Tyrosinaemia (unknown type)
What else is it called?
- hereditary tyrosinemia
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What causes it?
There are three types of Tyrosinaemia which are differentiated by their different symptoms and genetic cause.
- Type I is caused by mutations (change) in the FAH genes
- Type II is caused by mutations in the TAT genes
- Type III is caused my mutations in the HPD genes
Tyrosine is an amino acid found in most proteins. Tyrosine is broken down in the liver by enzymes in a five-step process. This results in molecules that will be excreted (removed) by the kidneys or used to produce energy in the body. The FAH gene gives instructions to the fumarylacetoacetate hydrolase enzyme which takes care of the final step of tyrosine breakdown. The enzyme, tyrosine aminotransferase is produced by the TAT gene which is involved in the first step of the process. The HPD gene gives the instructions for making the 4-hydroxyphenylpyruvate dioxygenase which is responsible for the second step of the process.
The mutations in the FAH, TAT or HPD gene causes a decrease in activity of one of the enzymes (mentioned above) when breaking down tyrosine. This causes tyrosine and its by products to reach toxic levels which may cause damage and death to cells in the liver, kidneys, nervous system and other organs.
How common is it?
Tyrosinemia type I affects around 1 in 100,000 individuals worldwide. It is more common in Norway, where 1 in 60,000 to 74,000 individuals are affected. It is even more common in Quebec, Canada with a prevalence of 1 in 16,000 individuals. In the Saguenay-Lac St. Jean region of Quebec specifically, Tyrosinaemia type I affects 1 in 1,846 people.
Tyrosinaemia type II is rarer and affects less than 1 in 250,000 individuals worldwide.
Tyrosinaemia type III is very rare and only a few cases have been reported.
What are the signs and symptoms?
(Signs and symptoms begin in the first few months of life)
- Failure to gain weight and grow at expected rate
- Poor food tolerance
- Diarrhoea and vomiting (from high protein foods)
- Yellowing of the skin and whites of the eyes (jaundice)
- A cabbage-like odour
- Increased tendency to bleed (especially nosebleeds)
Tyrosinaemia type I can lead to:
- Liver and kidney failure
- Softening and weakening of the bones (rickets)
- Increased risk of liver cancer (hepatocellular carcinoma)
Some affected children have repeated neurologic crises which consists of:
- Changes in mental state
- Reduced sensation in the arms and legs (peripheral neuropathy)
- Abdominal pain
- Respiratory failure
*These crises can last from 1-7 days
When untreated, children with tyrosinemia type I usually do not survive past the age of 10.
Type II: (Signs and symptoms usually begin in early childhood)
- Eye pain, redness, excessive tearing, abnormal sensitivity to light (photophobia)
- Thick, painful skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis)
- Some degree of intellectual disability (about 50% of individuals)
Type III: (very rare)
- Intellectual disability
- Seizures (also known as epilepsy)
- Periodic loss of balance and coordination (intermittent ataxia)
*Around 10% of newborn have temporarily elevated levels of tyrosine (transient tyrosinemia). In this case, the case is not genetic but mostly likely due to vitamin C deficiency or immature liver enzymes due to premature birth.
How is it diagnosed?
The disorder can be diagnosed by blood and urine tests. Liver function tests are also usually abnormal. The diagnosis will be confirmed by measuring the abnormal product Succinyl acetone in the urine.
Tyrosinaemia can be detected through newborn screening (blood spot/heel prick test) and is included in the newborn screening program in the United States. Therefore, children are often detected before they become unwell. However, unfortunately Tyrosinaemia is currently not one of the 6 metabolic disorders newborn babies are screened for in the UK.
It is also possible to test for tyrosinemia before the baby is born, while the baby is still developing in the womb. This is done by a doctor through detecting mutations or measuring succinyl acetone in the amniotic fluid.
Can it be treated?
Tyrosinaemia can be treated by a combination of a low protein diet (avoiding foods such as meats, dairy, nuts and beans) and using a drug called Nitisinone. Please be noted that any dietary changes require specialist dietitian’s advice and monitoring. Children with Tyrosinaemia require careful monitoring to make sure they are growing normally and there is no development of liver cancer.
Children treated after newborn screening are unlikely to develop liver disease in childhood.
The only way to fix the metabolism of tyrosine in through a liver transplantation however this is rarely necessary. Over 90% of children respond well to Nitisinone treatment and a low protein diet.
Do my family need to be tested?
Tyrosinaemia is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.
Carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with Tyrosinaemia are carriers.
The pattern of inheritance in this condition is autosomal recessive. This means:
When both parents are carriers, the risk to the baby in each pregnancy is
- 25% chance (1 in 4) of developing the condition
- 50% chance (1 in 2) for the baby to be a carrier of the condition
- 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier