Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults

[Background]: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. [Methods]: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77 yr) with unexplained low ALP levels. [Results]: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r = - 0.38, p = 0.012), pyridoxal phosphate (PLP; r = - 0.51, p = 0.001) and urine phosphoethanolamine (PEA; r = - 0.49, p = 0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p = 0.04), slightly lower levels of serum ALP (p = 0.002), higher levels of PLP (p < 0.0001) and PEA (p < 0.0001), as well as mildly increased serum phosphate (p = 0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. [Conclusion]: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.This work was supported by an unrestricted grant from Alexion.Peer Reviewe