Bone Abstracts

Background: Hypophosphatasia (HPP) is caused by inactivating mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). HPP is variable in clinical manifestations and prognosis, and is generally classified into six subtypes: perinatal lethal, perinatal benign (prenatal benign), infantile, childhood, adult, and odonto HPP. Although genetic test is broadly used for diagnosis of HPP, the genotype-phenotype relationship still remains unclear.

Objectives: We aimed to clarify the features of Japanese HPP and the relationship between ALPL mutations and the clinical manifestations.

Methods: We analyzed 98 unrelated Japanese patients of HPP, whose ALPL mutations had been identified in Osaka Women’s and Children’s Hospital, since 1996 to 2018. Novel mutations were characterized by transfection of the expression plasmids into COS-7 cells.

Results: Clinical classification of the 98 patients was as follows: 45 patients (45.9%) with perinatal lethal, 22 patients (22.4%) with perinatal benign, 12 patients (12.2%) with infantile, 3 patients (3.1%) with childhood, 1 patient (1%) with adult, and 14 patients (14.3%) with odonto HPP. There was 1 aborted patient (1%). Among the 196 ALPL alleles, c.1559delT was found in 89 alleles (45.4%) and was the most frequent. All of c.1559delT homozygotes were classified into perinatal lethal form. The second most frequent mutation was p.F327L and was detected in 23 alleles (11.7%). The third most frequent mutation was p.F327del (5 alleles; 5.1%). All of the 22 patients with perinatal benign HPP were compound heterozygous for ALPL mutations, and 19 out of them had p.F327L. The 1 adult form and 7 out of 14 patients with odonto HPP were positive for only one mutations, and we confirmed the dominant negative effects in some of the mutant proteins associated with autosomal dominant HPP.

Conclusion: More than 60% of Japanese HPP are perinatal onset. High frequency of perinatal benign HPP is characteristic. As we previous reported, c.1559delT is the most frequent mutation and p.F327L is the second most. The high prevalence of these mutations may underlie the high rate of perinatal lethal and perinatal benign HPP, respectively. Identification of ALPL mutations is beneficial for evaluation of severity and prediction of prognosis in Japanese HPP.

Disclosure: The authors declared no competing interests.