Family mapping of previously identified patients with pathogenic or likely pathogenic ALPL variants using predictive genotyping and detailed phenotyping approach: the FAME case-control study

Abstract

Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function variants in the ALPL gene, which encodes the tissue nonspecific isozyme of alkaline phosphatase (ALP). There is no typical phenotype in adults. We used a genotyping first approach to determine whether ALPL pathogenic variants were associated with musculoskeletal symptoms, mineral metabolism abnormalities, and an impact on quality of life. We recruited individuals with a pathogenic (or likely pathogenic) variant in ALPL gene (n = 26) and their relatives (n = 44). We performed genetic tests and compared the relatives with positive (n = 20) and negative (n = 24) genetic test. We applied standard questionnaires and physical tests (Brief Pain Inventory [BPI]; Western Ontario and McMaster Universities Arthritis [WOMAC]; Modified Hypophosphatasia Impact Patient Survey; Short Form of 36 Survey [SF-36]; and the Short Physical Performance Battery). In fasting blood samples, we measured creatinine, calcium, phosphate (P), parathyroid hormone (PTH), ALP, bone ALP, 25OHD-, 1,25(OH)2D, CTX, type 1 procollagen N-terminal peptide (PINP), osteocalcin, and tartrate-resistant acid phosphatase5b (TRACP5b). Relatives with positive genetic test had lower ALP (IU/L) [32.5(12.8) vs 87.8(32.6) p