tyrosinemias

Tyrosinemias are a group of rare inherited metabolic disorders caused by defects in the enzymatic steps of tyrosine catabolism. Most forms are autosomal recessive and result in the accumulation of tyrosine or toxic upstream metabolites, leading to liver, kidney, ocular, or neurological problems. The disorders are categorized mainly into type I, II, and III, based on the enzymatic defect.

Tyrosinemia type I is due to deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in tyrosine degradation. This defect causes accumulation of fumarylacetoacetate and its toxic derivatives, with early-onset liver dysfunction, hepatomegaly, renal tubular Fanconi syndrome, failure to thrive, and an elevated risk of hepatocellular carcinoma. Type I can present in infancy with rapid deterioration if untreated.

Tyrosinemia type II results from tyrosine aminotransferase (TAT) deficiency. It primarily affects the eyes and skin, causing keratitis, photophobia, corneal ulcers, and palmoplantar hyperkeratosis; intellectual disability may occur if treatment is delayed.

Tyrosinemia type III is produced by 4-hydroxyphenylpyruvate dioxygenase (HPPD) deficiency. It is rare and features variable symptoms, including intermittent ataxia and mild developmental issues; elevations of tyrosine are common.

Diagnosis often involves newborn screening for type I using markers such as succinylacetone, along with elevated tyrosine levels in plasma and urine and confirmatory genetic testing. Treatment depends on type: type I is managed with nitisinone (NTBC) to inhibit upstream toxic metabolite formation, combined with dietary restriction of tyrosine and phenylalanine; liver transplantation may be considered in severe cases or persistent cancer risk. Type II and III are managed with dietary restriction and ancillary therapies for ocular or neurological symptoms. Early diagnosis and treatment improve outcomes and prognosis.