Orimo Hideo
Division of Metabolism and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
Ther Clin Risk Manag. 2016 May 17;12:777-86. doi: 10.2147/TCRM.S87956. eCollection 2016.
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.
低磷酸酯酶症（HPP）是一种遗传性全身性骨病，其特征为骨矿化不足。根据发病年龄和严重程度，HPP可分为六种类型，即围产期（致死型）、围产期良性型、婴儿型、儿童型、成人型和牙型低磷酸酯酶症。该疾病的致病基因是编码组织非特异性碱性磷酸酶（TNAP）的ALPL基因。TNAP在全身广泛表达，其生理作用在骨矿化过程中较为明显。骨矿化缺陷可通过多种方式表现出来，包括HPP患者出现佝偻病或骨软化症。重症患者因胸廓发育不全而出现呼吸衰竭，这是主要死因。他们有时还会因神经元细胞中碱性磷酸酶活性缺乏导致维生素B6代谢缺陷而出现癫痫发作，这也是致命的。轻症患者表现为佝偻病或骨软化症以及运动功能缺陷。牙型低磷酸酯酶症仅表现为牙齿方面的症状。迄今为止，已报道了ALPL基因中的302种突变，主要为单核苷酸替换，并且表型与基因型之间的关系已部分阐明。直到最近酶替代疗法的出现，才出现了针对HPP的既定治疗方法。2008年报道了在模型小鼠中使用改良型人TNAP蛋白（阿加糖酶α）进行的首次成功酶替代疗法，随后在2012年报道了该疗法在重症患者中的成功应用。2015年，阿加糖酶α于7月在日本获批，随后于8月在欧盟和加拿大获批，10月在美国获得美国食品药品监督管理局批准。预计阿加糖酶α疗法将极大地改变HPP的治疗方法和预后。
