Tyrosinemias are characterized by elevated blood concentrations with the amino acid tyrosine. All forms of the disease have genetic causes. Type I tyrosinemia, in particular, leads to early death if left untreated.
What is tyrosinemia?
Tyrosinemia is a genetically caused degradation disorder of the amino acid tyrosine that leads to an increase in the concentration of tyrosine in the blood. To date, three different forms of tyrosinemia are known. They differ in the site of the tyrosine degradation disorder. All three forms of tyrosinemia are characterized by increased tyrosine and phenylalanine concentrations to varying degrees:
- In tyrosinemia type I, toxic breakdown products are additionally formed in the body because the normal breakdown pathway is blocked by an enzyme defect at the end of the breakdown chain. These misproducts of tyrosine degradation are toxic to the liver and kidneys, so that tyrosinemia type I takes a particularly severe course.
- Tyrosinemia type II is characterized mainly by increased tyrosine and phenylalanine concentrations with all their effects on the eyes, skin and nervous system. Here, the degradation of tyrosine is already blocked at the beginning of the degradation chain.
- The mildest and rarest form of tyrosinemia is tyrosinemia type III, in which tyrosine and phenalalanine concentrations are less elevated. However, the elevated concentrations have effects on the nervous system. In general, the tyrosinemias are very rare. Tyrosinemia type I affects cicra one to two per 100,000 people. Of tyrosinemia type III, there are only a few described cases.
Causes
The general cause of all three forms of tyrosinemia is the disruption of tyrosine degradation by defective enzymes. The form of the disease depends on the affected enzymes in the tyrosine degradation chain. All tyrosinemias are caused by autosomal recessive mutations. In tyrosinemia type I, the enzyme fumarylacetoacetate hydrolase is largely nonfunctional. Its coding gene is located on chromosome 15. This enzyme is responsible for the last step in the tyrosine degradation chain. Normally, this reaction step degrades the intermediates fumaryl acetoacetate and maleyl acetoacetate. However, if the enzyme is defective, these metabolites accumulate and are then converted to succinyl acetoacetate and succinylcholine in an alternative reaction. However, these substances are potent liver and kidney toxins. Depending on their concentration in the blood, they lead to complete destruction of the liver and kidneys either rapidly or via a chronic process. Tyrosinemia type II is caused by a defect in the enzyme tyrosine aminotransferase. This enzyme initiates the first step of tyrosine degradation. When it fails, tyrosine accumulates more and more in the blood. The concentration can be increased up to ten times the normal value. Since tyrosine is formed from the amino acid phenylalanine, the phenylalanine concentration also increases at the same time. Elevated phenylalanine concentrations are known to damage the nervous system. At the same time, high tyrosine levels attack the eyes and skin. Finally, tyrosinemia type III is caused by a defect in the enzyme 4-hydroxyphenylpyruvate dioxygenase. Tyrosine and phenylalanine levels are only slightly elevated in this case. Due to the blockage in the tyrosine degradation chain, a backlog of tyrosine develops in all three forms of tyrosinemia, which, of course, is more pronounced the closer it is to the beginning of the degradation chain.
Symptoms, complaints, and signs
Type I tyrosinemia is characterized by damage to the liver, kidneys, and brain. The disease is already evident in newborns by weakness in drinking, vomiting, liver disease, and renal insufficiency. There are two forms of progression, both of which lead to early death through liver and kidney failure if left untreated. In the fulminant form of progression, liver enlargement, edema, and severe growth failure occur early. Death occurs within a few months after birth. In the milder form of the disease, the liver and kidneys are chronically degraded. Over a long process, cirrhosis of the liver develops, often leading to liver cancer. If left untreated, death occurs by the age of ten at the latest. In tyrosinemia type II, corneal damage to the eyes, blistering and crusting of the skin, and a variety of neurological deficits occur.Type III tyrosinemia is characterized by mild mental impairment, disturbances in motor coordination, and epileptic seizures.
Diagnosis and course of the disease
Tyrosinemia can be diagnosed by various blood and urine tests. Elevated tyrosine levels are detected via urine tests. Furthermore, the toxic metabolites such as succinylacetone can also be detected in the urine in tyrosinemia type I.
