Metabolic Disorders and Management of Tyrosinemia

Tyrosinemia type I is a rare autosomal recessive disorder of amino acid metabolism characterised by deficiency of the enzyme fumarylacetoacetate hydrolase. This defect leads to accumulation of toxic metabolites, notably fumarylacetoacetate and succinylacetone, resulting in progressive hepatic failure, renal tubular dysfunction, neurological crises and an elevated risk of hepatocellular carcinoma. The introduction of nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, has transformed management by preventing formation of downstream toxic intermediates. Lifelong dietary restriction of tyrosine and phenylalanine, supplemented with specialised amino acid formulas, mitigates nitisinone-associated hypertyrosinaemia. Early detection through newborn screening using succinylacetone markers, combined with regular monitoring of biochemical parameters, liver imaging and neurocognitive assessment, underpins optimised patient outcomes. Ongoing advances in biomarker discovery and genomic diagnostics promise further refinement of therapeutic strategies.

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Technical terms

Tyrosinemia type I: An autosomal recessive metabolic disorder caused by fumarylacetoacetate hydrolase deficiency, leading to toxic metabolite accumulation and multi-organ injury.

Fumarylacetoacetate hydrolase: The hepatic enzyme catalysing the final step of tyrosine catabolism; its absence triggers the pathological cascade in type I tyrosinemia.

Succinylacetone: A diagnostic biomarker and toxic intermediate that accumulates in blood and urine when fumarylacetoacetate hydrolase is deficient.

Nitisinone (NTBC): A pharmacological inhibitor of 4-hydroxyphenylpyruvate dioxygenase, used to block upstream tyrosine degradation and prevent formation of harmful metabolites.

Newborn screening: Population-based testing of neonates for inborn errors of metabolism, employing markers such as succinylacetone to enable presymptomatic intervention.

Hypertyrosinaemia: An elevated plasma tyrosine concentration induced by nitisinone therapy, managed through dietary adjustments to prevent keratopathy and other complications.

References

1. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genetics in Medicine (2017).
2. Recommendations for the management of tyrosinaemia type 1. Orphanet Journal of Rare Diseases (2013).
3. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet Journal of Rare Diseases (2014).
4. Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy. Orphanet Journal of Rare Diseases (2017).