Tyrosinaemia type I

Tyrosinaemia type I is a multisystem metabolic disorder affecting the liver, kidneys (proximal tubule), nervous system, and skeletal growth. In children not identified through newborn screening, presentation is typically in early infancy with severe liver involvement or, later in the first year of life, with hepatic dysfunction, proximal tubulopathy, growth failure, and rickets. Untreated children commonly develop repeated neurologic crises resembling acute intermittent porphyria, with altered mental status, abdominal pain, peripheral neuropathy, and respiratory failure that may require mechanical ventilation.

Hepatocellular carcinoma is an established long-term complication. In the absence of treatment, death usually occurs before age ten from liver failure, neurological crisis, or hepatocellular carcinoma. In affected children younger than two years, combined treatment with nitisinone and a low-tyrosine diet results in greater than 90% survival, normal growth, improved hepatic function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement of secondary rickets.

The estimated prevalence is 1/90,000-1/120,000. Markedly higher birth prevalence is observed in founder populations, including approximately 1/1,846 in the Saguenay-Lac-Saint-Jean region of Quebec and approximately 1/60,000 in Finland.

Tyrosinaemia type I is caused by biallelic germline pathogenic variants in FAH (15q25.1), which are identified in essentially all affected individuals (~100% FAH). FAH encodes fumarylacetoacetase, the terminal enzyme of tyrosine catabolism, which converts fumarylacetoacetate to fumarate and acetoacetate. Loss of FAH activity leads to accumulation of fumarylacetoacetate in hepatocytes, with cellular damage and apoptosis, and to diversion into succinylacetoacetate and succinylacetone.

Succinylacetone inhibits δ-aminolevulinic acid dehydratase, reducing haem synthesis and elevating δ-aminolevulinic acid, which contributes to acute porphyria-like neurologic crises. Therapeutic inhibition of p-hydroxyphenylpyruvate dioxygenase is achieved by nitisinone, not by succinylacetone. The underlying mechanism is loss of function.

Tyrosinaemia type I is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes, each carrying one pathogenic FAH variant; recurrence risk for siblings of an affected individual is 25% with each pregnancy. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis rests on the detection of succinylacetone, which is pathognomonic for tyrosinaemia type I. Succinylacetone is increased in blood and urine and is detected directly from the newborn dried blood spot by tandem mass spectrometry, providing the diagnostic newborn-screening marker. Supporting biochemical findings include markedly elevated serum alpha-fetoprotein (mean approximately 160,000 ng/mL in affected infants), prolonged prothrombin and partial thromboplastin times not corrected by vitamin K, and elevated plasma tyrosine, methionine, and phenylalanine.

Main differential diagnoses include:

• : inherited copper-storage disorder presenting with hepatic and neuropsychiatric disease; succinylacetone is not elevated and ceruloplasmin is typically reduced; ATP7B
• : fructose-1-phosphate aldolase B deficiency causing liver dysfunction, hypoglycaemia, and a Fanconi-like proximal tubulopathy after fructose ingestion; succinylacetone absent; ALDOB
• Acute intermittent : porphobilinogen-deaminase deficiency presenting with neurovisceral crises that mimic the neurologic crises of untreated tyrosinaemia type I; succinylacetone is not elevated and urinary porphobilinogen is characteristically increased; HMBS

• Establishing the molecular diagnosis through identification of the disease-causing pathogenic variants.
• Enabling specific and individualised surveillance and clinical management; molecular confirmation is a prerequisite for targeted medical care, which is determined by the treating physicians in consultation with the affected individual.
• Allowing predictive and carrier testing of at-risk family members once the familial pathogenic variants have been identified.

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• de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;8:8. doi:10.1186/1750-1172-8-8. PMID: . PMCID: PMC3558375.
• Larochelle J, Alvarez F, Bussières JF, Chevalier I, Dallaire L, Dubois J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012;107(1–2):49–54. doi:10.1016/j.ymgme.2012.07.022. PMID: .