Complications
Depending on the type, tyrosinemia can cause various complications. Type I tyrosinemia, due to congenital liver, kidney, and brain damage, can cause symptoms such as poor drinking, liver disease, and renal insufficiency. Weakness in drinking can lead to dehydration and consequent dehydration relatively quickly. Liver disease always has serious effects on the entire body and can cause jaundice and severe inflammation of the internal organs, for example. Renal insufficiency is equally serious because, if left untreated, it can lead to kidney failure and consequent death. In the fulminant course, tyrosinemia can also promote growth disorders, edema, and liver cancer and cirrhosis. Type II tyrosinemia is associated with corneal damage, neurologic deficits, and other complications. Type III tyrosinemia can cause epileptic seizures, movement coordination disorders, and mental impairment as the disease progresses. When treating the degradation disorder, complications depend on the particular intervention and the patient’s constitution. The nitisinones typically prescribed can cause migraines and other side effects. Liver transplantation always carries the risk of the body rejecting the organ. In addition, infections and wound healing problems can occur.
When should you see a doctor?
A person with tyrosinemia should always see a doctor to prevent further complications or upset. Early detection with subsequent treatment is very important in this regard, so the affected person should see a doctor at the first signs and symptoms of the disease. In the worst case, the child may die from tyrosinemia. The doctor should be contacted in case of this disease if the child suffers from severe jaundice or diarrhea. Internal bleeding may also indicate this disease. Furthermore, poisoning of the liver and other internal organs also shows. Also an increased heart rate or misfeelings in different parts of the body often indicate the disease and should be checked by a doctor. Paralysis may occur over the entire body. Tyrosinemia should be treated immediately by a pediatrician or in a hospital. The further course depends on the time of diagnosis, so no general prediction can be made. It is also possible that the child’s life expectancy is reduced as a result of this disease.
Treatment and therapy
All forms of tyrosinemia are positively affected by a diet low in tyrosine and phenylalanine. In types II and III tyrosinemia, such a diet can reliably improve symptoms. However, the treatment of tyrosinemia type I is much more difficult. In addition to a strict diet, the formation of the toxic metabolites must be prevented. This can be achieved by the drug nitisinone (NTBC) due to the blocking of an earlier degradation step. This does increase the concentration of tyrosine in the blood. However, this can be kept low by diet. In advanced liver failure, liver transplantation must be considered.
Prevention
Because tyrosinemias are genetic, they cannot be prevented. However, by following a strict low-tyrosine and low-phenylalanine diet, at least patients with tyrosinemia types II and III are able to lead a largely normal life. In patients with type I tyrosinemia, the concentration of metabolites and of tyrosine and phenylalanine must be regulated by drug treatment and strict diet throughout life.
Follow-up
Tyrosinemia is a hereditary metabolic disorder. It is considered a rare disease and is classified using three forms, I, II, and III. Treatment options depend on the particular form. Appropriate follow-up is necessary to achieve a favorable prognosis.The patient should be able to lead as unrestricted a life as possible. In type II tyrosinemia, dietary treatment is often sufficient. However, the doctor’s orders must be followed exactly. During follow-up, the course of healing is monitored; it is set for the medium to long term. Type III tyrosinemia is the rarest form of metabolic disease. It is associated with mild mental impairment and epilepsy. During aftercare, patients and their relatives learn how to cope with the disease on a daily basis. Special aftercare is necessary for complete type I disease. If not treated, this tyrosinemia can be life-threatening. Internal organs such as kidneys or the brain are damaged. An unfavorable course requires lifelong follow-up. Organ transplantation may be an option at the doctor’s discretion. It is considered when other measures no longer help. Follow-up care is provided in the hospital, and the patient’s condition is closely monitored. Regular check-ups provide information on the tolerance of the new organ. Rejection reactions of the body must be avoided.
What you can do yourself
Tyrosinemia patients can take various dietary measures to support conservative treatment, depending on the type of disease. In type I tyrosinemia, a high-energy diet is important. The diet should produce as little tyrosine as possible in the body. Catabolic situations such as occur after prolonged starvation should be avoided by eating meals regularly. The consumption of dairy, egg and meat products should be severely limited. The diet can slow down the progression of the disease. It should be prepared together with a physician and a nutritionist and implemented consistently. Tyrosinemia type II can also be treated with an adapted diet. In the case of tyrosinemia type III, in addition to dietary measures, preparations must be made for medical emergencies. In the event of epileptic seizures, first aid measures must be initiated by calming the patient and administering emergency medication. The affected person must be placed in the stable lateral position so that he does not injure himself on objects or fall and also so that no vomit enters the trachea. Possible consequences of ataxia can be prevented by physiotherapy. Stairs, thresholds and dangerous objects in the household must be secured to minimize the risk of injury from falls. The exact measures for type I, II, and III tyrosinemia should be discussed with a specialist.
