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.

The human tissue nonspecific alkaline phosphatase (TNAP) is found in liver, kidney, and bone. Mutations in the TNAP gene can lead to Hypophosphatasia, a rare inborn disease that is characterized by defective bone mineralization. TNAP is 74% homologous to human placental alkaline phosphatase (PLAP) whose crystal structure has been recently determined at atomic resolution (Le Du, M. H., Stigbrand, T., Taussig The alkaline phosphatases (EC 3.1.3.1) (APs) 1 form a large family of dimeric enzymes common to all organisms. They catalyze the hydrolysis of phosphomonoesters (1) with release of inorganic phosphate. Mammalian APs have low sequence identity with the Escherichia coli enzyme (25-30%), although the residues involved in the active site of the enzyme and the ligands coordinating the two zinc atoms and the magnesium ion are largely conserved. Therefore, the catalytic mechanism deduced from the structure of the E. coli AP is believed to be similar in eukaryotic APs (2). This mechanism involves the activation of the catalytic serine by a zinc atom, the formation of a covalent phosphoseryl intermediate, the hydrolysis of the phosphoseryl by a water molecule activated by a second zinc atom, and the release of the phosphate product or its transfer to a phosphate acceptor (3).In humans, three out of four AP isozymes are tissue-specific: one is placental (PLAP), the second appears in germ cells (GCAP), and the third in the intestine (IAP). They are 90 -98% homologous, and their genes are clustered on chromosome 2q37.1. The fourth, TNAP, 50% identical to the other three, is nonspecific and can be found in bone, liver, and kidney (4, 5, 6). Its gene is located on chromosome 1p34 -36 (7), and mutations in the TNAP gene have been associated with hypophosphatasia, a rare inherited disorder, characterized by defective bone mineralization. The disease is highly variable in its clinical expression, due to the strong allelic heterogeneity in the TNAP gene. Such expression ranges from stillbirth without mineralized bone to pathological fractures developing only late in adulthood (8). Depending on the age of onset, five clinical forms are currently recognized: perinatal, infantile, childhood, adult, and odontohypophosphatasia. To date, 89 different mutations associated with this disease have been characterized (9 -22). Correlation between genotype and phenotype are difficult to establish, because most patients are compound heterozygous for missense mutations, making difficult the determination of the respective roles of each mutation.This difficulty arises mainly from the lack of data concerning the precise role that TNAP plays in bone mineralization. This may be partly solved by the use of site-directed mutagenesis of TNAP cDNA and cell transfection to assay residual activity of the mutant AP enzyme (16,18,20,(23)(24)(25). However, this only measures the ability of the enzyme to hydrolyze phosphomonoesters. Transfection assays cannot distinguish structural mutations from functional ones, and mutations that exhibit residual activi...

The study of family members underlines the variable expression of NC-CAH even within a family, suggesting that modifier factors may modulate phenotype expression. Post-ACTH 21dF cannot reliably detect heterozygous subjects. Considering the high frequency of heterozygotes in the general population, it is essential to genotype the partner(s) of the patients with one severe mutation to offer genetic counseling.