Knowledge on rare diseases and orphan drugs

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

The disease 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 (in Europe but not in Canada); 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).

The deficiency of fumarylacetoacetate hydrolase, FAH(15q23-q25) results in accumulation of fumaryl-,maleyl-acetoacetate and their derivates, succinyl-acetone (SA) and succinyl-acetoacetate (SAA), that cause hepatorenal damage. SA 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, 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. Newborn screening programs include testing for tyrosinemia type 1 (SA is the recommended marker).

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

Antenatal diagnosis is possible with chorionic villus sampling and amniocentesis when a mutation has been identified in the family.

Tyrosinemia type 1 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.

As soon as the diagnosis is confirmed (or even highly suspected) start nitisinone (NTBC) orally in a dose of 1-2 mg/kg 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, which increases the later the treatment is started.

Last update: June 2023 - Expert reviewer(s): Dr Corinne DE LAET | MetabERN*

* European Reference Network