ALPL genotypes in patients with atypical femur fractures or other biochemical and clinical signs of hypophosphatasia

Context: Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in patients with HPP, substantially increase the risk of atypical femur fractures (AFFs) and worsen the fracture healing process that is usually already compromised in these patients. Objective: Performing ALPL genetic testing to identify rare variants in suspected adult patients with HPP. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. Methods: Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Patients included were from 3 main European Bone Units (Florence, Naples, and Geneva); 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP were included. Results: Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity. Conclusion: The results suggest homozygosity of common ALPL variants as a possible genetic mark of risk for these fractures. Key Words: hypophosphatasia, tissue nonspecific alkaline phosphatase (TNSALP), ALPL gene, rare variants, common variants, atypical femur fracture (AFFs) Abbreviations: AFF, atypical femur fracture; ALP, alkaline phosphatase; BMD, bone mineral density; HPP, hypophosphatasia; TNSALP, tissue nonspecific alkaline phosphatase.