What is Hypophosphatasia?

Hypomineralisation of the bone associated with the impaired activity of the tissue- non-specific alkaline phosphatase (TNSALP). TNSALP is one of the isoenzymes of alkaline phosphatase (ALP), also known as liver/bone/kidney ALP. Different versions of the same emzyme are known as isoenzymes. They can be regulated slightly differently. They have different activity and are found in different parts of the body. Alkaline phophatase is one of these.

Alkaline phophosphate. EC Number code: E.C. (like a catalogue code). Alkaline phophatase is either of bacterial or mammilian origin. All Alkaline phosphatases catalyse the hydrolysis of phosphomonoesters (this is the substrate molecule). On hydrolysis there is a alcohol and phosphate release (these are the products). Alkaline phosphatase is dimeric (2-sub units). In humans there are four versions of Alkaline phophatase. Three of these are non-tissue specific, these include: 1)Placental (PALP), 2) Germ cell (GCAP) and Intestinal. The fourth Alkaline phosphatase is non-tissue specific. It is found in bone, liver and kidney. This non-tissue specific version is fifty per cent indentical with the other three and is the only one of the four that is found in bone.

Non specific alkaline phosphatase is the only isoenzyme that is mutated. It’s funtion ordinarily involves specific binding to collagen via the hydrolysis reaction mentined earlier. When mutated the ezymic funtion of alkaline phosphatase is impaired. The mechanism of bone mineralisation (pathway of bone mineralision) and the role of TNSALP is not yet known. Hypophosphatasia usually arises as a recessive genetic defect caused by mutations in the gene for alkaline phosphatase. This Alkaline phosphatase gene is located on the short arm of chromosome one.

Approximately fifty mutations, of this gene have been identified. These include: missense, deletion of codon and a deletion of a nucleotide with frame shift of complementary DNA, as well as three mutations in introns affecting splice sites. But the number of mutations is increasing all the time. The most recently reported cases include ten missense mutations reported from North America and seven new mutations in Japanese patients.

The mutations that occur either elicit a Dominant effect or a recessive effect. Dominant alleles (all alleles being one of a pair of homologous genes), give rise to mild type Hypophosphatasia. Where the homologous recessive genotype gives rise to more serious types of Hypophosphatasia such as the lethal type. The lethal type: Mutant TSNALP form disulphide bonds to form high molecular mass aggregates. These aggregates rapidly degrade within the cell. Analysis of the 3D model of the enzyme showes that mutations exhibiting a dominant effect were clustered in two regions ( the active site and an area probably interacting with a region having a particular biological function such as dimerisation, tetramerization or membrane anchoring).

The relationships between genotype and phenotype in Hypophosphatasia have been studied. Biological funtional levels are dependant on the extent to which the mutations result in impaired plasma membrane anchoring. The direct result of this is the level of enzymic activity that occurs. Activity levels govern the different protein domains (funtional parts of the protein that are left after mutation) being used and hence to what extent the surface expression is lost from the protein. ALP mutants with complete loss of enzymatic activity may be related to the most severe form of the disease. However, the relationship between the diversity involving the severity of the disease and site of mutation remains to be studied, especially in relatively mild forms.

Enzymic activity levels can be linked to the Hypophosphatasia sub-group (sub-groups have been discussed in the beginning of the report). A low amount of activity is linked to the autosomal recessive trait. This corresponds to the most severe forms of the disease (includes lethal forms), namely Perinatal and Infantile. A greater activity level is linked to the dominant/recessive alleles and these constitute the milder adult and childhood forms.

One point mutation, which converts glycine-317 to aspartate of tissue- non-specific alkaline phosphate, is associated with lethal Hypophosphatasia (this point mutation is passed on in the recessive allele of the gene). Biosynthesis of TNSALP with a GLY317 to Asp resulted in no alkaline phosphate activity in the resultant mutant TNSALP at all. This suggests that the replacement of glycine-317 with aspartate abolishes the catalytic activity of TNSALP.

With the milder forms of the disorder it is difficult to say whether the phenotype is caused by the dominant or the recessive allele and in terms of genetic counselling, distinguishing between the two is important. There is no known overall established cure for the different forms of Hypophosphatasia but possible treatments do exist for some of the forms.


Adult form; Marrow transplantation in the hope of promoting osteoblast formation containing ALP. This induces clinical improvement but there is no correction of biochemical abnormalities. Immunosupressents in combination with this can cause improvements. Child form; Physicians/ Parents are tempted to give their children Vit. D supplements since Hypophosphatasia is a form of rickets. However there is deficiency of Vit. D in the disorder. This added Vit. D could bring in excess calcium leading to crystal deposition outside the skeleton even the formation of kidney stones.

Infant form; A few physicians feel that injections of natural hormone calcitonin blocks bone breakdown. This may help to control high blood calcium levels; this keeps that skeleton from dissolving with severe Hypophosphatasia, in infant children. A water pill (diuretic), was thought to be helpful in one child. Pseudofractures may need to heal by having a steel rod pushed through hollow centres of bone.

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