Newborn screening · Amino acid disorder
Tyrosinemia, Type I · TYR-I
Tyrosine metabolism defect. Liver failure and hepatocellular carcinoma risk. Nitisinone (NTBC) transformed outcomes.
Description
Tyrosinemia, Type I, is an inherited block in the final step of tyrosine breakdown. The enzyme fumarylacetoacetate hydrolase, encoded by FAH, normally cleaves fumarylacetoacetate. Two damaging copies of FAH leave the enzyme nonfunctional, and upstream intermediates including succinylacetone build up in liver and kidney. Inheritance is autosomal recessive.
Untreated infants present in the first months of life with liver failure, coagulopathy, renal tubular dysfunction with hypophosphatemic rickets, and a high lifetime risk of hepatocellular carcinoma. A milder later-onset form presents with chronic liver disease and rickets in childhood. Detection is by newborn screening on the dried blood spot, with succinylacetone as the analyte. Confirmation uses urine succinylacetone, plasma amino acids, and FAH gene sequencing.
Reported live-birth incidence is approximately 1 in 100,000 worldwide. The Saguenay-Lac-Saint-Jean region of Quebec carries a well-documented founder effect for the IVS12+5G to A FAH variant. De Braekeleer and Larochelle (American Journal of Human Genetics, 1990) reported a regional incidence of approximately 1 in 1,846 live births and a carrier frequency near 1 in 22, traceable to seventeenth-century French settlers.
Treatments to date
Standard of care combines nitisinone with a tyrosine-restricted and phenylalanine-restricted diet, started as soon as the diagnosis is suspected after newborn screening. Nitisinone, also known as NTBC, inhibits 4-hydroxyphenylpyruvate dioxygenase upstream of the FAH block and prevents the accumulation of toxic intermediates. The diet limits the substrate that nitisinone diverts into circulating tyrosine. A metabolic team monitors plasma tyrosine, succinylacetone, alpha-fetoprotein, and liver imaging across childhood and adulthood.
Nitisinone (brand Orfadin) was approved by the FDA in January 2002 for hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine. A generic nitisinone became available in the United States in 2017. Liver transplantation remains the option for children who present late with established hepatocellular carcinoma or who do not respond to nitisinone, and it cures the metabolic defect.
Long-term outcome data from the era of nitisinone plus diet show survival and growth that approach those of unaffected children when treatment starts in the first month of life. Cohort follow-up from Quebec and from European national registries documents reduced but not eliminated risk of hepatocellular carcinoma when treatment is delayed beyond the first weeks. Gene-replacement and gene-editing approaches for FAH remain in preclinical and early clinical development.