Fumarylacetoacetate hydrolase (FAH) (FAH)

Fumarylacetoacetate hydrolase (FAH) is a critical metabolic enzyme that catalyzes the final step of the tyrosine degradation pathway, specifically the hydrolysis of fumarylacetoacetate into fumarate and acetoacetate [UniProt P16930, NCBI Gene 2184]. It is primarily expressed in the liver and kidneys, where it maintains metabolic homeostasis [NCBI Gene 2184]. Genetic mutations in the FAH gene lead to Hereditary Tyrosinemia Type I (HT1), a severe autosomal recessive disorder characterized by the accumulation of toxic intermediates such as maleylacetoacetate and fumarylacetoacetate [StatPearls, OMIM 276700]. These metabolites are converted into succinylacetone, a potent toxin that causes progressive liver failure, renal tubular dysfunction, and a significantly increased risk of hepatocellular carcinoma [StatPearls]. While current standard of care involves the use of nitisinone to inhibit the pathway upstream and prevent toxin formation, FAH itself is the primary target for emerging curative strategies, including gene therapies and mRNA-based enzyme replacement [ClinicalTrials.gov]. These novel approaches aim to restore endogenous FAH activity to normalize tyrosine metabolism and eliminate the long-term risks associated with metabolite buildup [ClinicalTrials.gov]. Consequently, FAH is a focal point for both neonatal screening and the development of advanced genetic medicines [StatPearls, ClinicalTrials.gov]. Successful therapeutic intervention targeting FAH could potentially offer a permanent cure for patients with HT1 by restoring the natural metabolic flux of the tyrosine pathway [StatPearls].

Other names

FumarylacetoacetaseFAABeta-ketobutyrolactone hydrolaseFAH gene

Restoration of enzyme activity via gene addition or mRNA-mediated protein expression to prevent toxic metabolite accumulation [StatPearls, ClinicalTrials.gov].