Hypophosphatasia is a rare, inherited metabolic disorder that affects the bones and teeth by disrupting a process called mineralization.
During mineralization, calcium and phosphorus are deposited in the bones and teeth to strengthen them. In hypophosphatasia, disruption of this process means the bones become soft and weak, which leads to skeletal abnormalities. The most severe forms of hypophosphatasia develop before birth or during early infancy. Infants born with the condition have short limbs, soft skull bones and abnormally formed ribs. Other complications may include difficulty feeding, poor weight gain, breathing problems and hypercalcemia, which can cause recurrent vomiting and kidney dysfunction.
Hypophosphatasia that develops during childhood or adulthood rather than infancy tends to be less severe. In children, the first symptom is often loss of primary (baby) teeth. Other characteristics of the disorder include an abnormally shaped skull, bowed legs and short stature. In affected adults, the condition is characterized by a softening of the bones referred to as osteomalacia, which can lead to repeated fracturing of bones in the thighs and feet and chronic pain. Adults may also lose their teeth prematurely and find that their joints become painful and inflamed.
Hypophosphatasia arises as a consequence of low levels of an enzyme called alkaline phosphatase (ALP). An enzyme is a protein that metabolizes other chemicals (substrates) so that they can be used by the body. In healthy individuals, ALP is present in large amounts in the bones and liver. However, in hypophosphatasia, mutation of the gene that codes for ALP leads to the production of ALP that is inactive. This gene is called the tissue nonspecific alkaline phosphatase gene (ALPL or TNSALP).
As a result, a number of substrates that are usually metabolized by ALP accumulate in the body and can be detected in large amounts in the blood and urine. Three critical substrates metabolized by ALP are pyridoxal 5/-phosphate (PLP or vitamin B6), inorganic pyrophosphate (PPi) and phosphoethanolamine (PEA). As a consequence of these substances accumulating in the body, biochemical abnormalities occur that lead to systemic disease pathology and these are described in more detail below.
When ALP activity is low, PLP accumulates and fails to move into the central nervous system because it requires dephosphorylation by ALP to do this. This results in neurologic PLP deficiency and related vitamin B6-responsiveness seizures. These effects are worsened by irregular skull shape (craniosynostosis) and increased cerebral spinal fluid (CSF) pressure.
PPi inhibits the mineralization of bone. Low ALP activity leads to PPi building up and disrupting the mineralization process and therefore bone formation and stability. This can lead to debilitating and painful recurring fractures that tend not to heal easily. Impaired deposition of calcium into bone increases the concentration of calcium in the blood and urine, which is associated with nephrocalcinosis and a risk of renal failure. Impaired mineralization of the ribs leads to pulmonary hypoplasia and respiratory problems. A high level of PPi also leads to the deposition of calcium pyrophosphate dihydrate which can cause rheumatologic disease, pain and inflammation.
The accumulation of PPi and PLP can therefore lead to life-threatening skeletal and systemic complications.
This amino acid derivative is used to form some phospholipids. Accumulating PEA is a diagnostic marker of hypophosphatasia, but how it contributes to the pathology of this disorder is not yet fully understood.
Forms of hypophosphatasia that develop as severe perinatal or infantile conditions are inherited in an autosomal recessive pattern, which means a mutated copy of the ALPL gene needs to be inherited from each parent if the disorder is to develop. Some of the more mild forms that develop during childhood may be inherited in this way or in an autosomal dominant pattern, where only one mutated copy of the ALPL gene needs to be inherited for the disorder to develop. Hypophosphatasia that develops during adulthood is typically inherited in an autosomal dominant pattern, although the pattern may be autosomal recessive in some rare cases.