Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum
alkaline phosphatase (ALP) activity and defective mineralization of bone, but the phenotype varies greatly in severity depending on the degree of residual
enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous
bone disease, who suffered numerous disabling fractures after he developed progressive
renal failure (for which he eventually needed dialysis treatment) and was prescribed
alendronate treatment. A bone biopsy showed marked
osteomalacia with low osteoblast numbers and greatly elevated
pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP
protein with almost no
enzyme activity; the second, G438S, produced a
protein with normal activity, but its activity was inhibited by raising the media
phosphate concentration, suggesting that
phosphate retention (attributable to
uremia) could have contributed to the phenotypic change, although a pathogenic effect of
bisphosphonate treatment is also likely.
Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with
teriparatide, which significantly reduced the
osteomalacia. Eighteen months after successful
renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (
bisphosphonate treatment) and physiologic (
renal failure) changes in the "environment" can dramatically affect the phenotype of a
genetic disorder.