Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, and Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.
J Bone Miner Res. 2017 Apr;32(4):667-675. doi: 10.1002/jbmr.3075. Epub 2017 Jan 31.
Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal inheritance (dominant or recessive) from among more than 300 predominantly missense defects of TNSALP (ALPL) explains HPP's broad-ranging severity, the greatest of all skeletal diseases. In health, TNSALP is linked to cell surfaces and richly expressed in the skeleton and developing teeth. In HPP,TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi), an inhibitor of mineralization. The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B . Now, significant successes are documented for newborns, infants, and children severely affected by HPP given asfotase alfa, a hydroxyapatite-targeted recombinant TNSALP. Since fall 2015, this biologic is approved by regulatory agencies multinationally typically for pediatric-onset HPP. Safe and effective treatment is now possible for this last rickets to have a medical therapy, but a number of challenges involving diagnosis, understanding prognosis, and providing this treatment are reviewed herein. © 2017 American Society for Bone and Mineral Research.
低磷酸酯酶症（HPP）是由编码组织非特异性碱性磷酸酶（TNSALP）同工酶的基因的功能丧失突变引起的。TNSALP（ALPL）的 300 多种主要错义缺陷中的常染色体遗传（显性或隐性）解释了 HPP 广泛的严重程度，这是所有骨骼疾病中最严重的。在健康状态下，TNSALP 与细胞表面相关，在骨骼和正在发育的牙齿中表达丰富。在 HPP 中，TNSALP 的底物在细胞外积累，包括无机焦磷酸盐（PPi），一种矿化抑制剂。PPi 过多会导致牙齿脱落、佝偻病或骨软化症、钙化性关节病，以及肌肉无力。严重受影响的婴儿可能因吡哆醛 5'-磷酸（PLP）的水解不足而痉挛，PLP 是主要的细胞外维生素 B6。现在，对于接受 asfotase alfa 治疗的严重 HPP 新生儿、婴儿和儿童，有大量的成功案例被记录下来。自 2015 年秋季以来，这种生物制剂已被多个国家的监管机构批准用于儿科发病的 HPP。现在，对于这种最后一种佝偻病，有了一种可以进行医学治疗的方法，但本文回顾了涉及诊断、了解预后和提供这种治疗的一些挑战。© 2017 美国骨骼与矿物质研究协会。
