Initially recognized by Rathbun in 1948, hypophosphatasia is a rare inborn error of metabolism caused by mutations in the gene encoding tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).  TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. Alterations in the TNSALP gene lead to low alkaline phosphatase activity levels and ultimately to rickets, osteomalacia, or both, which characterize this disorder. Incidence has been estimated at 1 case per 100,000 live births. Clinical presentation varies widely, from death in utero to cases in which pathologic fractures first present in adulthood.
At least 6 clinical forms of hypophosphatasia have been reported, although form assignment is often challenging as the age when skeletal lesions are discovered determines the type, and less severe bone lesions may be missed for years, until a radiograph is obtained for chronic pain or a pathological fracture. Because hypophosphatasia is often misdiagnosed, patients considered to have an adult form may have had signs of the disease earlier in life but were not diagnosed with hypophosphatasia.
The types include perinatal (lethal), infantile, childhood, and adult. Two other forms include odontohypophosphatasia (no clinical changes in long bones are present, only biochemical and dental manifestations) and pseudohypophosphatasia. The latter is clinically indistinguishable from infantile hypophosphatasia, but serum alkaline phosphatase (ALP) activity is normal. Pseudohypophosphatasia has been suggested as a possible consequence of a mutant TNSALP gene that still has activity in vitro but not in vivo. Conversely, in these patients, phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal-5'-phosphate (PLP) levels are elevated in serum and urine despite normal or elevated alkaline phosphatase activity levels.
Patients may present with varying signs and symptoms, history, and inheritance patterns. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is variable. Analysis of the TNSALP gene aids prenatal diagnosis. Compound heterozygosity and autosomal dominant mutations in the TNSALP gene may cause childhood and adult hypophosphatasia. At least 2 mutations occur in specific populations and are lethal when homozygous: c.1559delT affects Japanese patients and gly317asp is found in a Canadian Mennonite population.
Alkaline phosphatase is present as 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. TNSALP is known to cleave the phosphate-containing substrates PLP, PEA, and PPi, which are all extracellular substrates. The TNSALP gene is located on chromosome 1p36.1 and consists of 12 exons distributed over 50 kb. More than 250 distinct mutations have been described for this gene, the vast majority (79%) of which are missense mutations.
Patients with hypophosphatasia have low alkaline phosphatase activity levels, which leads to increased PPi, an inhibitor of hydroxyapatite crystal formation. The increase in PPi causes defects in calcium and phosphate balance.
Incidence of the severe form is believed to be approximately 1 case per 100,000 live births.  In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns.
International incidence is unknown. It appears that the disease is more prevalent in Japan and in a specific Mennonite population in Canada.
The most severe cases are lethal. The mortality rate in infants with hypophosphatasia is 50% in patients who manifest within 6 months of birth. The most common cause of death in infants with hypophosphatasia is respiratory complications.
Individuals with less severe disease can reach adulthood, although often with significantly increased morbidity. Children with hypophosphatasia often have rachitic deformities, and adults may have increased morbidity from poorly healing stress fractures and may be severely affected and not able to ambulate. Commonly, patients experience premature loss of dentition. Patients may also present with nephrocalcinosis, neurological damage secondary to vitamin B-6–respondent seizures, increased intracranial pressure secondary to craniosynostosis, and joint problems secondary to calcium deposits. Adults may present with severe mobility impairment (about 23% require the use of a wheelchair; about 25% require the use of a walking device) On the other side of the spectrum, adults may be diagnosed incidentally after a low alkaline phosphatase level is detected.
Hypophosphatasia occurs in all races.
Males and females are equally affected.
Hypophosphatasia affects all age groups; however, the severity of the disease in general varies with age, from a lethal disorder in neonates to a less severe condition in some adults.
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