title: Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment.
abstract: Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, 4400 Clayton Avenue, Saint Louis, Missouri 63110, USA.|Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics; D016026:Bone Marrow Transplantation; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D056947:Enzyme Replacement Therapy; D004827:Epilepsy / Q000503:physiopathology*; D015316:Genetic Therapy; D006801:Humans; D006934:Hypercalcemia / Q000503:physiopathology*; D054559:Hyperphosphatemia / Q000503:physiopathology*; D007014:Hypophosphatasia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D009154:Mutation; D011859:Radiography
chemical_list: C548267:ALPL protein, human; D000469:Alkaline Phosphatase