A two-year follow-up of asfotase alfa replacement in a patient with hypophosphatasia: clinical, biochemical, and radiological evaluation

Abstract

Hypophosphatasia (HPP) is a rare disease with a high mortality rate in its severe forms. It is caused by mutations within the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme responsible for bone mineralization. In 2015, the Food and Drug Administration approved the use of asfotase alfa, the first medication showing benefit in the treatment of HPP. We describe a case with a 2-year follow-up of the first Brazilian child treated with asfotase alfa. A 5-year-old boy, born to consanguineous parents, was diagnosed with HPP at the age of 20 months. During prenatal ultrasonography, polyhydramnios and shortening of long bones were detected. After birth, he presented delayed motor development, repeated respiratory infections, and bone deformities. At the age of 2 years and 8 months, he started walking and had already lost his primary teeth. He had reduced levels of alkaline phosphatase (ALP), elevated levels of pyridoxal 5'-phosphate (PLP), and a p.Ala33Val (c.98C>T) missense mutation in homozygosis in the TNSALP gene. His parents and sister also had reduced ALP levels, high PLP levels, and the same mutation in heterozygosis. His father and sister were healthy, and his mother was diagnosed with rickets in childhood, which resulted in short physical stature and lower limb deformities. The patient was started on asfotase alfa at the age of 2 years and 10 months. After 2 years of treatment, he improved his motor skills, had no further episodes of severe respiratory infection, and showed improved radiological findings of rickets, without any severe side effect.

Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia

“…His mother (36-year-old) was diagnosed with rickets in her childhood while his father had no history of fractures bone deformity or other clinical abnormalities observed. A homozygous c.98C>T (p.Ala33Val) missense mutation in the TNSALP gene was identified (19).…”

Case Report: Efficacy of Reduced Doses of Asfotase Alfa Replacement Therapy in an Infant With Hypophosphatasia Who Lacked Severe Clinical Symptoms

“…The involvement of phosphatonin insufficiency in patients with HPP is supported by the results of a recent study indicating a low level of fibroblast growth factor 7 (a potent phosphatonin) in pediatric patients with HPP (29). Furthermore, the initial changes of serum phosphate levels in response to AA therapy can either increase or decrease (20); these values typically normalize with treatment, but continued hyperphosphatemia related to AA therapy is regarded as an adverse effect (9), which may lead to worsening of craniosynostosis (30). In our patient, serum phosphate levels remained above the upper limit of the reference range throughout the study, regardless of the use of AA therapy.…”

Dental loss, stress fractures, and musculoskeletal pain in a 48‐year‐old woman

“…Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and low serum and bone alkaline phosphatase. [1][2][3] Severe cases include stillbirth without mineralized bone while milder cases include recurrent fractures of the lower extremities or premature tooth loss in adulthood. Perinatal and infantile hypophosphatasia are inherited in an autosomal recessive manner in which both parents contribute one copy of the mutated gene while adult/milder forms can be inherited in an autosomal dominant or recessive manner where only one copy of the mutated gene is needed for the person to show symptoms.…”

“…Dental findings and medical history are all consistent with the diagnosis of juvenile onset hypophosphatasia. Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and low serum and bone alkaline phosphatase 1–3 . Severe cases include stillbirth without mineralized bone while milder cases include recurrent fractures of the lower extremities or premature tooth loss in adulthood.…”