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

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BackgroundLow 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. MethodsIn order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20–77yr) with unexplained low ALP levels. ResultsNine 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. ConclusionOne-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.