Tyrosinemia type 1

Tyrosinemia type 1 (also known as hepatorenal tyrosinemia or fumarylacetoacetate hydrolase deficiency) is a rare inherited metabolic disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway. This deficiency leads to the accumulation of toxic metabolites, particularly fumarylacetoacetone and succinylacetone, which cause severe damage to multiple organ systems, most notably the liver, kidneys, and peripheral nerves. The disease primarily affects the liver, where it can cause acute liver failure in infancy, chronic liver disease, cirrhosis, and a significantly increased risk of hepatocellular carcinoma. Kidney involvement manifests as renal tubular dysfunction (Fanconi syndrome), leading to phosphate wasting, rickets, and impaired growth. Neurological crises resembling acute porphyria can occur, presenting with severe pain, peripheral neuropathy, and sometimes respiratory failure. Without treatment, the acute form presenting in infancy is often fatal within the first years of life. The treatment landscape was transformed by the introduction of nitisinone (NTBC), a drug that inhibits an upstream enzyme in the tyrosine degradation pathway, preventing the formation of toxic metabolites. Nitisinone, combined with a diet restricted in tyrosine and phenylalanine, has dramatically improved survival and reduced the need for liver transplantation. Early detection through newborn screening programs, which measure succinylacetone in dried blood spots, allows for prompt initiation of treatment and significantly better outcomes. Liver transplantation remains an option for patients who do not respond to nitisinone therapy or who develop hepatocellular carcinoma. Long-term monitoring for liver complications, renal function, and neurocognitive development is essential for all affected individuals.

Common questions about Tyrosinemia type 1