Diagnostic Criteria

Suggestive Findings

Tyrosinemia type I should be suspected in:

• An infant with an out-of-range newborn screening (NBS) result;

• An individual at any age with clinical and biochemical findings suggestive of tyrosinemia type I (including late-onset tyrosinemia type I).

Infant with Out-of-Range NBS Result

NBS for tyrosinemia type I is based on use of dried blood spots collected between 24 and 72 hours after birth to quantify succinylacetone concentration by tandem mass spectrometry (MS/MS). This is the first-tier test, as succinylacetone is the most specific and sensitive marker for tyrosinemia type I. Tyrosine is also measured as part of NBS for tyrosinemia type I, typically as a second-tier test; however, it is neither a specific nor sensitive marker for this condition.

Source: GeneReviews — "Tyrosinemia Type I"

Differential Diagnosis

Abnormal Newborn Screening (NBS) Result Elevated tyrosine concentration on NBS can be the result of transient tyrosinemia of the newborn, tyrosinemia type II, tyrosinemia type III , or other liver disease. Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism (e.g., adenosine kinase deficiency [OMIM 614300] and S-adenosylhomocysteine hydrolase deficiency [OMIM 613752)], or classic homocystinuria (see Homocystinuria due to Cystathionine Beta-Synthetase Deficiency). The detection of succinylacetone in the NBS specimen is pathognomonic for tyrosinemia type I. Symptomatic Individual When evaluating a symptomatic individual for tyrosinemia type I, it is essential to consider other genetic disorders and acquired conditions (e.g., non-genetic causes of liver disease) that can present with similar clinical features, especially in infants and young children with liver dysfunction, renal tubular disease, or poor growth. Clinical correlation is recommended. Table 3. Tyrosinemia Type I: Differential Diagnosis

Management Guidelines

Management guidelines for tyrosinemia type I have been published, including US recommendations and European recommendations .

Evaluation of a Newborn with an Out-of-Range Newborn Screening (NBS) Result

To confirm the diagnosis and establish the extent of disease and needs in an individual with a positive NBS for tyrosinemia type I, the evaluations summarized in are recommended.

Table 4.

Tyrosinemia Type I: Recommended Evaluations Following an Out-of-Range Newborn Screening Result

System/Concern | Evaluation | Comment

Biochemical

| Consultation w/metabolic physician/ biochemical geneticist metabolic dietitian1 | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).

• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, low-protein diet, maintenance emergency treatment, prognosis, risks for acute encephalopathic crises).

Laboratory eval | • CBC w/differential platelet count, comprehensive metabolic panel

• Assessment of liver function (blood AST, ALT, GGT, ALP, total direct bilirubin, prothrombin time, PTT/INR, AFP, plasma amino acids, urine organic acids, blood urine succinylacetone)

Clinical Guidance

Avoid the following:

• Excessive dietary protein or protein malnutrition inducing catabolic state

• Prolonged fasting

• Catabolic illness (intercurrent infection, brief febrile illness post vaccination)

• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

Source: GeneReviews — "Tyrosinemia Type I"

Surveillance Guidelines

In addition to evaluations by a metabolic specialist and metabolic dietician, frequent evaluation of the parameters summarized in are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Table 10. Tyrosinemia Type I: Recommended Surveillance

Source: GeneReviews — "Tyrosinemia Type I"