Hypophosphatasia (HPP) is a rare, inherited metabolic disorder that impairs mineralization, the process of depositing calcium and phosphorus into bones and teeth. This genetic condition leads to soft, weak bones that are prone to fractures and deformities. The severity of HPP varies significantly, with symptoms ranging from severe issues at birth to milder presentations that appear in adulthood.
The Underlying Cause and Mechanism
Hypophosphatasia is caused by mutations in the ALPL gene, which provides instructions for producing an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). The primary function of TNSALP is to facilitate mineralization. It works by breaking down chemicals that would otherwise interfere with the hardening of bone tissue.
When the ALPL gene is mutated, the TNSALP enzyme is either deficient or functions incorrectly. This leads to an accumulation of a chemical substrate called inorganic pyrophosphate (PPi). High levels of PPi inhibit mineralization by blocking calcium and phosphate crystals from being incorporated into the bone matrix.
The inheritance pattern of HPP can be autosomal recessive, where an individual inherits a mutated gene from both parents, or autosomal dominant, where one copy is sufficient. The autosomal recessive forms are more severe. The dominant forms often result in milder symptoms that may not appear until later in life.
Forms and Associated Symptoms
Hypophosphatasia is categorized into six main forms, classified by the age at which symptoms first appear. The perinatal form is the most severe and is often detected in the womb or at birth. Newborns may have skeletal malformations, like an abnormally shaped chest and short limbs, leading to respiratory complications. A benign perinatal form also exists, where skeletal issues are present at birth but may improve.
Infantile HPP becomes apparent within the first six months of life. These infants often fail to gain weight and may exhibit rickets-like changes in their bones, such as widened wrists and ankles. A prominent symptom is craniosynostosis, the premature fusion of skull bones, which can increase pressure on the brain. Respiratory difficulties and high blood calcium levels are also common.
Childhood HPP can range from mild to severe, with symptoms often including the premature loss of baby teeth before the age of five, typically with the root intact. Children may have a short stature, a waddling gait, and bone and joint pain. Bone deformities, such as bowed legs or knock-knees, can also become apparent as the child grows.
The adult form of HPP presents in middle age and is characterized by a softening of the bones known as osteomalacia. Affected individuals are prone to recurrent and poorly healing stress fractures, particularly in the feet and thighs. Chronic joint pain and the early loss of adult teeth are also frequent. Odontohypophosphatasia is the mildest form and is restricted to dental abnormalities, causing premature tooth loss without the skeletal issues seen in other forms.
The Diagnostic Process
The diagnosis of hypophosphatasia involves a clinical evaluation and biochemical testing. A primary indicator is a consistently low level of serum alkaline phosphatase (ALP) activity in a blood test. The degree of ALP reduction often correlates with the disease’s severity. Physicians may also test for pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, as its levels are elevated in the blood when TNSALP is deficient.
Imaging studies are also part of the diagnostic process. X-rays can reveal skeletal abnormalities that suggest HPP, including poor mineralization, rickets-like changes, fractures, or bone deformities. In infants, X-rays might show abnormal skull bone fusion or an underdeveloped rib cage.
For a definitive diagnosis, genetic testing is often performed to identify mutations in the ALPL gene. The combination of clinical symptoms, characteristic biochemical markers, and specific findings on imaging studies provides a comprehensive picture that allows clinicians to diagnose HPP accurately and distinguish it from other bone disorders.
Current Treatment Approaches
The primary treatment for hypophosphatasia is enzyme replacement therapy (ERT) with a medication called asfotase alfa. This drug is a synthetic form of the TNSALP enzyme that the body lacks. By replacing the deficient enzyme, asfotase alfa helps break down pyrophosphate, allowing calcium and phosphorus to be deposited into bones. This therapy can lead to significant improvements in bone strength and function, particularly in the more severe perinatal and infantile forms.
Management of HPP also relies on a supportive, multidisciplinary approach. Physical and occupational therapy are recommended to help manage muscle weakness, improve mobility, and address chronic pain. These therapies help patients maintain function and adapt to physical limitations from bone deformities or fractures.
Specialized dental care is also important, especially for the childhood or odontohypophosphatasia forms. Dentists knowledgeable about HPP can help manage premature tooth loss and other oral health complications. In some cases, surgery may be necessary to correct severe bone deformities or relieve brain pressure caused by craniosynostosis.