Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment

Abstract

Hypophosphatasia (HPP) is a rare, inherited form of rickets or osteomalacia due to reduced activity of tissue non-specific alkaline phosphatase (TNSALP) caused by a loss of function mutation in the TNSALP gene marked by a low serum alkaline phosphatase. The ratio of PPi to Pi is crucial in the mineralization process. This process is regulated by the interaction of three phosphatases present in matrix vesicles: the mineralization promotors TNSALP and phosphatase orphan 1 (PHOSPHO1) and the mineralization inhibitor nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). HPP is seen worldwide affecting all races. The broad-ranging clinical severity of HPP is correlated to the pattern of inheritance and degree of TNSALP activity, with lower levels of activity seen in the more severe autosomal recessive forms. HPP is marked by compromise of phase 2 hydroxyapatite crystal formation beyond the matrix vesicle resulting in skeletal hypomineralization, spontaneous fractures, tooth loss, and chondrocalcinosis. The major forms in declining order of severity include the following: perinatal, infantile, childhood, and adult HPP in addition to OdontoHPP and benign prenatal HPP. Biochemistry typically reveals a low serum alkaline phosphatase and elevated alkaline substrates such as pyridoxal-5′-phosphate (PLP) and phosphoethanolamine (PEA). Asfotase alfa, a recent novel enzyme replacement therapy for the treatment of HPP, has transformed this once lethal disease to one that is less severe.

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

“…A common manifestation of loss of TNAP activity or mutations to ALPL gene causes a systemic bone disease called hypophosphatasia (HPP) resulting in hypomineralization of hard skeletal tissues including bone and teeth [ 106 , 107 ]. Several missense mutations are reported in human ALPL gene corresponding to aminoacid changes in the protein [ 106 , 107 , 108 ]. At the time of writing this review, 409 mutations in TNAP have been reported owing to its clinical heterogeneity.…”

“…Milder forms of the disease include deformities of extremities, early deciduous teeth loss and other dental manifestations. In severe cases of HPP, prenatal death of foetuses is seen due to complete absence of minerals in their skeleton [ 106 , 107 , 108 ]. Epileptic seizures, craniosynostosis, respiratory failure and death are also associated in extreme forms of HPP.…”

Síntese de filmes nanocompósitos de hidroxiapatita e óxido de grafeno reduzido em titânio

“…O recobrimento de superfícies utilizando HA foi introduzido em meados dos anos 80 para promover a fixação entre o osso e o implante e tem sido bem sucedido devido ao seu favorável comportamento in vivo 84 . Porém, suas propriedades mecânicas fracas, como baixa resistência a flexão e tenacidade, continuam sendo um obstáculo.…”