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Disease Overview

Hypophosphatasia (HPP) is a rare, genetic (inherited), metabolic disease characterized by impaired mineralization (“calcification”), the process that hardens and strengthens bones and teeth. HPP can affect males and females of all ages and include signs and symptoms beyond bones and teeth, including muscular, renal (relating to the kidneys), respiratory, neurological (relating to the brain, spinal cord, or nerves), and others. Patients may present with symptoms that affect one or more of these areas. New symptoms can appear at any age and worsen over time and can cause significant disability.

When signs and symptoms are present before 6 months of age, HPP is referred to as perinatal/infantile-onset and can be fatal. All patients, including those whose signs or symptoms are not recognized until childhood or adulthood, may experience significant disease burden that impacts their daily life, including the ability to perform daily tasks or walk. For example, infants may experience life-threatening symptoms such as respiratory problems and seizures, while older patients may experience muscle weakness, musculoskeletal pain, limited mobility, fractures/pseudofractures, and other signs and symptoms.

People born with HPP are not able to make enough of an enzyme called alkaline phosphatase (ALP). When ALP functions normally, it allows calcium and phosphate to bind together to form healthy, strong bones. In people with HPP, age- and sex-adjusted ALP levels are low, which can cause calcium and phosphate to build up in other places throughout the body, damaging organs. ALP is low in HPP because of a defect, or mutation, in the ALPL gene that is responsible for making ALP. There are over 400 different mutations of the ALPL gene that have been identified, which contributes to the variability in clinical signs and symptoms of HPP that are observed. A parent may or may not show symptoms of the disease and may pass it on to their children. If you are diagnosed with HPP there is a chance other family members may be affected as well.

HPP Diagnosis

Once a person shows signs and symptoms of HPP, a full clinical assessment and blood test for low ALP can help lead to a correct diagnosis. Elevated serum pyridoxal 5'-phosphate (PLP or vitamin B6) or urinary phosphoethanolamine (PEA) can help confirm the diagnosis but may not be elevated in all patients. Genetic testing may also be helpful in confirming HPP, however negative or inconclusive results do not rule out a diagnosis of HPP.

However, since HPP is rare (1 case per 300,000 people with perinatal/infantile-onset HPP with potentially higher rates in older patients) and has broad symptoms that may overlap with other more common diseases it can be difficult to diagnose. While HPP is frequently diagnosed during childhood, it may not be diagnosed until adulthood in some patients, even though patients may have had symptoms of the disease for years.

Misdiagnosis of HPP is common and can lead to treatments that worsen symptoms. Infants and children are often misdiagnosed with nutritional rickets or osteogenesis imperfecta. Additionally, children may also be misdiagnosed with X-linked hypophosphatemia. Misdiagnoses in adults may include osteoporosis, osteoarthritis, pseudogout, or periodontal disease. Differences in laboratory values are important when diagnosing and differentiating HPP from other related disorders.

Diagnosis of HPP may be based on:
  • Low age- and sex-adjusted serum ALP activity level
  • ALP substrate testing:
    • Pyridoxal 5’-phosphate (PLP, vitamin B6)
    • Phosphoethanolamine (PEA)
  • Family history of siblings or parents with HPP
  • Physical therapy evaluation
  • Tests that assess physical functioning (6-minute walk testa, chair rise testb, etc.)
  • Radiologic exams
  • Skeletal and/or dental symptoms
  • Systemic signs and symptoms (neurological (relating to the brain, spinal cord, or nerves), renal (relating to the kidneys), respiratory, muscular, rheumatologic (relating to the immune system))

It is important to note that normal ranges for serum ALP activity are higher in infants, children, and adolescents than they are in adults. Laboratories vary in their age- and sex-adjusted reference ranges; therefore, serum or plasma ALP activity must be interpreted based upon laboratory-specific reference ranges.

aThe 6-minute walk test is a test used in adults with HPP that measures how far they can walk on a hard, flat surface for 6 minutes.
bThe chair rise test is a test used in adults with HPP that measures the time it takes to stand 5 times without using arms.

Health Management Strategies

Historically, management of HPP was aimed at address symptoms (eg, pain) and the skeletal, dental, or systemic signs and symptoms. There have been various attempts at managing skeletal and systemic signs and symptoms of HPP including:
  • Symptomatic interventions
  • Surgical care
  • Dental management
  • Medical strategies
  • Other interventions

Symptom management

There have been several attempts to minimize the symptoms of the systemic complications seen in HPP
  • Non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and improve physical abilities
  • Vitamin B6 to control seizures, as the seizures associated with HPP do not respond to conventional antiseizure medications
  • Dietary Restrictions, such as lowering dietary phosphate and calcium intake, to improve hyperphosphatemia (high amount of phosphate in the blood) and hypercalcemia (high amount of calcium in the blood)
  • Assistive devices, such as braces, splints, canes, walkers, and wheelchairs, to help with mobility

Surgical care

Orthopedic surgical intervention may be necessary to treat fractures and pseudofractures (a bone defect that looks like a fracture on imaging), especially in adult patients.

Craniectomy may be necessary to treat craniosynostosis (a condition where the skull bones in an infant join too soon), which is sometimes observed in children with HPP, which leads to increased intracranial pressure and can lead to neurological complications.

Neurosurgical interventions may be necessary in patients with neurological symptoms such as:
  • Persistent headache
  • Seizures
  • Paralysis or numbness of extremities
  • Papilledema (a condition where the optic nerve that connects the eye and brain swells)

Dental management

Preventative dental care is very important for patients with HPP. Replacement of teeth lost due to HPP is also essential.

Bone marrow transplant

Bone marrow transplant has been attempted in infants with HPP with some improvement, but without correction of ALP levels.

Enzyme replacement therapy (ERT)

ERT has been approved for some metabolic diseases. There is a risk of life-threatening allergic reactions, injection site reactions, and other serious side effects.