Prevent Hypophosphatasia
Fortunately, you can help prevent Hypophosphatasia from developing in your child by recognizing the signs and symptoms of the disease. These symptoms include muscle weakness, weight loss, and a lack of energy. If you or your child has these symptoms, seek treatment immediately. A genetic counselor can help you determine if your child is likely to develop the disorder and, if so, what treatment options are available.
Prenatal
During pregnancy, a person can be diagnosed with Prenatal Hypophosphatasia (HPP). This is a rare genetic disease that affects the mineralization of bones. It is inherited as an autosomal recessive disorder and can be fatal. The cause is a mutation in the TNSALP gene. The TNSALP gene encodes a protein called tissue non-specific alkaline phosphatase. This protein is present in developing teeth and is also abundant in the kidney and liver. It is believed that the abnormally low activity of this enzyme results in a decrease in the absorption of calcium.
Symptoms of HPP include short limbs, low muscle tone, and a soft skull. Other signs include hypomineralization of the bones, short ribs, and underdeveloped ribs. There are also signs of respiratory distress, including difficulty breathing and seizures. The diagnosis of HPP is based on clinical and radiographic findings. However, the disease can be difficult to diagnose in the uterus.
In the United Kingdom, the National Institute for Health and Care Excellence recommends US screening at 18 to 22 weeks of gestation. In addition, chorionic villus sampling has been used to diagnose HPP as early as 11 to 12 weeks gestation. These findings may help distinguish HPP from other skeletal dysplasias.
As a result of the low activity of this enzyme, teeth become weak, prone to fracture, and are more likely to become cavities. Other complications include kidney damage, hyperphosphatemia, and myelophthisic anemia. Although most children with HPP have mild disease, there is a rare phenotype known as odontohypophosphatasia, which is characterized by dental caries and early loss of primary teeth.
Although odontohypophosphatasia is a relatively mild form of hypophosphatasia, it is still a critical disease. Early diagnosis and proper dental care are crucial. It is also essential that parents discuss the symptoms of their child with the medical team. A genetic evaluation is also important to document hereditary patterns and to determine if there is a risk of recurrence. During pregnancy, patients may benefit from preventative dental care, as hypophosphatasia patients are more likely to develop cavities.
Other symptoms of HPP include premature tooth loss, low muscle tone, and breathing difficulties. It is important to recognize HPP early, as it can lead to short limbs and life-threatening complications. The disease is also linked to bone issues, including hypomineralization of the cranium, skeletal deformities, and shortened long bones.
There are six main clinical forms of HPP, separated by their severity and age at onset. The least severe form is odontohypophosphatasia, while the most severe is perinatal lethal HPP. The condition is usually fatal, though some children live several days after birth.
Other forms of HPP include benign prenatal HPP, which may improve intrauterine deformity during the third trimester. The signs of prenatal HPP include short limbs, low rib tone, and hypomineralization of the bones of the extremities. In infantile HPP, the symptoms include seizures and poor muscle tone.
Adult
Approximately one in every 100,000 live births is born with hypophosphatasia. The condition is caused by mutations in a gene on chromosome 1p36. The mutations alter the ability of the tissue-nonspecific alkaline phosphatase gene (TNSALP) to function properly. This alteration leads to defective mineralization, resulting in soft bones and teeth. The condition can be either mild or severe.
The disorder can be diagnosed based on physical examination, medical history, and lab tests. The laboratory tests measure the amount of alkaline phosphatase in the blood and urine. Low alkaline phosphatase levels indicate that the individual is affected by hypophosphatasia. Symptoms include weak bones, premature loss of teeth, and respiratory problems. The condition can also lead to joint pain and deformities of the limbs. In some cases, the kidneys become affected, leading to hypercalcemia. In severe cases, hypercalcemia can be life-threatening.
Hypophosphatasia can affect people of any ethnicity and is most common among the white population. There are six different clinical forms, classified according to their severity. A mild form of HPP occurs more frequently in later life, while a severe form is found mostly in infants. The condition may affect children of any age, and adults may not be aware of it. The disease is caused by a heterozygous mutation in the ALPL gene.
