Hypophosphatasia

Michael P. Whyte, MD

II. History

In 1923, an English chemist, Robert Robison, discovered a new enzyme that is plentiful in cartilage and in bone in animals.  Especially high levels were found in animals with rickets.  Robison demonstrated that this enzyme released phosphate from sugars containing phosphate.  Because this enzyme released phosphate especially well in alkaline (non-acid) solutions, he called the enzyme alkaline phosphatase (ALP).  He speculated that ALP released phosphate in solutions bathing cartilage and bone tissue so that phosphate could combine with calcium to form crystals of calcium-phosphate (hydroxyapatite) to mineralize the skeleton (the skeleton is very much like fiberglass: calcium-phosphate crystals are the glass; collagen is the fiber).

By the 1930s, chemists found that ALP could be measured in blood (serum). Patients with bone or liver disease were found to have high levels of serum ALP, reflecting ALP release into the blood from diseases in these tissues, including rickets, hepatitis, etc..  Ever since, measurement of serum ALP has been a common laboratory procedure used to screen for bone or liver disease.

In 1948, a young Canadian physician, John Rathbun, was referred an infant who had inexplicably developed rickets, but had low (not high) ALP levels in blood.  The child died soon after.  Rathbun found no ALP in bone or liver at autopsy.  He called this new disease "hypophosphatasia" (meaning low ALP levels).

To date, about 300 cases of hypophosphatasia have been reported in the medical literature.  By the 1950s hypophosphatasia was recognized in siblings and, therefore, was likely inherited (rather than due to an infection, malnutrition, etc.).  In 1952, chemists discovered that hypophosphatasia patients had high levels of phosphoethanolamine (PEA) in their urine.  Because PEA contains phosphate, PEA seemed to be a substrate for ALP.  The purpose of PEA in the body was not understood, but PEA measurements served as a chemical "marker" for hypophosphatasia.

In the 1960s, inorganic pyrophosphate (PPi) was also found in high levels in urine and blood in hypophosphatasia.  It too seems to be an ALP substrate.  This was an important discovery because PPi is known to inhibit the formation of calcium-phosphate crystals.  PPi accumulation in skeletal fluids (because of low ALP) could explain why patients with hypophosphatasia do not mineralize their skeletons properly.

In 1985, we found very high levels of pyridoxal 5'-phosphate (PLP) - a form of vitamin B6 - in the blood of hypophosphatasia patients.  PLP seems to be the third natural substrate for ALP.  By knowing how PLP is processed in the body, this discovery showed that ALP functions not inside of cells, but on cell surfaces.

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