Clinical characteristics: Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.
Diagnosis/testing: Tyrosinemia type I results from deficiency of the enzyme fumarylacetoacetase (FAH). The diagnosis is established in a proband with typical biochemical findings (increased succinylacetone concentration in the blood and urine; elevated plasma concentrations of tyrosine, methionine, and phenylalanine; and elevated urinary concentration of tyrosine metabolites and the compound δ-ALA) and/or by the identification of biallelic pathogenic variants in FAH on molecular genetic testing.
Management: Treatment of manifestations: Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone. Nitisinone treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone increases the blood concentration of tyrosine, dietary management with controlled intake of phenylalanine and tyrosine should be started immediately after diagnosis to prevent tyrosine crystals from forming in the cornea. If the blood concentration of phenylalanine becomes too low (<20 μmol/L), additional natural protein should be added to the diet. Prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now should be reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue.
Prevention of primary manifestations: Initiation of treatment with nitisinone as soon as the diagnosis is confirmed.
Prevention of secondary complications: Treatment of early signs of carnitine deficiency, osteoporosis, and rickets that are secondary to renal tubular Fanconi syndrome.
Surveillance: Guidelines for routine surveillance of individuals with tyrosinemia type I have been established.
Agents/circumstances to avoid: Inappropriate protein intake.
Evaluation of relatives at risk: All subsequent children of the parents of a child with tyrosinemia type I should have urine and blood succinylacetone analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy. If the pathogenic variants in the family are known, prenatal molecular genetic testing of an at-risk pregnancy may be considered.
Pregnancy management: Little data exist on the use of nitisinone during human pregnancy; however, at least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone.
Genetic counseling: Tyrosinemia type I is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if both pathogenic variants in a family are known.
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