Tyrosinemia, Type I via the FAH Gene

Type I tyrosinemia (OMIM 276700) results from deficiency of fumarylacetoacetate hydrolase (FAH), the enzyme that catalyzes the final step in tyrosine catabolism. The precursor metabolite, fumarylacetoacetate, accumulates in hepatocytes in the absence of FAH activity. This results in cellular damage and diversion to succinylacetone, a reactive metabolite known to interfere with hepatic enzymes (Lindblad et al. Proc Nat Acad Sci 74:4641-4645, 1977). The first clinical signs usually appear in newborns with severe liver pathology. Biochemical findings include elevated succinylacetone in the blood and urine, elevated plasma concentrations of tyrosine, methionine, and phenylalanine, and elevated tyrosine metabolites in the urine. Some patients present after the newborn period with rickets and failure to thrive secondary to hepatic and renal dysfunction. A significant number of patients have neurological symptoms including peripheral neuropathy characterized by severe pain with extensor hypertonia, muscle weakness, paralysis requiring ventilation, and self-mutilation (Mitchell et al. N Eng J Med 322:432-437, 1990). If untreated, death usually occurs before the age of ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma (Sniderman King et al. GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1515/). Effective treatment is achieved with nitisinone (NTBC) along with avoidance of dietary phenylalanine and tyrosine. Liver transplantation may be indicated in cases with severe liver damage or hepatocellular carcinoma (Holme et al. J Inherit Metab Dis 21:507-517, 1998).

Tyrosinemia is an autosomal recessive disorder. Variants in the FAH gene (OMIM 613871) are the genetic cause of type I tyrosinemia (OMIM #276700). Pathogenic variants include missense, nonsense, splicing, and frameshift variants. Founder variants have been identified in Ashkenazi Jewish (c.782 C>T, or p.Pro261Leu; Elpeleg et al. Hum Mut 19:80-81, 2002) and French Canadians (c.1062+5G>A; Grompe et al. N Eng J Med 331:353-357, 1994). The birth incidence of type I tyrosinemia in the USA is thought to be ~1:100,000 (Mitchell et al. in Scriver et al. (ed) The Metabolic and Molecular Basis of Inherited Disease pp.1777-1806, 2001). Higher incidences of disease in Finland and Norway result from elevated carrier rates for c.786 G>A (p.Trp262Stop) and c.1062+5G>A variants, respectively.

Four variants (c.1062+5G>A, c.456-1G>T, c.554-6T>G, p.Pro261Leu) account for 60% of the FAH variants in the USA. p.Pro261Leu accounts for >99% of the variants in the Ashkenazi Jewish population (Elpeleg et al. Hum Mut 19:80-81, 2002) and the c.1062+5G>A accounts for nearly 90% of variants in the French Canadian population (Poudrier et al. Prenat Diagn 16:59-64, 1996).

The sensitivity of duplication/deletion testing for this rare disorder is currently unknown. However, it should be noted that at least one pathogenic gross deletion encompassing multiple FAH exons has been reported (Park, H.D. et al. Clin Chem Lab Med 47:930-933, 2009).

This test provides full coverage of all coding exons of the FAH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).