A Japanese single-center experience of the efficacy and safety of enzyme replacement therapy in childhood-onset hypophosphatasia

BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The phenotype of HPP is widely diverse from the perinatal severe form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to impaired development of the lungs and severe hypomineralization of the bones. Enzyme replacement therapy (ERT) using asfotase alfa was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of ERT experience in ten cases of childhood-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 years [7.6–12.5] years; 60% male). This is the largest study of a single-center cohort describing the clinical course of HPP patients treated with ERT in Asia. ResultsOne case of perinatal lethal form of HPP, two cases of perinatal benign form, six cases of childhood form, and one case of odontohypophophatasia were observed. The most common symptom at onset was bone abnormalities. All patients had low serum ALP levels as compared to the age-matched reference range before the commencement of ERT. All HPP patients responded to ERT without serious adverse effects. Genetic analysis showed that eight out of ten patients had compound heterozygosity; two patients had only one heterozygous variant. In this study, two patients had a heterozygous variant of ALPL and responded to ERT, although the variants did not have the dominant-negative effect. ConclusionsERT may be effective in patients with symptoms of HPP even with only one pathogenic variant of ALPL without dominant-negative effect. Early diagnosis based on symptoms such as bone abnormalities or low serum alkaline phosphatase levels might be essential for early treatment and can contribute to better prognosis.