Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
Department of Chemistry, Indiana University-Purdue University, Fort Wayne, IN 46805, USA.
Bone. 2018 May;110:96-106. doi: 10.1016/j.bone.2018.01.022. Epub 2018 Jan 31.
Hypophosphatasia (HPP) is the inborn-error-of-metabolism due to loss-of-function mutation(s) of the ALPL (TNSALP) gene that encodes the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). TNSALP represents a family of cell-surface phosphohydrolases differing by post-translational modification that is expressed especially in the skeleton, liver, kidney, and developing teeth. Thus, the natural substrates of TNSALP accumulate extracellularly in HPP including inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B. The superabundance of extracellular PPi regularly causes tooth loss, and when sufficiently great can lead to rickets or osteomalacia. Sometimes diminished hydrolysis of PLP engenders vitamin B-dependent seizures in profoundly affected babies. Autosomal dominant and autosomal recessive inheritance from among >340 ALPL mutations identified to date, typically missense and located throughout the gene, largely explains the remarkably wide-ranging severity of HPP, greatest of all skeletal diseases. In 2015, our demographic, clinical, and DXA findings acquired over 25 years from 173 children and adolescents with HPP validated and expanded the clinical nosology for pediatric patients to include according to increasing severity "odonto" HPP, "mild childhood" HPP, "severe childhood" HPP, "infantile" HPP, and "perinatal" HPP. Herein, we assessed this expanded nosology using biochemical hallmarks of HPP. We evaluated exclusively data from the 165 preteenage HPP patients in this cohort to exclude potential effects from physiological changes in TNSALP levels across puberty. All patients had subnormal serum total and bone-specific ALP and elevated plasma PLP, and nearly all had excessive urinary PPi excretion. Only the PLP levels were unchanged across puberty. Mean levels of all four biomarkers correlated with HPP severity ranked according to the HPP nosology, but the data overlapped among all four patient groups. Hence, these four biochemical hallmarks represent both a sensitive and reliable tool for diagnosing children with HPP. Furthermore, the hallmarks validate our expanded clinical nosology for pediatric HPP that, with limitations, is an improved framework for conceptualizing and working with this disorder's remarkably broad-ranging severity.
低磷酸酯酶症（HPP）是一种先天性代谢缺陷疾病，由碱性磷酸酶组织非特异性同工酶（TNSALP）基因的功能丧失突变引起。TNSALP 是一种细胞表面磷酸水解酶家族，通过翻译后修饰而不同，主要在骨骼、肝脏、肾脏和正在发育的牙齿中表达。因此，TNSALP 的天然底物在 HPP 中会在细胞外积聚，包括无机焦磷酸盐（PPi），一种强有力的矿化抑制剂，以及吡哆醛 5'-磷酸（PLP），维生素 B 的主要循环形式。细胞外 PPi 的大量积聚通常导致牙齿脱落，而当积聚量足够大时，可导致佝偻病或骨软化症。有时，PLP 水解减少会导致严重受影响的婴儿发生维生素 B 依赖性癫痫发作。迄今为止，已从 >340 种 ALPL 突变中鉴定出常染色体显性和常染色体隐性遗传，这些突变通常是错义突变，且分布在整个基因中，这在很大程度上解释了 HPP 非常广泛的严重程度，这在所有骨骼疾病中都是最严重的。2015 年，我们从 173 名患有 HPP 的儿童和青少年中获得了超过 25 年的人口统计学、临床和 DXA 发现，这些发现验证并扩展了儿科患者的临床分类学，根据严重程度包括“牙”HPP、“轻度儿童”HPP、“重度儿童”HPP、“婴儿”HPP 和“围产期”HPP。在此，我们使用 HPP 的生化标志物评估了这种扩展的分类学。我们仅评估了该队列中 165 名青春期前 HPP 患者的数据，以排除青春期 TNSALP 水平变化对潜在影响。所有患者的血清总碱性磷酸酶和骨特异性碱性磷酸酶均低于正常水平，血浆 PLP 升高，几乎所有患者的尿 PPi 排泄量均过多。只有 PLP 水平在整个青春期内保持不变。根据 HPP 分类学对根据严重程度排列的所有四种生物标志物的平均水平进行相关性分析，但数据在所有四个患者组中均有重叠。因此，这四种生化标志物既是诊断 HPP 儿童的敏感可靠工具，又验证了我们对儿科 HPP 的扩展临床分类学，该分类学具有局限性，但可以更好地用于概念化和处理这种疾病的广泛严重程度。
