Clinical, biochemical and genetic findings in adult patients with chronic hypophosphatasemia

Abstract

Purpose The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). Methods Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5’-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. Results Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive breast cancer. Mineral and bone markers were similar in the three groups. Mean urine PEA levels were significantly higher in patients harboring pALPL than those detected in patients harboring bALPL and wtALPL; by contrast, serum PLP levels were similar in the three groups. A 6-points score, considering clinical and biochemical features, was predictive of pALPL detection [P = 0.060, OR 1.92 (95% CI 0.972, 3.794)], and more significantly of pALPL or bALPL [P = 0.025, OR 14.33 (95% CI 1.401, 14.605)]. Conclusion In osteopenic/osteoporotic patients, single clinical or biochemical factors did not distinguish hypophosphatasemic patients harboring pALPL or bALPL from those harboring wtALPL. Occurrence of multiple clinical and biochemical features is predictive of ALPL anomalies, and, therefore, they should be carefully identified. Tamoxifen emerged as a hypophosphatasemic drug.

Pain and health-related quality of life in patients with hypophosphatasemia with and without ALPL gene mutations

“…Interestingly, in this study, we did not find differences in healthrelated quality of life scores in patients with or without pathogenic variants. This is also in line with previous reports showing similar levels of bone turnover markers and other biochemical parameters in patients with low alkaline phosphatase with or without ALPL pathogenic variants (10,19). Overall, both patient subgroups seem to be homogeneous and part of a similar disease spectrum, which would be consistent with the hypothesis that most patients with hypophosphatasemia of unknown cause may have an unidentified variant in ALPL.…”

“…Then, the diagnosis of hypophosphatasia can be confirmed by finding a pathogenic variant in ALPL . However, that only happens in about one-third to one-half of patients with low alkaline phosphatase without other obvious causes ( 8 – 10 ). The reason for the low enzyme activity in those patients is unclear.…”

“…However, this is not always the case. In several case series, in about one-third to one-half of patients with otherwise unexplained low alkaline phosphatase gene analysis does not reveal a causative genetic defect ( 8 – 10 ).…”

Do alkaline phosphatases have great potential in the diagnosis, prognosis, and treatment of tumors?

“…These polymorphisms can have implications for various biological processes and disease conditions ( 91 ). ALP isozyme polymorphisms, the ALPL gene encodes TNAP ( Table 2 ), mutations or single nucleotide polymorphisms in the ALPL gene can lead to different forms of TNAP with varying enzymatic activity and stability ( 92 ). Vitamin D plays a role in the regulation of ALP expression.…”

“…Vitamin D plays a role in the regulation of ALP expression. Polymorphisms in the vitamin D receptor ( VDR ) gene can affect ALP levels ( 92 ). For example, the FokI and BsmI polymorphisms in the VDR gene have been associated with ALP activity variations in different populations ( 93 ).…”