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Tyrosinemia type I
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Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves.[1] The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease.[2] If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.[1] If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
Tyrosinemia type I | |
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Other names | Hereditary Tyrosinemia type I, HT1 |
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Mutation of enzyme fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway | |
Specialty | Hepatology, nephrology, neurology |
Symptoms | Failure to thrive, enlarged liver, fever, vomiting, diarrhea |
Usual onset | Variable, usually with the first 2 years of life |
Duration | Lifelong |
Causes | Genetic (autosomal recessive) |
Diagnostic method | Dried blood spot testing, urinalysis, genetic testing |
Treatment | Dietary restrictions, Nitisinone, liver transplantation |
Medication | Nitisinone |
Prognosis | 93% survival rate at six years with treatment |
Frequency | 1 in 1,850 (Saguenay-Lac Saint-Jean region, Quebec) |
Tyrosinemia type I is an autosomal recessive disorder caused by mutations in both copies of the gene encoding the enzyme fumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain metabolic intermediates in the tyrosine catabolic pathway.[2] These compounds are toxic to cells and lead to differential gene expression and apoptosis in high concentrations.[2] HT1 is diagnosed when elevated levels of succinylacetone (SA), one of the metabolites in this pathway, is detected in blood and urine samples.[1]
While there is no cure for tyrosinemia type I, management of the disease is possible utilizing dietary restrictions and medications. A diet low in tyrosine and phenylalanine is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug nitisinone (brand name Orfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs.[1] Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.[2]
Tyrosinemia type I is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec, where the prevalence is 1 in 1,850 births. It is most common among those with French-Canadian ancestry and this frequency of infliction has been attributed to the founder effect.[3] There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.[2]