SCIENTIFIC BACKGROUND

FAH

Tyrosinemia type I is an autosomal recessive inherited metabolic disorder belonging to the group of amino acid metabolism defects. The prevalence is about 1:100,000. The disease is based on a deficiency of the enzyme fumarylacetoacetate hydrolase, which blocks tyrosine metabolism at the final step. This leads to accumulation of the metabolites maleyl acetoacetate and fumaryl acetoacetate, which are converted into succinyl acetoacetate and succinyl acetone. These substances have toxic effects on the liver and kidney and also inhibit the enzyme delta-aminolevulinate dehydratase, a key enzyme in porphobilinogen synthesis.

 

The clinical picture is highly variable. Different forms of tyrosinemia type I are distinguished according to the age of initial presentation. The acute form presents primarily with severe liver disease in the first weeks and months of life. The chronic form manifests clinically later and is associated with a variety of symptoms, particularly liver and kidney dysfunction and vitamin D-independent rickets. All forms are at high risk for hepatocellular carcinoma. In addition, porphyria-like symptoms also occur. Treatment with nitisinone and a low-tyrosine diet alleviates the symptoms and progression of the disease.

 

The fumarylacetoacetate hydrolase deficiency is caused by pathogenic variants in the FAH gene. The splice variants c.554-1G>T (IVS6-1G>T) and c.1062+5G>A (IVS12+5G>A) are frequently causative for the disease in the northwestern European population and in the Mediterranean region.

 

Diagnosis of tyrosinemia type 1 is part of newborn screening, and if the findings are abnormal, the diagnosis can be confirmed by molecular genetics. The disease is treatable with nitisinone and a low protein diet.

 

References
Prescribing information Orfadin® / Sniderman King et al. 2014, Tyrosinaemia Type I, Gene Reviews / de Lae et al. 2013, Orphanet Journal of Rare Diseases 8:8 / Bergmann et al. 1998, Hum Mutat. 12:19

GENES

FAH

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