What is Hypophosphatasia?

Hypophosphatasia (HPP) is a rare genetic disorder that affects the mineralization of bones and teeth. It is caused by mutations in the ALPL gene, which encodes an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is responsible for breaking down a molecule called inorganic pyrophosphate, which inhibits mineralization. When TNSALP activity is reduced or absent, inorganic pyrophosphate accumulates and prevents the formation of hydroxyapatite, the mineral component of bones and teeth.

HPP can present with a wide range of symptoms, depending on the severity of the disease and the age of onset. The most severe form of HPP, perinatal lethal HPP, is usually diagnosed prenatally or at birth and is characterized by severely undermineralized bones, respiratory failure, and early death. Infantile HPP, which can present in the first six months of life, is characterized by soft and weak bones, delayed motor milestones, respiratory problems, and a high risk of fractures. Childhood HPP, which typically presents after six months of age, is characterized by dental problems, rickets, bone pain, and a risk of fractures. Adult HPP, which can present at any age, is characterized by dental problems, osteomalacia (softening of the bones), bone pain, and a risk of fractures.

HPP can be diagnosed through a combination of clinical evaluation, laboratory testing, and imaging studies. Laboratory testing typically includes measurement of alkaline phosphatase (ALP) activity, which is usually low in HPP, as well as measurement of inorganic pyrophosphate levels, which are usually high. Imaging studies, such as X-rays, can show undermineralization of bones and teeth.

There is currently no cure for HPP, and treatment is supportive and aimed at managing the symptoms of the disease. Treatment may include calcium and vitamin D supplementation, bisphosphonates to increase bone mineral density, pain management, and dental interventions such as extractions or implants. Enzyme replacement therapy (ERT) with a recombinant form of TNSALP is currently available in some countries and has shown promising results in improving bone mineralization and reducing pain.

The prognosis for HPP varies depending on the severity of the disease and the age of onset. Perinatal lethal HPP is usually fatal, while infantile HPP has a high mortality rate and a risk of long-term complications such as cognitive impairment and skeletal deformities. Childhood and adult HPP are usually milder forms of the disease, but can still have a significant impact on quality of life.

In conclusion, hypophosphatasia is a rare genetic disorder that affects the mineralization of bones and teeth. It is caused by mutations in the ALPL gene, which encodes the enzyme tissue-nonspecific alkaline phosphatase. HPP can present with a wide range of symptoms, depending on the severity of the disease and the age of onset, and can be diagnosed through a combination of clinical evaluation, laboratory testing, and imaging studies. Treatment is supportive and aimed at managing the symptoms of the disease, and the prognosis varies depending on the severity of the disease and the age of onset.