Confirming the Diagnosis: Understanding the Tests

Navigating the diagnostic process for a rare condition like Tyrosinemia Type 2 can be complex. Because the symptoms often mimic more common illnesses, reaching a definitive diagnosis requires a specific set of metabolic and genetic tests.

The Diagnostic Pathway

The journey to a diagnosis usually begins when a doctor notices high levels of tyrosine in a child’s blood. However, one high reading is not enough to confirm the condition, as transient elevation can happen due to prematurity or liver issues.

1. Quantitative Plasma Amino Acids: This is a detailed blood test that measures the exact amount of various amino acids ^[1]. In Tyrosinemia Type 2, the tyrosine level is typically markedly and persistently elevated. While levels are often observed exceeding 600 μmol/L, this is not an absolute diagnostic cutoff ^[2][3].
2. Succinylacetone (SA) Testing: This is perhaps the most critical step in the early evaluation. Succinylacetone is a toxic byproduct that is almost always present in Tyrosinemia Type 1 (a much more severe form of the disease that affects the liver) but is normal in Tyrosinemia Type 2 ^[3][4]. Measuring SA in the blood or urine helps differentiate between the two types quickly, though a normal result alone does not confirm Type 2 ^[3].
3. Genetic Testing: A definitive diagnosis generally relies on identifying mutations in both copies of the TAT gene ^[1]. This test confirms that the body’s machinery for breaking down tyrosine is fundamentally altered, but the results must always be interpreted alongside clinical symptoms ^[2].

The Common “Mistaken Identity”: HSV Keratitis

One of the biggest hurdles in diagnosing Tyrosinemia Type 2 is that its eye symptoms look remarkably like a viral infection called Herpes Simplex Keratitis (HSV) ^[1].

Both conditions cause painful, branch-like patterns (called pseudodendrites) on the surface of the eye, along with redness and light sensitivity ^[5][1]. Because HSV is common and Tyrosinemia Type 2 is extremely rare, doctors often prescribe antiviral eye drops first.

Important Clues for Parents:

• Both Eyes vs. One: HSV usually affects only one eye, while the eye lesions in Tyrosinemia Type 2 frequently appear bilaterally (in both eyes) ^[5][1]. However, HSV can occasionally be bilateral as well.
• Treatment Failure: If eye lesions do not improve with antiviral treatment, doctors should consider testing for Tyrosinemia Type 2 ^[1][6]. However, a negative HSV PCR test can occasionally be falsely negative. Do not dismiss a potentially vision-threatening infection or stop prescribed antiviral treatment without your eye doctor’s instruction.
• Skin Connection: If eye issues occur at the same time as painful skin thickening on the hands or feet, it is a strong signal that the cause is metabolic rather than viral ^[6].

Why the Newborn Screen Might “Miss” It

It is a common misconception that a “normal” newborn screen rules out all metabolic disorders. While many regions now include Tyrosinemia Type 1 in their screening, Tyrosinemia Type 2 is not always detected for several reasons:

• Varying Thresholds: Each state or country sets its own “cutoff” for what is considered a high tyrosine level. If a baby’s tyrosine level hasn’t risen high enough by the time the heel-prick test is done (usually 24–48 hours after birth), the test may appear normal ^[7].
• Timing of Symptoms: In some children, tyrosine levels take weeks or months to climb to a level that causes symptoms ^[6]. A documented case showed a child with a negative newborn screen who was not diagnosed until 15 months of age after developing eye and skin issues ^[6].

If your child shows the hallmark signs of light sensitivity, eye pain, or thickened skin on the palms and soles, a negative newborn screen should not stop further testing. A simple plasma amino acid test can provide the clarity needed.