In hypophosphatasia, a genetic enzyme defect prevents mineralization of the skeleton. Affected individuals suffer from skeletal deformities and are more likely to suffer fractions. Although no curative therapy is available to date, the condition may be curable in the future with enzyme replacement therapy, for example.
What is hypophosphatasia?
Hypophosphatasia is the name given to a rare inherited disease of bone metabolism. Phosphatase deficiency results in numerous skeletal malformations as part of this disease. In hypophosphatasia, the bones are not sufficiently mineralized. So to speak, the disease is in a narrower sense a mineralization disorder. To be distinguished from hypophosphatasia is hyperphosphatasia, in which overmineralization occurs. This metabolic disorder is also genetically determined and can be inherited in an autosomal recessive manner. Hypophosphatasia is often confused with other bone disorders such as osteoporosis. An exact prevalence is not yet known for the hereditary disease. One study determined an approximate ratio of 1:100,000 for occurrence. Subgroups of the disease include the perinatal, infantile, adolescent, and adult forms. By extension, odontohypophosphatasia and pseudohypophosphatasia are also included in the group.
Causes
Genetic mutations cause hypophosphatasia. The mutation has been localized to gene locus 1p34-36 of chromosome 1. The gene located there codes for the enzyme alkaline phosphatase. As a result of the mutation, only defective variants of this enzyme are formed, which display reduced activity. From inorganic pyrophosphate, the enzyme forms phosphate by cleavage in healthy humans. This phosphate is required by osteoblasts for bone mineralization. If there is too little alkaline phosphatase or only mutated alkaline phosphatase, the enzyme forms too little phosphate. The bones can therefore only be mineralized by the osteoblasts to a limited extent. There is too much inorganic pyrophosphate in the organism because it is only broken down to a limited extent. This overconcentration of inorganic pyrophosphate inhibits bone formation even more and can cause pyrophosphate calcium crystals to precipitate in the organs.
Symptoms, complaints, and signs
The severity of the disease determines the symptoms. The form of hypophosphatasia also affects the onset of symptoms. As a rule of thumb, early-onset disease is considered more severe than disease onset in the later decades of life. The infantile form in particular is therefore often lethal, since it leads not only to severe skeletal malformations but also to organic damage. The adult form of the disease, on the other hand, is less severe. As a rule, hypophosphatasia results in bone deformity due to the lack of mineralization, which is accompanied by fractures. These fractures mainly affect the long bones. Tooth loss and high calcium levels occur concomitantly. Rapid fatigue, muscle weakness, loss of appetite and pain may also occur. Inflammatory manifestations often accompany the fractures as the inorganic pyrophosphate combines with calcium to form crystals and is deposited in the body. Hypophosphatasia is therefore often confused with osteoporosis or rheumatism.
Diagnosis and course of the disease
Because hypophosphatasia can be associated with a wide variety of symptoms and can also have onset in any decade of life, diagnosis of the disease is challenging. To date, no direct detection of the mutation is possible. Only blood values can be used to make an initial tentative diagnosis. Phosphorethanol as well as inorganic pyrophosphate and pyridoxal-5-phosphate are elevated in affected individuals. Severe forms of the mineralization disorder can also be traced on an X-ray, on which the skeleton can be seen only dimly. For infants with this disorder, the prognosis is most unfavorable. The lethality is high. Adults are thought to have a more favorable course.
Complications
Hypophosphatasia usually results in various malformations and deformities of the patient’s skeleton. Likewise, fractures occur more frequently and more easily throughout the body. In most cases, the symptoms hypophosphatasia appear in late adulthood. Children are usually not affected by this disease.Likewise, the skeletal malformation can also cause damage to the organs, so that a transplant may be necessary for the patient to survive. Not infrequently, tooth loss also occurs, which can lead to discomfort when eating. The loss of teeth not infrequently leads to aesthetic discomfort and thus to depression. Furthermore, the patient’s resilience decreases enormously and the affected person feels ill and tired. Severe pain and a loss of appetite occur, which can lead to malnutrition. The patient’s everyday life seems severely limited by hypophosphatasia and the quality of life is considerably reduced. Treatment of hypophosphatasia can be done with the help of medications and leads to a positive course of the disease. In many cases, therapies are also necessary. Life expectancy may be reduced if organ damage has occurred as a result of hypophosphatasia.
