Hypophosphatasia

Etienne Mornet

doi:10.1186/1750-1172-2-40

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.

Highlights

Genetic counseling of the disease is complicated by the variable inheritance pattern, the existence of the uncommon prenatal benign form, and by incomplete penetrance of the trait
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
Hypophosphatasia (OMIM 146300, 241500, 241510) is an inherited disorder characterized by defective bone and teeth mineralization and deficiency of serum and bone alkaline phosphatase (AP) activity

Summary

Cell membrane

Absence on cell surface protein lacking GPI; aggregation due to disulphide bonds beween new cystein residues. Class 1 represents the most severe mutations resulting in mutant proteins accumulated in the cytoplasm, subsequently degraded, and producing no in vitro residual activity These mutations affect residues of functional domains of the enzyme and were mostly found in patients with severe hypophosphatasia. Mutations of class 2 are accumulated in the cell but exhibit low but significant in vitro residual activity and could be degraded with delay These mutations, that do not affect particular functional domains of the protein, must be considered as severe alleles. Mutations of class 3 are in part accumulated in the cytoplasm and in part reach the cell membrane They exhibit high in vitro residual activity and except G438S, do not affect residues of functional domains. It is possible that the maternal alkaline phosphatase plays a role via fetal-maternal exchanges, as suggested by the prenatal benign form that seems to be observed only when the mutation is inherited from the mother [4,5,6]

Diagnostic methods

Fraser D

54. Rasmussen H

Findings

78. Antonarakis SE