Elevated Tyrosine and Succinylacetone/Tyrosinemia Type I via the FAH Gene

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006. PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is appropriate for individuals with NBS results showing elevated tyrosine and succinylacetone, which can indicate a deficiency of the fumarylacetoacetate hydrolase (FAH) enzyme. FAH deficiency is a core condition on the RUSP. 

Individuals with FAH deficiency may be unaffected during the newborn period but if untreated, generally develop failure to thrive, liver disease, and renal failure within the first year of life (King et al. 2017. PubMed ID: 20301688; https://www.acmg.net/PDFLibrary/Tyrosine.pdf). 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. 1990. PubMed ID: 2153931). If untreated, death usually occurs before the age of ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma (King et al. 2017. PubMed ID: 20301688). 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. 1998. PubMed ID: 9728331).

The overall prevalence of FAH deficiency is estimated at ~1/100,000-120,000, though it is significantly higher in Scandinavian countries (~1/74,000), Finland (~1/60,000), and Quebec (~1/16,000, and 1/1,846 live births in the Saguenay-Lac Saint-Jean region of Quebec) (King et al. 2017. PubMed ID: 20301688).

Fumarylacetoacetate hydrolase (FAH) deficiency, also known as hereditary tyrosinemia type I (HT1), is an autosomal recessive disorder. Over 100 pathogenic variants have been reported in the FAH gene in the Human Gene Mutation Database (HGMD, https://www.hgmd.cf.ac.uk/), with approximately half being missense changes. The remaining reported variants are nonsense, splice site, and small insertion/deletion variants. Copy number variants (CNVs) have only rarely been reported (Park et al. 2009. PubMed ID: 19569981). Several founder variants have been reported in a variety of populations: the Ashkenazi Jewish population (c.782C>T, p.Pro261Leu), the Finnish population (c.786G>A, p.Trp262*), the French Canadian and Northern European populations (c.1062+5G>A), the Pakistani population (c.192G>T, p.Gln64His), the Scandinavian population (c.1009G>A, p.Gly337Ser), the Turkish population (c.698A>T, p.Asp223Val), and the Southern European population (c.554-1G>T) (King et al. 2017. PubMed ID: 20301688). To our knowledge, de novo variants in FAH have not been reported. 

Pathogenic variants in the FAH gene lead to disruption of the fumarylacetoacetate hydrolase enzyme, 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. 1977. PubMed ID: 270706). FAH deficiency results in elevation of tyrosine and succinylacetone, as well as possible elevation of methionine and phenylalanine and 5-aminolevulinic acid (King et al. 2017. PubMed ID: 20301688; http://www.iembase.com/disorder/19).

Based on studies of individuals with a diagnosis of hereditary tyrosinemia type I, approximately 90-100% of expected FAH variants are identified by molecular testing (Bergman et al. 1998. PubMed ID: 9633815; Arranz et al. 2002. PubMed ID: 12203990; Baydakova et al. 2018. PubMed ID: 30414057; Ibarra-González et al. 2019. PubMed ID: 31568711).

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).