Tyrosinemia type I (HT1) is a rare inherited disorder characterized by the deficiency of an enzyme called fumarylacetoacetate hydrolase (FAH). This enzyme is essential for the breakdown of the amino acid tyrosine. When FAH is deficient, toxic byproducts accumulate in the body, leading to various health problems. Tyrosinemia type I is also known as hepatorenal tyrosinemia or fumarylacetoacetase deficiency. The prevalence of HT1 is estimated at 1 case per 100.000 population, although it is widespread in the Quebec region of Canada.
Tyrosinemia type I genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
The key features and aspects of tyrosinemia type I are:
- Genetic Basis: Tyrosinemia type I is an autosomal recessive disorder, meaning an individual must inherit two copies of the mutated gene (FAH) — one from each parent — to develop the condition. The mutations in the FAH gene lead to a deficiency of the FAH enzyme.
- Accumulation of Tyrosine Metabolites: Due to the lack of FAH activity, there is a buildup of tyrosine and its metabolites, including fumarylacetoacetate and succinylacetone. These substances can be toxic, particularly to the liver, kidneys, and nervous system.
- Symptoms: Symptoms of tyrosinemia type I can manifest in early infancy. They may include failure to thrive, a cabbage-like odor to the urine (due to succinylacetone), liver disease, kidney problems, and neurological issues. Without treatment, the disease can progress rapidly and lead to liver failure, renal dysfunction, and a high risk of hepatocellular carcinoma.
- Liver Involvement: Liver disease is a significant component of tyrosinemia type I. Hepatomegaly (enlarged liver), jaundice, and liver dysfunction are common. In severe cases, liver failure can occur.
- Renal Involvement: The kidneys are also affected, and kidney dysfunction may occur, potentially leading to Fanconi syndrome.
- Neurological Complications: Neurological symptoms may include developmental delay, intellectual disability, and peripheral neuropathy. Neurological involvement can occur if the disease is not adequately treated.
- Diagnosis: Diagnosis is typically based on clinical presentation, biochemical testing, and genetic analysis to identify mutations in the FAH gene. Newborn screening may also detect elevated levels of tyrosine and succinylacetone.
- Treatment: The mainstay of therapy for tyrosinemia type I involves a special diet restricting the intake of tyrosine and phenylalanine. This low-protein diet, combined with medication such as nitisinone (which inhibits the production of toxic metabolites), aims to prevent the accumulation of harmful substances and manage the disease. In severe cases, liver transplantation may be considered.
Early diagnosis and intervention are crucial for managing tyrosinemia type I. Regular medical monitoring and lifelong dietary management are often necessary for individuals with this condition.
More Information
Type I tyrosinemia is caused by mutations in the FAH gene and is inherited in an autosomal recessive manner. Pathogenic variants, either homozygotic or compound heterozygotic, in the FAH gene can lead to the accumulation of toxic intermediates and inhibition of porphobilinogen synthesis.
The c.554-1G>T variant (IVS6-1G>T) is common in European tyrosinemia type I patients. It represents more than 16% of the alleles associated with this disease worldwide.
Other variants are predominant in certain populations, such as c.782C>T (p.Pro261Leu), which is one of the most frequent in individuals of Ashkenazi Jewish ancestry with HT1. The c.786G>A (p.Trp262Ter) and c.1009G>A (p.Gly337Ser) mutations are frequent in patients from Scandinavian countries; the c.786G>A variant is the most abundant HT1-causing variant in Finland.
The c.1062+5G>A variant (IVS12+5G>A) is one of the most frequent. It is particularly prevalent in the French-Canadian population, where it represents 90% of the mutated alleles. The c.1062+5G>A mutation is also widespread throughout the Mediterranean.
Tyrosinemia type I genetic testing analyzes the 8 most frequent pathogenic mutations of the FAH gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
