Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment

• Published in: Nature reviews. Endocrinology Vol. 12; no. 4; pp. 233 - 246
• Main Author: Whyte, Michael P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2016; Nature Publishing Group
• Subjects: 692/163/2743/316; 692/420/2489/144; 692/698/1671/63; 692/699/317/821; 692/700/565/1436; Alkaline phosphatase; Alkaline Phosphatase - genetics; Bone and Bones - diagnostic imaging; Bone Marrow Transplantation; Care and treatment; Development and progression; Endocrinology; Enzyme Replacement Therapy; Enzymes; Epilepsy - physiopathology; Etiology; Genes; Genetic Therapy; Health aspects; Humans; Hypercalcemia - physiopathology; Hyperphosphatemia - physiopathology; Hypophosphatasia; Hypophosphatasia - diagnosis; Hypophosphatasia - genetics; Hypophosphatasia - physiopathology; Hypophosphatasia - therapy; Liver; Medical diagnosis; Medicine & Public Health; Mineralization; Mutation; Pathogenesis; Pediatrics; Phosphatase; Radiography; Recombinant molecules; review-article; Rickets; United States > US
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/nrendo.2016.14

Key Points Hypophosphatasia is the autosomal dominant or autosomal recessive inborn error of metabolism with an extraordinary range of severity caused by loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) Extracellular accumulation of the TNSALP substrate inorganic pyrophosphate results in defective mineralization of the dentition causing tooth loss and often of the skeleton causing rickets or osteomalacia Hypophosphatasaemia (low serum alkaline phosphatase activity) for age and sex is the biochemical hallmark An elevated serum level of the TNSALP substrate pyridoxal 5′-phosphate (the major circulating form of vitamin B 6 ) is expected TNSALP gene ( ALPL ; also known as TNSALP ) mutation analysis is necessary to understand recurrence risks and for prenatal diagnosis Recombinant, bone-targeted TNSALP replacement has been shown to be effective for paediatric-onset hypophosphatasia Hypophosphatasia — a form of metabolic bone disease characterized by low serum alkaline phosphatase activity — results from loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Here, Michael Whyte discusses the aetiology, nosology, pathogenesis, diagnosis and treatment of hypophosphatasia, which is particularly timely given the recently reported successes and approvals of treating the disease using asfotase alfa, a bone-targeted, recombinant TNSALP. 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 B 6 , 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.