Abstract
ABSTRACTHypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic‐based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10‐year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss‐of‐function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Highlights
Hypophosphatasia (HPP) is a rare inherited disorder characterized by low circulating concentrations of total alkaline phosphatase (ALP), rickets, muscular hypotonia, seizures, and multiple fractures.[1]
Eight individuals with low ALP had been treated with bisphosphonates before being referred to the clinic (6 with alendronic acid and 2 with risedronate), but serum ALP levels were low in 7 of these individuals before starting bisphosphonates
We have found that about 0.5% of patients attending our osteoporosis clinic had low circulating concentrations of ALP and that the majority of these individuals had pathogenic mutations in n 4 ALONSO ET AL
Summary
Hypophosphatasia (HPP) is a rare inherited disorder characterized by low circulating concentrations of total alkaline phosphatase (ALP), rickets, muscular hypotonia, seizures, and multiple fractures.[1]. HPP, the proportion of dominant mutations, and the penetrance of the ALPL mutations,(2) one would expect about 1 in 500 individuals in the general population to be carriers, it is unclear to what extent these individuals are symptomatic.[9] The ALPL gene encodes the tissue-nonspecific ALP, a 50 kDa protein expressed in bone, liver, and kidney In bone, it is essential for the mineralization process, because it hydrolyzes pyrophosphate, an inhibitor of hydroxyapatite formation and, at the same time, releases inorganic phosphate, which combines with calcium to promote mineralization.[10] To date, at least 397 variants have been described in this gene as causing HPP (as reported in The Tissue Nonspecific Alkaline Phosphatase Gene Mutation Database).(11) Most are missense mutations found in homozygous or compound heterozygous form. Low-frequency, heterozygous missense variants in ALPL have been observed in men with low bone mineral density[12] and at low frequency in adults with various rheumatologic disorders, including osteoarthritis, rheumatoid arthritis, Castleman disease, and patients with recurrent fractures.[13]
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