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Tyrosinemia type 1

Orpha number ORPHA882
Synonym(s) FAH deficiency
Fumarylacetoacetase deficiency
Fumarylacetoacetate hydrolase deficiency
Hepatorenal tyrosinemia
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset All ages
ICD-10
  • E70.2
ICD-O -
OMIM
UMLS
  • C0268490
MeSH -
MedDRA
  • 10069462

Summary

Tyrosinemia type 1 (HTI) is an inborn error of tyrosine catabolism caused by defective activity of fumarylacetoacetate hydrolase (FAH) and is characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone.

Birth incidence is 1/100,000 in most areas but is more common is some regions, notably in Québec, Canada.

HT1 is clinically heterogenous. Symptoms may start during the first few months (acute type), in second half of the first year (subacute type) or in the following years up to adulthood (chronic type). In the acute type, manifestations of hepatic failure predominate (bleeding diathesis, hypoglycemia, ascites etc) with frequent sepsis and rapid deterioration. Mild proximal tubular disease is usually present. Subacute type manifests a similar but less severe clinical picture presenting usually with hepatomegaly or hypophosphatemic rickets (due to tubular dysfunction). Intercurrent illness may precipitate hepatic crisis. Chronic type presents with hepatomegaly secondary to cirrhosis and often tubulopathy, leading to rickets and renal failure. Neurological crises are infrequent presenting symptoms; however they can complicate any type of the disease when untreated. The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation. All patients stand a high risk of developing hepatocellular carcinoma (HCC) secondary to cirrhosis.

The deficiency of fumarylacetoacetate hydrolase, FAH(15q23-q25) results in accumulation of fumaryl- and maleyl-acetoacetate that cause hepatorenal damage. The accumulation of their derivatives (succinyl-acetone (SA) and succinyl-acetoacetate (SAA)) leads to accumulation of delta-aminolevulinate (δ-ALA) resulting in inhibition of porphobilinogen synthesis and porphyria-like crises.

Liver synthetic functions are usually severely affected with coagulopathy and hypoalbuminemia. Elevated levels of SA in dried blood spots, plasma or urine are pathognomonic. Other abnormalities include elevated α -fetoprotein (especially in acutely ill infants), increased plasma levels of tyrosine, phenylalanine and methionine, increased urinary δ-ALA excretion and features of Fanconi tubulopathy. Confirmation of diagnosis is usually by mutation analysis.

Differential metabolic diagnoses include classic galactosemia, hereditary fructose intolerance, and fructose 1,6 diphosphatase deficiency, Wilson's disease and some mitochondrial disorders (see these terms).

Prenatal diagnosis is feasible by mutation analysis on chorionic villus sampling (CVS), if the familial causative mutations are known or alternatively by FAH assay on CVS or amniocytes and determination of SA levels in amniotic fluid. Newborn screening is available in many countries.

HT1 is an autosomal recessive disorder with a 25% risk of recurrence within a family.

As soon as the diagnosis is confirmed (or even highly suspected) start nitisinone (NTBC) orally in a dose of 1-2 mg/kg once a day along with the emergency treatment for acute liver failure if necessary. A protein-restricted diet must also be started in parallel. Patients should be referred to a specialist center for long term management. Liver transplantation should be considered in acutely ill infants (if liver function fails to respond to nitisinone within a week), suspected or diagnosed HCC, and non-compliance or unavailability of medical treatment.

Nitisinone treatment, combined with a low-protein diet allows most the patients to survive in good health. The prognosis is dominated by the risk of HCC.

Expert reviewer(s)

  • Dr Hélène OGIER DE BAULNY

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Detailed information

Summary information
Clinical practice guidelines
  • EN (2013,pdf)
Clinical genetics review
  • EN (2014)
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  • EN (2011)
  • FR (2011)
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