Tyrosinemia Panel

Tyrosinemia is an inborn error in the metabolism of tyrosine, resulting in elevated levels of tyrosine and derivative metabolites. Succinylacetone is elevated in tyrosinemia type I, but not in types II or III. Tyrosinemia is caused by pathogenic variants in the FAH, TAT, or HPD genes (Sniderman King et al. 2017. PubMed ID: 20301688). In addition, hypersuccinylacetonemia is observed in the clinically benign disorder maleylacetoacetate isomerase deficiency, caused by variants in the GSTZ1 gene (Yang et al. 2017. PubMed ID: 27876694).

Type I tyrosinemia is caused by pathogenic variants in the FAH gene. The first clinical signs usually appear in newborns with severe liver pathology. 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; Sniderman King et al. 2017. PubMed ID: 20301688).

Tyrosinemia Type II, also known as Oculocutaneous Tyrosinemia or Richner-Hanhart syndrome, is caused by pathogenic variants in the TAT gene. Affected patients present with eye, skin and neurologic symptoms. Typically, the ocular symptoms are the first to appear and are usually observed during the first year of life. Skin abnormalities, which affect approximately 80% of patients and usually arise after the first year of life, are most commonly painful palmoplantar keratoderma. Lastly, over 60% of affected patients present with intellectual disability, which can range from a mild decrease in intelligence to severe intellectual disability associated with microcephaly and other organ abnormalities (Charfeddine et al. 2006. PubMed ID: 16574453; Mitchell et al. 2014; Sniderman King et al. 2017. PubMed ID: 20301688).

Both tyrosinemia type III and Hawkinsinuria are rare inborn errors of tyrosine metabolism caused by pathogenic variants in the HPD gene (Mitchell et al. 2014). The onset for both disorders is in infancy. Very few patients have been reported with tyrosinemia type III, and thus far a consistent clinical picture has not emerged for this disorder. However, the symptoms most commonly reported in affected patients have been ataxia, developmental delay, intellectual disability and behavior abnormalities (Rüetschi et al. 2000. PubMed ID: 10942115; Tomoeda et al. 2000. PubMed ID: 11073718; Item et al. 2007. PubMed ID: 17560158; Mitchell et al. 2014).

Variants in the GSTZ1 gene have been shown to lead to maleylacetoacetate isomerase deficiency, resulting in hypersuccinylacetonemia (Yang et al. 2017. PubMed ID: 27876694). Elevated succinylacetone has been considered to be pathognomonic for tyrosinemia type I, and thus these individuals were initially flagged for follow up studies and possible initiation of treatment for tyrosinemia type I. As maleylacetoacetate isomerase deficiency is considered a clinically benign disorder, it is useful to be able to distinguish between individuals with hypersuccinylacetonemia as a result of GSTZ1 variants versus those with true tyrosinemia type I.

Tyrosinemia types I, II and III are autosomal recessive disorders. Variants in the FAH gene are the genetic cause of type I tyrosinemia, which is the most commonly reported genetic tyrosinemia. Pathogenic variants include missense, nonsense, splicing, small deletions, small indels, and at least one gross deletion (Human Gene Mutation Database). Founder mutations have been identified in Ashkenazi Jews (c.782 C>T, or p.Pro261Leu; Elpeleg et al. 2002. PubMed ID: 11754109) and French Canadians (c.1062+5G>A; Grompe et al. 1994. PubMed ID: 8028615). The overall prevalence of tyrosinemia type I is estimated at ~1:100,000 – 1:120,000. This number is higher in Scandinavian countries (~1:60,000 – 1:74,000) and as high as 1:1,846 births in the Saguenay-Lac Saint-Jean region of Quebec (Sniderman King et al. 2017. PubMed ID: 20301688).

Variants in the TAT gene are the genetic cause of type II tyrosinemia. To date, over 30 causative variants have been reported in the TAT gene. The majority of reported variants are missense, although nonsense, splice site, small deletions and insertions, indels and gross deletions have all been reported (Human Gene Mutation Database).

Both tyrosinemia type III and Hawkinsinuria are caused by defects in the HPD gene. Tyrosinemia type III is an autosomal recessive disorder whereas Hawkinsinuria is an autosomal dominant disorder. To date, fewer than 10 pathogenic variants have been reported in the HPD gene. The majority of the reported variants are missense changes, though a few nonsense and splice variants have also been reported (Human Gene Mutation Database).

Fewer than five variants in GSTZ1 have been reported in association with autosomal recessive hypersuccinylacetonemia. Two of these variants were missense, one was nonsense, and one was an intronic variant predicted to create a novel splice acceptor site (Yang et al. 2017. PubMed ID: 27876694).

The FAH, HPD, TAT, and GSTZ1 genes all encode enzymes in the phenylalanine/tyrosine metabolic pathway. TAT encodes tyrosine aminotransferase, which is responsible for the conversion of tyrosine to 4-hydroxyphenylpyruvic acid. The 4-hydroxyphenylpyruvic acid is subsequently converted to homogentisic acid by the action of the 4-hydroxyphenylpyruvic acid dioxygenase enzyme, which is encoded by the HPD gene. Further in the pathway, the enzyme maleylacetoacetate isomerase (encoded by the GSTZ1 gene) converts maleylacetoacetic acid to fumarylacetoacetic acid, which is then converted to fumaric acid and acetoacetic acid by the fumarylacetoacetic acid hydrolase enzyme (encoded by FAH) (Sniderman King et al. 2017. PubMed ID: 20301688; Yang et al. 2017. PubMed ID: 27876694).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Although the overall sensitivity of this test panel is not precisely known, nearly all pathogenic variants reported for the genes in this panel are of the type which can be detected by sequencing with CNV analysis.

The most commonly affected gene in tyrosinemia patients is FAH. Over 95% of causative FAH variants have been reportedly detected by gene sequencing (Dursun et al. 2011. PubMed ID: 23430822; Imtiaz et al. 2011. PubMed ID: 21764616; Sniderman King et al. 2017. PubMed ID: 20301688). At least one pathogenic gross deletion encompassing multiple FAH exons has been reported (Park et al. 2009. PubMed ID: 19569981).

For the HPD and TAT genes, clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Analytical sensitivity should be high because the great majority of variants reported are expected to be detectable via this test methodology.

As only a few patients have been reported to date, it is uncertain what proportion of individuals identified based on hypersuccinylacetonemia on newborn screening tests would be expected to harbor causative variants in GSTZ1.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).