Tyrosinemia type I
Tyrosinemia type I is a hereditary metabolic disorder primarily affecting the liver and kidneys, caused by mutations in the FAH gene that disrupt the breakdown of the amino acid tyrosine. This disorder is classified as autosomal recessive, meaning both parents must carry the mutated gene for a child to be affected, with a notable prevalence in specific regions, such as the Saguenay Lac St-Jean area of Quebec, Canada. Symptoms often manifest in infancy and can include severe liver dysfunction, jaundice, and gastrointestinal bleeding, potentially leading to liver failure or death if untreated.
Diagnosis typically involves the detection of succinylacetone in urine and blood, alongside DNA sequencing for confirmation. Treatment usually includes the medication Orfadin (nitisinone), which prevents the formation of harmful metabolites, combined with dietary restrictions to manage tyrosine levels. While liver transplantation was once the primary treatment, the availability of effective medications has significantly altered management approaches. Long-term monitoring is essential for assessing liver and kidney function, especially given the risks of liver cancer associated with the condition. Advances in treatment have notably improved patient outcomes, increasing life expectancy and reducing the need for transplants.
Tyrosinemia type I
ALSO KNOWN AS: Hepatorenal tyrosinemia; fumarylacetoacetase deficiency
DEFINITION Tyrosinemia type I is a hereditary disorder affecting primarily the liver and kidneys. It is caused by mutations in the FAH gene that lead to an inability to fully break down the amino acid tyrosine. It can lead to liver failure, liver cancer, rickets, pain crises, and death if untreated.
Risk Factors
Tyrosinemia type I is an autosomal recessive disorder and affects males and females equally. Parents who are carriers of a mutation in the FAH gene have a 25 percent risk of having an affected child. Overall, the disorder has a of 1 in 100,000 live births but is more common in the Saguenay Lac St-Jean region of Quebec, Canada, where the prevalence is 1 in 1,846, according to the US National Institutes of Health.
Etiology and Genetics
Amino acids are the building blocks of protein. The tyrosine is broken down via several steps to form fumarate and acetoacetate, which are then sent through other metabolic pathways to create energy. Fumarylacetoacetate hydrolase (FAH) is the last in this pathway and is defective in tyrosinemia type I. FAH deficiency leads to the accumulation of fumarylacetoacetate (FAA), which is converted to succinylacetoacetate and succinylacetone. The accumulated FAA is predicted to cause cellular damage and premature cell death in the liver and kidneys. Succinylacetone inhibits two enzymes: parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), which increases plasma tyrosine concentration, and PBG synthase, which leads to reduced heme synthesis and increased delta-aminolevulinic acid, which can induce neurologic pain episodes.
The FAH enzyme is encoded by the FAH gene, located on the long arm of chromosome 15. More specifically, FAH is located at 15q25.1. The FAH gene consists of fourteen exons and is primarily expressed in the liver and kidney, but it can be found at low levels in all tissues. There are several mutations found more frequently in specific populations due to founder effects or genetic drift. The p.P261L mutation accounts for virtually 100 percent of alleles in affected individuals of Ashkenazi Jewish descent. The common French Canadian mutation is c.1062+5GA (IVS 12+5 GA). There are common mutations in Finland, Turkey, Pakistan, Northern Europe, Southern Europe, and individuals of Scandinavian descent. Reported mutations are missense, nonsense, and splice-site mutations, and small deletions have been reported but no large multi-exon deletions that cannot be picked up by standard DNA sequencing methodology.
In the childhood-onset chronic form, the liver nodules show a high incidence of allele reversion—that is, the mutant allele self-corrects to the normal allele, yielding a normal and normal expression of the FAH enzyme in those cells. Milder expression of symptoms can be correlated to the amount of allelic reversion; the corrected cells modify the phenotype. Gene reversion may explain the variability of symptoms within the same family.
Symptoms
Infants presenting earlier than six months of age have severe liver dysfunction. Symptoms include markedly reduced ability to clot, ascites, jaundice, and gastrointestinal bleeding. Untreated affected infants can die from liver failure within weeks of first symptoms. Children presenting at older than six months can have chronic liver dysfunction with significant risk of hepatocellular carcinoma (HCC) and renal dysfunction causing rickets. Episodes of neurologic pain crises are not uncommon and can be severe enough to require mechanical breathing assistance. If untreated, death occurs typically before the age of ten from liver failure, neurologic crisis, or hepatocellular carcinoma.
Screening and Diagnosis
The presence of succinylacetone in the urine and blood in the setting of the patient with liver disease is the hallmark of tyrosinemia type I. Succinylacetone can be detected on urine organic acid analysis.
Final confirmation of diagnosis can be performed by DNA sequencing of the FAH gene. Measuring FAH enzyme activity in cultured skin fibroblasts will also provide confirmation.
Tyrosinemia type I has been added to state newborn screening programs. Measuring succinylacetone from the newborn blood spot by tandem mass spectroscopy is a more sensitive indicator of tyrosinemia type I than measuring tyrosine.
Treatment and Therapy
Treatment consists of medication and dietary restriction. Orfadin (nitisinone) formerly known as NTBC, prevents FAA and succinylacetone formation, but elevates blood tyrosine levels. A low tyrosine diet is required to keep levels in a safe range. Liver transplantation was once the only treatment, but it is used much less frequently now, given the effectiveness of nitisinone and the significant risks associated with liver transplant. However, in parts of the world where resources are limited, liver transplants may be preferred. Patients should be monitored with regular lab tests for liver and kidney function, plasma amino acids, succinylacetone, blood nitisinone levels, and yearly liver imaging for risk of HCC.
Prevention and Outcomes
Response to nitisinone has markedly increased life spans, reduced the incidence of HCC, and dramatically lowered the need for liver transplant. Patients who have had transplants may still require nitisinone to prevent ongoing renal damage from FAA and succinylacetone that is still being produced in kidney cells.
Bibliography
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