Hypophosphatasia

Abstract

Hypophosphatasia is a rare inherited disorder characterized by defective bone and teeth mineralization, and deficiency of serum and bone alkaline phosphatase activity. The prevalence of severe forms of the disease has been estimated at 1/100 000.The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early loss of teeth without bone symptoms. Depending on the age at diagnosis, six clinical forms are currently recognized: perinatal (lethal), perinatal benign, infantile, childhood, adult and odontohypophosphatasia. In the lethal perinatal form, the patients show markedly impaired mineralization in utero. In the prenatal benign form these symptoms are spontaneously improved. Clinical symptoms of the infantile form are respiratory complications, premature craniosynostosis, widespread demineralization and rachitic changes in the metaphyses. The childhood form is characterized by skeletal deformities, short stature, and waddling gait, and the adult form by stress fractures, thigh pain, chondrocalcinosis and marked osteoarthropathy. Odontohypophosphatasia is characterized by premature exfoliation of fully rooted primary teeth and/or severe dental caries, often not associated with abnormalities of the skeletal system. The disease is due to mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL; OMIM# 171760) encoding the tissue-nonspecific alkaline phosphatase (TNAP). The diagnosis is based on laboratory assays and DNA sequencing of the ALPL gene. Serum alkaline phosphatase (AP) activity is markedly reduced in hypophosphatasia, while urinary phosphoethanolamine (PEA) is increased. By using sequencing, approximately 95% of mutations are detected in severe (perinatal and infantile) hypophosphatasia.Genetic counseling of the disease is complicated by the variable inheritance pattern (autosomal dominant or autosomal recessive), the existence of the uncommon prenatal benign form, and by incomplete penetrance of the trait. Prenatal assessment of severe hypophosphatasia by mutation analysis of chorionic villus DNA is possible. There is no curative treatment for hypophosphatasia, but symptomatic treatments such as non-steroidal anti-inflammatory drugs or teriparatide have been shown to be of benefit. Enzyme replacement therapy will be certainly the most promising challenge of the next few years.

Cellular function and molecular structure of ecto-nucleotidases

“…TNAP has been shown to hydrolyze the mineralization inhibitor PP i thereby maintaining proper bone mineralization [330]. Accordingly, mutations in the TNAP gene that cause impairment or loss of functional activity lead to hypophosphatasia in humans [486,487]. Similarly, TNAP knockout mice (Akp2−/−) accumulate extracellular PP i , reveal hypomineralization [488][489][490][491], and can serve as a model for the infantile form of hypophosphatasia [492].…”

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

“…17 Two more genes, the tissue-nonspecific alkaline phosphatase gene (ALPL, 1p36.12, OMIM# 171760) and human orthologue of the mouse progressive ankylosis gene (ANKH, 5p15.1, OMIM# 605145) have been implicated in calcium and ePPi/Pi homeostasis. [17][18][19] It should be mentioned that although the role of ENPP1 in energy metabolism and fat tissue physiology has been extensively discussed in the scientific literature, 20 the potential relevancy of its partners in bone mineralization, that is ANKH and ALPL, to adipose tissue and OB etiology has hardly been addressed.…”

Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers

“…Correlations of genotype and phenotype have been reported on the basis of clinical data of the patients with hypophosphatasia, enzymatic activity and computerassisted modeling. 2 We previously reported that the most and the second-most frequent mutations in Japanese patients are T1559del and F310L, respectively. 5 These mutations are renamed to c.1559delT and p.F327 L, respectively, based on the recent standardized nomenclature.…”