Tyrosinemia, Type II via the TAT Gene

Tyrosinemia Type II, also known as Oculocutaneous Tyrosinemia or Richner-Hanhart syndrome, results from a deficiency of cytosolic hepatic tyrosine aminotransferase (TAT), the enzyme that catalyzes the first step in tyrosine catabolism (Natt et al. 1992; Mitchell et al. 2014). 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. These symptoms most frequently include lacrimation, photophobia, redness and pain, as well as dendritic corneal erosions that stain poorly or not at all with fluorescein. Approximately 75% of affected patients manifest such ocular symptoms. Skin abnormalities, which affect approximately 80% of patients and usually arise after the first year of life, are most commonly painful palmoplantar keratoderma. TAT deficient patients may present with only skin or eye symptoms, or with both. 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; Mitchell et al. 2014). Biochemically, these patients are found to have greatly increased plasma and urine concentrations of tyrosine and its derivatives. It is important to note that TAT deficiency can be distinguished biochemically from fumarylacetoacetate hydrolase (FAH) deficiency (Tyrosinemia Type I) because urinary succinylacetone is not elevated in TAT deficient patients as it is in FAH deficient patients (Mitchell et al. 2014).

Effective treatment for these patients is dietary restriction of phenylalanine and tyrosine. In patients already presenting with skin and eye abnormalities, dietary restriction can reverse existing problems. However, dietary changes have not been shown to be effective at reversing cognitive impairment. Therefore, it is essential that TAT deficient patients are diagnosed early so that dietary changes can be implemented prior to the onset of intellectual disability (Natt et al. 1992; Mitchell et al. 2014).

Tyrosinemia Type II is an autosomal recessive disorder, and TAT is the only gene in which defects are known to cause TAT deficiency. To date, over 20 causative variants have been reported in the TAT gene. The majority of reported variants are missense, although nonsense, frameshift, splice site, indels and gross deletions have all been reported (Human Gene Mutation Database). Pathogenic variants have been identified throughout the length of the gene, but most reported variants are found in the last coding exon.

TAT deficiency is caused by defects in the tyrosine aminotransferase enzyme, which is the first enzyme in the tyrosine catabolic pathway and is responsible for the conversion of tyrosine to 4-hydroxyphenylpyruvate. A defect in this enzyme results in the accumulation of tyrosine and its metabolites, although a direct causal link between hypertyrosinemia and the associated phenotype has not yet been established (Mitchell et al. 2014).

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 detectable by direct sequencing.

To date, very few gross deletions or insertions have been reported in the TAT gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TAT 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).