When should you see a doctor?
When symptoms of hypophosphatasia are noticed, a visit to the primary care physician should be made. Medical advice is needed if fatigue and muscle weakness occur with even mild physical exertion. Other warning signs that need to be clarified are loss of appetite and pain in the limbs. This is often accompanied by inflammation and increasing stiffness in the joints. These signs indicate hypophosphatasia and must be quickly investigated and treated if necessary. Individuals who have been suffering from unusual muscle, joint, or bone pain for a long time that cannot be attributed to any specific cause should also consult a physician. Because it is a genetic condition, any risk factors cannot be treated preventively. Only once the disease has been diagnosed can the progression of the individual complaints be slowed down. Individuals who suspect a serious bone disease should speak with their primary care physician. The physician can make an initial diagnosis and then refer the patient to an orthopedic surgeon or a specialist in bone disease. Further treatment usually takes place in a specialist clinic.
Treatment and therapy
Therapeutically, there is no curative treatment available for hypophosphatasia. There is also no causal therapy at the current state of medical knowledge so far. Therefore, treatment is generally symptomatic. Drug therapy is used to alleviate the symptoms. Both the administration of vitamin D and the administration of painkillers achieve symptomatic improvements in most cases. Pain, in particular, reduces the quality of life of those affected. Since symptomatic therapies are particularly aimed at improving the quality of life, pain relief is the focus of treatment. Patients with elevated levels of prostaglandin E2, for example, can be given a non-steroidal anti-inflammatory drug for five weeks for this purpose. In this way, physical activity can be increased again with less pain. To increase mobility, physiotherapy, for example, may be useful as part of the therapy. Any kind of physical activity has a positive influence on the course of the disease, as the targeted development of muscles can stabilize the musculoskeletal system. A change in diet is also recommended as part of the treatment. Low-phosphate diets, for example, reduce elevated serum concentrations of phosphate and can reduce the formation of crystals. If neurological symptoms occur that are caused by increased intracranial pressure, neurological intervention takes place. Medical research is now investigating innovative concepts for the treatment of hypophosphatasia. In the future, curative treatments may become available with enzyme replacement therapy or foreign donor transplantation.
Prevention
Because hypophosphatasia is an inherited disease based on a gene mutation, the disease cannot be prevented.
Follow-up care
Following a treated hypophosphatasia, one of the issues for patients is improving mobility. This is where physical therapy usually helps. Physical exercise makes improvement rapid, as the musculature receives good stabilization. During aftercare, nutritional habits also need to be examined. A low-phosphate diet can lower the concentration in the blood so that fewer crystals form.If neurological symptoms occur due to the disease, appropriate measures must be initiated in this area. There is no generally valid advice for such therapy in terms of aftercare. This is related to the purely symptomatic treatment. Typically, patients have to take vitamin D over a long period of time. In addition, if the pain is severe, doctors prescribe helpful medications to alleviate this discomfort. However, if sufferers take the painkillers long term, damage to the stomach is to be expected. Here, it is important not to put too much strain on the body. A reduction in activities may be necessary to relieve the pain. Depending on the psychological problems that often accompany the disease, individual psychotherapy may be advisable as part of aftercare.
Here’s what you can do yourself
In hypophosphatasia, there are usually no self-help options available to the affected person. Treatment of the condition is purely symptomatic, as causal treatment is not possible. Patients are dependent on taking vitamin D for this. If the affected person suffers from pain, painkillers must be taken. When taking painkillers, it should be noted that long-term use can damage the stomach. Furthermore, physical activities should be restricted if possible, as these are mostly responsible for the pain. Therefore, the affected person is often restricted in his daily life and should also not practice any sports. The mobility can be increased by various exercises and therapies. These exercises can also be done at home. If the affected person also suffers from psychological discomfort due to hypophosphatasia, contact with other affected persons is very useful in this regard. Thus, information and tips for a pleasant everyday life can be exchanged and psychological discomfort or depression can be avoided. Conversations with one’s own friends and parents can also be helpful. However, a complete cure for this disease is not possible.