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. 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. 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.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. These compounds are toxic to cells and lead to differential gene expression and apoptosis in high concentrations. HT1 is diagnosed when elevated levels of succinylacetone (SA), one of the metabolites in this pathway, is detected in blood and urine samples.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.
Consequently, porphyrin deposits form in the bloodstream and cause neuropathic pain, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibit renal tubular function, the synthesis of heme, and the immune system.The accumulation of unprocessed tyrosine itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of hormonal signaling and neurotransmission. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly Dopamine, norepinephrine, and thryoxine. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth, motor function, and speech development. Diagnosis
Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) in blood and urine. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis. Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates. Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth. However, prompt assessment upon the manifestation of physical symptoms such as fever, vomiting, increased tendency to bleed, diarrhea along with bloody feces, and jaundice is critical for improving long term prognosis. Management
The primary treatment for type 1 tyrosinemia is nitisinone and restriction of tyrosine in the diet.