low alkaline phosphatase (AP) and elevated PLP and PEA levels. Perinatal HPP may cause early death with respiratory insufficiency and hypomineralization resulting in deformed limbs and sometimes near-absence of bones and skull. Infantile HPP is diagnosed before 6 months of life. Respiratory failure, rib fractures and seizures due to vitamin B6 deficiency in the brain indicate poor prognosis. Craniosynostosis is frequent. Unlike in other forms of rickets, calcium and phosphorus are not decreased, resulting in hypercalciuria and nephrocalcinosis. Hypercalcemic crisis may occur. Failure to thrive and growth retardation are concerns. In infantile and adult forms of HPP, non-traumatic fractures may be the prominent manifestation, with otherwise unexplained chronic pain. Progressive myopathy has been described. Dental manifestations with early loss of teeth are usual in HPP and in a specific form, odontohypophosphatasia. HPP has been studied in knock-out mice models which mimic its severe form. Animal models have made a major contribution to the development of an original enzyme therapy for human infantile HPP, which is however essentially targeted at mineralized tissues. Better knowledge of its extraskeletal manifestations, including pain and neurological symptoms, is therefore required.
authors.affiliation: Unité d'Endocrinologie Maladies Osseuses, Hôpital Des Enfants, CHU de Toulouse and Inserm UMR 1043 UPS, Toulouse Cedex, France, Salles.jp@chu-toulouse.fr.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Salles
mesh_terms: D000328:Adult; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D007014:Hypophosphatasia / Q000145:classification* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D007223:Infant; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000175:diagnosis / Q000209:etiology / Q000473:pathology