2 The condition

2.1 Hypophosphatasia is a genetic disorder caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which reduce its activity. This causes disruption of mineralisation, a process in which calcium and phosphorous are deposited in developing bones and teeth. Several clinical forms of hypophosphatasia are currently recognised:

  • perinatal onset (onset before or at birth)

  • infantile onset (onset at 0–6 months)

  • juvenile onset (also referred to as childhood-onset; onset between 6 months and 17 years)

  • adult onset (onset at 18 years and over) and

  • odontohypophosphatasia (only dental symptoms).

    Paediatric-onset hypophosphatasia includes everyone with hypophosphatasia of perinatal, infantile, or juvenile onset.

2.2 The signs and symptoms of hypophosphatasia vary widely and can appear any time from before birth to adulthood. These include rickets, softening and weakening of the bones (osteomalacia), bone deformity and a greater incidence of fractures. Hypophosphatasia can also lead to chronic debilitating pain, muscle weakness, generalised seizures because of vitamin B6 deficiency, and renal and respiratory complications. The most severe forms of the condition tend to occur before birth and in early infancy. People who present with hypophosphatasia in the first 6 months of life (that is, people with perinatal- or infantile-onset disease) have a high mortality rate. About 50–100% of babies die within the first year of life, primarily because of respiratory failure. Juvenile-onset hypophosphatasia that develops later in childhood is associated with a substantially lower mortality rate than the form that appears in infancy, but is often debilitating and leads to bone deformities that may result in delayed walking, limb weaknesses, skeletal pain and non-traumatic fractures.

2.3 The prevalence of severe forms of hypophosphatasia is unknown in England. However, in Europe, the rate is estimated as 1 per 300,000 live births. Milder forms, in which signs and symptoms have a later onset, are more common and are estimated to be present in 1 per 6,370 of the population. The evidence submissions NICE received from the company and clinical experts estimated that between 1 and 7 people are diagnosed with perinatal- and infantile-onset hypophosphatasia each year in England.

  • National Institute for Health and Care Excellence (NICE)