The gene is a critical enzyme that plays an important role in the mineralization of bones. The enzyme is essential for the absorption and retention of minerals in the body. Mineralization deposits calcium and phosphorus in the developing bones and teeth. This is important for the development of strong bones and teeth. In adults, hypophosphatasia can cause chronic joint pain, recurrent fractures, and muscle weakness. In children, the condition may cause bowed legs, knock knees, and short stature. It can also cause deformities of the skull, including wide pulp chambers.
The symptoms of hypophosphatasia are similar to those of rickets and can range from mild to severe. Patients can also develop recurrent fractures of the thigh bones and feet, and they may experience joint pain and poor healing of fractures. Treatment may include the use of recombinant alkaline phosphatase. This medication can be used to treat the condition, but patients should be monitored for side effects.
HPP is an extremely rare inherited disease that can have severe consequences. It is caused by a mutation in the ALPL gene, which controls the production of the enzyme TNSALP. This gene plays a vital role in the mineralization of bones and teeth. It is important to diagnose HPP as soon as possible. The condition can be life-threatening, and treatment is aimed at preventing or correcting complications.
An adult form of HPP is characterized by bone recurrent fractures, muscle weakness, and osteomalacia. It can be diagnosed based on physical examination, laboratory tests, and a history of dental abnormalities.
Genetic counseling
Symptoms of hypophosphatasia vary from asymptomatic to life-threatening. The most common clinical form is adult-onset, but infantile forms are rare. The disease is typically inherited in an autosomal dominant or recessive manner. The disorder primarily affects bone mineralization. In the adult form, patients often develop musculoskeletal symptoms, such as arthritis, and osteomalacia, which can lead to rickets. The main symptom of adult-onset hypophosphatasia is pain from fractures. In infantile forms, respiratory complications can lead to high mortality. In addition, dental abnormalities are common in adult forms. In pediatric forms, nonsteroidal anti-inflammatory drugs are often used. A variety of therapies are used, including enzyme replacement therapy. Some patients with hypophosphatasia experience improvements in functional outcomes with asfotase alfa. However, the data are insufficient to make strong recommendations.
The diagnosis of hypophosphatasia is usually made by a combination of clinical and genetic factors. Early symptoms in both infantile and adult forms can be difficult to distinguish. The onset of symptoms in adulthood is usually around middle age. In infantile forms, the disease is typically fatal within days of birth. In pediatric forms, the disease is usually mild and goes undiagnosed. A genetic diagnosis can be made through the prenatal testing of fetal genomic DNA. In addition, ALPL mutation testing can be used to distinguish between subclinical and asymptomatic patients.
In 2015, the ACMG and AMP guidelines recommended that the disease be classified as pathogenic. The pathogenic forms of hypophosphatasia are characterized by low serum alkaline phosphatase activity, as well as skeletal complications, such as rickets. The gene responsible for the disease is the tissue nonspecific alkaline phosphatase gene (TNSALP). Mutations in this gene cause severe forms of hypophosphatasia. In addition to rickets, extracellular accumulation of TNSALP substrates leads to calcific arthropathies. These calcifications are often associated with a number of bone and joint complications, including pseudarthrosis, fractures, and calcifying polyarthritis.
In recent years, researchers have identified many mutations in the TNSALP gene, and many of these mutations are associated with an increased risk of severe hypophosphatasia. Some of these mutations result in a frameshift. Others result in premature protein termination. In some cases, a mutation causes an inherited rickets syndrome, called hypophosphatemic rickets. However, the phenotype is often difficult to distinguish from osteoporosis, and clinical examination of children with hypophosphatemic rickets should be performed to exclude osteoporosis.
Other mutations of the TNSALP gene have been discovered in patients with mild forms of hypophosphatasia. However, these mutations are not yet sufficiently prevalent to make a reliable diagnosis. For this reason, testing the ALPL gene for pathogenic variants has become increasingly important. A 41-year-old male with a rare ALPL gene mutation was diagnosed with hypophosphatasia. This study is one of the first to characterize a patient with an uncommon mutation.
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