Hypophosphatasia is a rare genetic condition that affects the development of bones and teeth. This inherited disorder causes bones to become soft and weak, making them susceptible to deformity and fracture. Its severity varies widely, impacting how the body forms and maintains its skeletal structure.
Understanding Hypophosphatasia
Hypophosphatasia is characterized by unusually low levels of alkaline phosphatase (ALP), an enzyme central to the mineralization process. ALP, specifically the tissue-nonspecific isoenzyme (TNSALP), is crucial for the proper hardening of bones and teeth. It functions by breaking down inorganic pyrophosphate (PPi), a substance that inhibits mineralization, into inorganic phosphate (Pi).
When ALP levels are low, PPi accumulates in the body. This excess PPi prevents calcium and phosphate from properly forming hydroxyapatite crystals, the hard mineral components of bone and tooth enamel. Impaired mineralization leads to conditions like rickets in children, where bones soften and deform, and osteomalacia in adults, characterized by bone pain and increased fracture risk. The condition can also lead to the buildup of other substances, such as pyridoxal 5′-phosphate (PLP), the active form of vitamin B6.
Genetic Basis and Inheritance
Hypophosphatasia results from specific changes, or mutations, in the ALPL gene. This gene provides the instructions for producing the tissue-nonspecific alkaline phosphatase enzyme. Over 400 different mutations in the ALPL gene have been identified, leading to the wide spectrum of clinical presentations seen in individuals with hypophosphatasia.
The inheritance pattern of hypophosphatasia can vary. The more severe forms, such as those appearing in infancy or around the time of birth, are typically inherited in an autosomal recessive manner. This means that an individual must inherit two copies of the mutated ALPL gene, one from each parent, to develop the condition. Milder forms of hypophosphatasia, which may emerge later in childhood or adulthood, can be inherited in either an autosomal recessive or an autosomal dominant pattern. In autosomal dominant inheritance, only one copy of the mutated gene is needed from a single parent for the condition to manifest.
Recognizing the Signs
The manifestations of hypophosphatasia are diverse, with symptoms varying significantly based on the age of onset and the severity of the genetic mutation. The most severe form, perinatal hypophosphatasia, can be identified before or shortly after birth. Infants with this form often show profoundly underdeveloped bones, which can be seen on imaging, and may experience respiratory distress due to chest wall abnormalities. Stillbirth is possible, and without intervention, this form can be fatal due to respiratory failure.
Infantile hypophosphatasia typically appears within the first six months of life. Affected infants may have difficulty gaining weight and growing, and show signs of rickets, including soft and misshapen bones, and widened wrist and ankle bones. Respiratory problems can also occur due to weakened ribs, and some infants may experience seizures. Childhood hypophosphatasia has a variable presentation, often marked by bone deformities like bowed legs or knock-knees, and a delayed start to walking. A characteristic sign in children is the premature loss of primary teeth, especially the incisors, often before the age of five years.
Adult hypophosphatasia usually presents in middle age, with individuals experiencing softened bones (osteomalacia), chronic bone pain, and an increased risk of stress fractures, particularly in the feet. Some adults may also report a history of rickets or early tooth loss during childhood. The mildest form, odontohypophosphatasia, primarily affects the teeth, leading to premature exfoliation of primary teeth without significant skeletal involvement.
Diagnosis and Confirmation
Diagnosing hypophosphatasia primarily relies on identifying consistently low levels of alkaline phosphatase (ALP) in blood tests. This persistently low ALP activity is a hallmark biochemical indicator of the condition. However, a low ALP level alone is not sufficient for a definitive diagnosis, as other conditions can also cause reduced ALP.
To support the diagnosis, other blood tests may be performed, looking for elevated levels of substances that accumulate when ALP is deficient. These include pyridoxal 5′-phosphate (PLP), often elevated in the blood, and phosphoethanolamine (PEA), which can be increased in both blood and urine. Genetic testing provides confirmation by analyzing the ALPL gene for specific mutations. Imaging studies, such as X-rays, are also used to assess bone abnormalities and the extent of skeletal mineralization, helping to characterize the disease’s severity.
Managing the Condition
Management of hypophosphatasia centers on addressing the underlying enzyme deficiency and providing supportive care for diverse symptoms. A significant advancement in treatment is enzyme replacement therapy, specifically with asfotase alfa. This medication provides a functional alkaline phosphatase enzyme to the body, aiming to replace the deficient enzyme and promote proper bone mineralization. Asfotase alfa has shown positive outcomes, particularly in severe forms affecting infants and children.
Beyond enzyme replacement, supportive care measures are important to manage the condition’s various manifestations. Pain management is often necessary to alleviate bone and joint discomfort. Physical therapy can help improve muscle strength and mobility, especially for individuals experiencing muscle weakness or skeletal deformities. Respiratory support may be crucial for infants with severe forms who experience breathing difficulties due to chest wall issues. Dental care is also a regular part of management, addressing issues such as premature tooth loss and other dental complications. A multidisciplinary approach is often adopted to provide comprehensive and coordinated care.