Hypophosphatasia: a clinically and genetically variable disease

Abstract

Hypophosphatasia (HPP) is a hereditary metabolic multisystemic disease whose main clinical characteristics are mineralization disorders of bones and teeth as well as muscle and joint pain. The clinical symptoms depend on the age of onset of HPP and are highly variable, both interindividually and within families. Six subtypes of HPP are defined, with fluent transitions. They range from the severe perinatal form, which was previously lethal owing to a lack of skeletal mineralization, to the adult form, with typical symptoms such as fracture healing disorders or stress fractures. Nonspecific symptoms, such as muscle pain and weakness, migraine or depression, can also be part of HPP. Although severe forms, with a prevalence between 1/100,000 and 1/300,000, are rare, mild forms of HPP are much more common. Perinatal and manifestations in early childhood are mostly inherited in an autosomal-recessive manner, whereas those with later onset are inherited in an autosomal-recessive or autosomal-dominant manner. HPP is caused by reduced or absent activity of the tissue-nonspecific alkaline phosphatase (AP), which is encoded by the ALPL gene. Laboratory testing of serum shows an age- and gender-specific low AP activity and a consecutive increase in AP substrates, e.g., pyridoxal‑5‐phosphate (PLP). Since the disease was first described in 1948, the diagnosis and treatment of HPP have improved dramatically. Four years ago, enzyme replacement therapy with asfotase alfa (Strensiq®) was approved for severely affected HPP patients with the onset of the disease before the age of 18 years. This article provides an overview of the broad clinical spectrum of HPP, pathophysiological background, laboratory and molecular genetic diagnostics, as well as current therapy options and their treatment indications.