Hypophosphatasia is a rare, inherited, progressive metabolic disorder. In its most severe form, it is an ultra-rare disease, occurring in approximately 1 in 100,000 live births and is characterized by defective bone/tooth mineralization, weakness, seizures, respiratory failure, and premature death.
2 Less-severe forms of the disease occur more frequently, although still uncommonly.
3 In a natural history study, infants who had their first symptom of hypophosphatasia within the first 6 months of life had an overall mortality rate of 73% at 5 years, primarily due to respiratory failure.
4
Hypophosphatasia is caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP or TNAP).
3, 5 Marked reduction in alkaline phosphatase activity results in elevated circulating serum levels of inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate (PLP; the principal circulating form of vitamin B6), and elevated urine levels of PPi and phosphoethanolamine (PEA), all molecules presumed to be substrates of TNAP.
6 High extracellular levels of PPi block hydroxyapatite crystal growth, resulting in impaired bone/tooth mineralization and rickets-like symptoms;
5 severely affected patients can develop hypercalcemia and hyperphosphatemia.
5 The derangement in vitamin B6 metabolism can result in pyridoxine-responsive seizures.
5 Hypomineralization of the ribcage (“rachitic chest”) results in hypoinflation of the lungs and respiratory failure.
3
Hypophosphatasia can manifest as neonatal death with almost no skeletal mineralization to dental problems in adults without any bone symptoms. The disease has generally been classified according to patient age when the first signs and symptoms manifest; six clinical forms are currently recognized (Table 1). These clinical subtypes can overlap, e.g., infantile and childhood hypophosphatasia share some clinical symptoms, and patients with adult hypophosphatasia often had some clinical symptoms already in childhood.
3 Oral manifestations characteristic of various forms of hypophosphatasia can include early loss of deciduous teeth, severe dental caries, improperly formed teeth, and alveolar bone loss.
3
Table 1. Clinical Forms of Hypophosphatasia (adapted from Mornet 20073)
Clinical Form (Inheritance) |
Bone/Dental Symptoms |
Perinatal lethal (AR) |
Bone:
- hypomineralization
- osteochondral bone spurs
Dental: N/A
|
Perinatal benign (AD) |
Bone:
- bowing of long bones
- benign postnatal course
Dental: N/A
|
Infantile (AR; first symptom 6 months of age or younger) |
Bone:
- craniosynostosis
- hypomineralization
- rachitic ribs
- hypercalciuria
Dental:
- premature loss of deciduous teeth
|
Childhood/Juvenile (AR [frequent] or AD [rare]; first symptom younger than 18 years of age7) |
Bone:
- short stature
- skeletal deformity
- waddling gait
- bone pain/fractures
Dental:
- premature loss of deciduous teeth
|
Adult (AR or AD) |
Bone:
- Stress fractures: metatarsal, tibia
- Osteoarthritis
Dental: Symptoms may be present or absent
|
Odontohypophosphatasia (AR or AD) |
Bone:
Dental:
- exfoliation (incisors)
- reduced dentin thickness
- enlarged pulp chambers
- caries
|
AD: autosomal dominant; AR: autosomal recessive; N/A: not applicable;
Oral manifestations characteristic of various forms of hypophosphatasia can include early loss of deciduous teeth, severe dental caries, improperly formed teeth, and alveolar bone loss.
3, 8, 9
Enzyme-Replacement Therapy for Hypophosphatasia. Asfotase alfa (Strensiq
®, Alexion Pharmaceuticals, Inc.) is the first agent approved for the treatment of perinatal, infantile, and childhood-onset forms of hypophosphatasia.
2, 5, 10 A recombinant form of TNAP, asfotase alfa is intended to enhance deficient alkaline phosphatase enzyme activity in patients with these forms of hypophosphatasia.
2, 10 Safety and efficacy of asfotase alfa were established in patients with perinatal, infantile- or juvenile-onset hypophosphatasia who received treatment for up to 6.5 years during four prospective, open-label studies.
2, 5, 10 Results showed that patients with perinatal- and infantile-onset hypophosphatasia treated with asfotase alfa had improved overall and ventilator-free survival compared with historical controls; patients with the juvenile form of the disease showed improvements in growth and bone health compared to control patients selected from a natural history database.
Asfotase alfa is administered as a subcutaneous injection (3 to 6 injections per week) in weight-based dosing regimens.
10 Warnings and precautions include hypersensitivity reactions, lipodystrophy at injection sites (i.e., abnormal thickening or thinning of the skin), and ectopic calcifications in the eye and kidneys.
10 The most common adverse reactions occurring in 10% or more of patients include injection site reactions, lipodystrophy, ectopic calcifications, and hypersensitivity reactions.
10