Pathophysiology of hypophosphatasia and the potential role of asfotase alfa
Hideo Orimo Division of Metabolism and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan Abstract: Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms accordin...
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Dove Medical Press
2016-05-01
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| Series: | Therapeutics and Clinical Risk Management |
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| Online Access: | https://www.dovepress.com/pathophysiology-of-hypophosphatasia-and-the-potential-role-of-asfotase-peer-reviewed-article-TCRM |
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| author | Orimo H |
| author_facet | Orimo H |
| author_sort | Orimo H |
| collection | DOAJ |
| description | Hideo Orimo Division of Metabolism and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan Abstract: Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. Keywords: hypophosphatasia, alkaline phosphatase, mutation, asfotase alfa, rickets, respiratory failure |
| first_indexed | 2024-12-18T01:22:51Z |
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| id | doaj.art-9456a692ab4b4e0e8818ab6e0f05fa20 |
| institution | Directory Open Access Journal |
| issn | 1178-203X |
| language | English |
| last_indexed | 2024-12-18T01:22:51Z |
| publishDate | 2016-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Therapeutics and Clinical Risk Management |
| spelling | doaj.art-9456a692ab4b4e0e8818ab6e0f05fa202022-12-21T21:25:47ZengDove Medical PressTherapeutics and Clinical Risk Management1178-203X2016-05-012016Issue 177778626966Pathophysiology of hypophosphatasia and the potential role of asfotase alfaOrimo HHideo Orimo Division of Metabolism and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan Abstract: Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. Keywords: hypophosphatasia, alkaline phosphatase, mutation, asfotase alfa, rickets, respiratory failurehttps://www.dovepress.com/pathophysiology-of-hypophosphatasia-and-the-potential-role-of-asfotase-peer-reviewed-article-TCRMhypophosphatasiaalkaline phosphatasemutationasfotase alfaricketsrespiratory failure |
| spellingShingle | Orimo H Pathophysiology of hypophosphatasia and the potential role of asfotase alfa Therapeutics and Clinical Risk Management hypophosphatasia alkaline phosphatase mutation asfotase alfa rickets respiratory failure |
| title | Pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| title_full | Pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| title_fullStr | Pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| title_full_unstemmed | Pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| title_short | Pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| title_sort | pathophysiology of hypophosphatasia and the potential role of asfotase alfa |
| topic | hypophosphatasia alkaline phosphatase mutation asfotase alfa rickets respiratory failure |
| url | https://www.dovepress.com/pathophysiology-of-hypophosphatasia-and-the-potential-role-of-asfotase-peer-reviewed-article-TCRM |
| work_keys_str_mv | AT orimoh pathophysiologyofhypophosphatasiaandthepotentialroleofasfotasealfa |