Hereditary Tyrosinemia Type I
Fumarylacetoacetate Hydrolase Deficiency
Tyrosinemia type 1 is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine, a building block of most proteins. This condition is caused by a shortage of the enzyme fumarylacetoacetate hydrolase, one of the enzymes required for the multi-step process that breaks down tyrosine. This enzyme shortage is caused by mutations in the FAH gene. Symptoms usually appear in the first few months of life and include failure to thrive, diarrhea, vomiting, jaundice, cabbage-like odor, and increased tendency to bleed (particularly nosebleeds). Tyrosinemia type I can lead to liver and kidney failure, problems affecting the nervous system, and an increased risk of liver cancer. This condition is inherited in an autosomal recessive manner.
Tyrosinemia type I, the most severe form of this disorder, is characterized by signs and symptoms that begin in the first few months of life. Affected infants fail to gain weight and grow at the expected rate (failure to thrive) due to poor food tolerance because high-protein foods lead to diarrhea and vomiting. Affected infants may also have yellowing of the skin and whites of the eyes (jaundice), a cabbage-like odor, and an increased tendency to bleed (particularly nosebleeds). Tyrosinemia type I can lead to liver and kidney failure, softening and weakening of the bones (rickets), and an increased risk of liver cancer (hepatocellular carcinoma). Some affected children have repeated neurologic crises that consist of changes in mental state, reduced sensation in the arms and legs (peripheral neuropathy), abdominal pain, and respiratory failure. These crises can last from 1 to 7 days. Untreated, children with tyrosinemia type I often do not survive past the age of 10.
The symptoms can vary a great deal from person to person. There are two types of tyrosinemia 1. The more common form happens in infants. The less common form is seen in older children and adults.
Babies usually show effects of the condition within the first few months of life. Some of the first symptoms may be:
- Diarrhea and bloody stools
- Poor weight gain
- Extreme sleepiness
- Cabbage-like odor to the skin or urine
Liver problems are common. They can lead to:
- Enlarged liver
- Yellowing of the skin
- Tendency to bleed and bruise easily
- Swelling of the legs and abdomen
Kidney problems also happen and can lead to:
- Rickets, a bone thinning condition
- Delays in walking
Without prompt and careful treatment, babies with severe liver and kidney problems usually die.
Some babies also have episodes that include:
- Pain or weakness, especially in the legs
- Breathing problems
- Rapid heartbeat
- Coma, sometimes leading to death
Children with the chronic form usually start having symptoms after two months of age. Some of the first signs may be trouble gaining weight and episodes of vomiting and diarrhea. Over time, the condition can cause liver, kidney and nerve problems.
- Liver: If the condition is not treated, a rare type of liver scarring called nodular cirrhosis can happen. This gets worse over time and can lead to liver failure. If not treated, many children develop liver failure or liver cancer before the age of 10. Medication, when started early, can prevent liver failure in most children.
- Kidneys: Serious kidney problems can occur in untreated children. When the kidneys are not working properly, episodes of vomiting, weakness and fever can happen. Rickets, a bone thinning condition, may happen in children with kidney damage. Medication can prevent kidney problems in most children.
- Neurologic crises: Some children have episodes of weakness, pain or numbness in their arms, legs or other parts of the body. Breathing problems and rapid heartbeat may also happen. Some children have seizures that can lead to coma. Medication can stop episodes of neurologic crisis in most children.
- Other: A small number of children have had heart problems. Some have had high blood pressure.
In order for the body to use protein from the food we eat, it is broken down into smaller parts called amino acids. Special enzymes then make changes to the amino acids so the body can use them.
Tyrosinemia 1 occurs when an enzyme, fumarylacetoacetase (FAH), is either missing or not working properly, therefore it cannot break down tyrosine. The accumulation of tyrosine in the blood, causes serious liver and kidney damage. It may also cause episodes of weakness or pain.
Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing alleles in a family are known.
When treatment is started early, severe liver, kidney, and neurologic symptoms can be prevented. Children who are treated usually have normal growth and intelligence.
If treatment is not started right away, children may have some liver or kidney damage. Rickets may already be present and need to be treated. Delays in growth and development may also be present. The effects of delayed treatment vary from child to child.
- An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
- An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
- Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
- National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.
With treatment, >90% survival rate can be expected, along with normal growth, normalization of liver function and prevention of cirrhosis, correction of renal tubular acidosis and resolution of secondary rickets. Treatment may not affect the incidence of hepatic cancer. Treatment consists of a diet low in tyrosine and phenylalanine and use of a drug (nitisone or NTBC) that prevent formation of succinylacetone, the toxic agent responsible for liver and kidney damage. Patients with evidence of cirrhosis or liver cancer require liver transplantation. If treatment is begun too late, rickets, failure to thrive, and hypotonia may result. Without treatment, chronic problems ensue, including: liver disease leading to cirrhosis and hepatocellular carcinoma, renal tubular disease (Fanconi syndrome), seizures, cardiomyopathy, and coagulation disorders. Repeated neurologic crises may occur involving mental status change, peripheral neuropathy, and/or respiratory failure. Death usually occurs by 10 years of age.
Lifelong treatment is usually needed to prevent liver and kidney problems. Treatment consists of medication and a diet low in tyrosine and another amino acid called phenylalanine (phe). The low-tyrosine/phenylalanine diet is made up of a special medical formula and carefully chosen foods. You must start the treatment as soon as you know your child has the condition.
The following treatments are often recommended for children with tyrosinemia 1:
- nitisinone (Orfadin® ), also known as NTBCis approved by the FDA in the indication "Treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine".
- Nitisinone will increase the level of tyrosine in your child’s blood. So, a low-tyrosine diet is a very important part of treatment.
- Vitamin D is sometimes used to treat children who have rickets.
The special medical formula gives babies and children the nutrients and protein they need while helping keep their tyrosine levels within a safe range. Your metabolic doctor and dietician will tell you what type of formula is best and how much to use.
Low-tyrosine / phenylalanine diet:
The diet is made up of foods that are very low in tyrosine and phenylalanine. This means your child will need to limit foods such as cow’s milk and regular formula. He or she will need to avoid meat, eggs and cheese. Regular flour, dried beans, nuts and peanut butter contain these amino acids and must also be limited.
Many vegetables and fruits have only small amounts of phenylalanine and tyrosine and can be eaten regularly in carefully measured amounts.
There are other medical foods such as special flours, pastas, and rice that are made especially for people with tyrosinemia 1. Some states offer help with payment, or require private insurance coverage for formula and other special medical foods.
Your metabolic doctor and dietician will decide on the best food plan for your child. The exact plan will depend on many things such as your child’s age, weight, general health, and how well the medication is working. Your dietician will fine-tune your child’s diet over time.
Blood, urine and other tests:
The child will have regular blood and urine tests to check:
- Amino acid levels
- The amount of succinylacetone
- Nitisinone level
- Liver and kidney function
These tests help your doctor and dietician figure out whether any changes to the medication or diet are needed.
Some experts suggest that children with tyrosinemia 1 have a CT or MRI scan of their liver once a year to check for scarring or cancer.
Liver transplantation is still an option to prevent liver cancer. It may also be considered for children who show signs of liver cancer or liver failure. If you have questions, talk to your metabolic doctor or doctor about the benefits and risks of transplantation.
Refer to research Publications.