Hypophosphatasia (HPP) is an ultra-rare, life-threatening metabolic disease whose molecular cause is well characterized.
Due to a genetic defect, patients with HPP are deficient in an enzyme known as tissue non-specific alkaline phosphatase (TNSALP).
Without this enzyme, patients experience life-long abnormalities in phosphate and calcium mineral metabolism, which leads to progressive
damage to vital organs with destruction and deformity of bones, debilitating muscle weakness, refractory seizures, impaired renal function,
and respiratory failure.1,2,3,4
HPP affects people of all ages. Tragically, about one-half of newborns with HPP do not survive past one year of age.1
Pathophysiology of HPP
Clinical Presentation and Outcomes
The clinical presentation and outcomes of HPP are remarkably varied, and the severity of the disease typically reflects the age
at which symptoms first appear.5 The most severe and life-threatening form presents in the perinatal or infantile period, leading to a
profound lack of bone mineralization and compromised respiratory function that can lead to death. Osteomalacia (soft bones), a debilitating,
crippling and sometimes progressive complication of HPP, occurs in adults, in addition to progressive damage to multiple vital organs.1,2,3,4
Morbidity is cumulative and can worsen with age.
Given the broad range of symptoms at presentation, the index of suspicion for HPP may be low for many physicians. Physicians typically
diagnose HPP in patients who have evidence of bone destruction or deformity plus an abnormally low level of TPAN in the blood. Patients may
also show evidence of HPP in their urine. Laboratory tests for the following clinical markers can aid in diagnosis of HPP:
- Alkaline Phosphastase: HPP is characterized by subnormal levels of alkaline phosphatase (ALP) in the blood. Clinicians should suspect HPP if ALP is at or below the lower range of normal. In general, the lower the age-adjusted serum ALP level, the more severe the clinical symptoms of HPP.
- Pyridoxal 5’-phosphate (PLP):Increased PLP level in the blood is the most sensitive substrate marker for HPP, and it often correlates with disease severity.
- Urinary inorganic pyrophosphate (PPi): PPi levels are elevated in most HPP patients and have been reported to accurately detect carriers, although this is typically only used in research.
- Phosphoethanolamine (PEA): Increased levels of PEA are observed in most HPP patients’ urine.
In addition to laboratory tests, radiography can be useful in diagnosing HPP and revealing characteristic abnormalities in newborns, infants, and adults.
Mutation analysis is also available in several laboratories (available on www.genetests.org).
An up-to-date list of mutations is available at www.sesep.uvsq.fr/database_hypo/Mutation.html.