Abstract
Tyrosinemia type I (TT1) is an inborn error of tyrosine metabolism with features including liver dysfunction, cirrhosis, and hepatocellular carcinoma; renal dysfunction that may lead to failure to thrive and bone disease; and porphyric crises. Once fatal in most infantile-onset cases, pre-symptomatic diagnosis through newborn screening (NBS) protocols, dietary management, and pharmacotherapy with nitisinone have improved outcomes. Succinylacetone provides a sensitive and specific marker for the detection of TT1 but is not universally utilized in screening protocols for the disease. Here, we report an infant transferred to our facility for evaluation and management of hyperinsulinism who subsequently developed acute-onset liver, respiratory, and renal failure around one month of life. She was found to have TT1 caused by novel pathogenic variant in fumarylacetoacetate hydrolase (c.1014 delC, p.Cys 338 Ter). Her NBS, which utilized tyrosine as a primary marker, had been reported as normal, with a tyrosine level of 151 µmol/L (reference: <280 µmol/L). Retrospective analysis of dried blood spot samples via tandem mass spectrometry showed detectable succinylacetone ranging 4.65–10.34 µmol/L. To our knowledge, this is the first patient with TT1 whose initial presenting symptom was hyperinsulinemic hypoglycemia. The case highlights the importance of maintaining a high suspicion for metabolic disease in critically ill children, despite normal NBS. We also use the case to advocate for NBS for TT1 using succinylacetone quantitation.
Highlights
The defect was later found to arise from decreased fumarylacetoacetase activity, resulting in toxic accumulation of tyrosine metabolites fumarylacetoacetate and succinylacetone (SUAC) [2]
We present the case of an infant presenting with hyperinsulinemic hypoglycemia and subsequently critically ill with multiorgan failure, found to have TT1 caused by a novel pathogenic variant in FAH (c.1014 delC in exon 12; p.Cys 338 Ter) that was missed by newborn screening (NBS) utilizing tyrosine quantification as the first-line disease marker
We report the case of an infant presenting with hyperinsulinism and developing multi-organ failure who harbored a novel homozygous pathogenic nonsense mutation in FAH (c.1014 delC; p.Cys 338 Ter) consistent with TT1
Summary
Gentz and colleagues first described tyrosinemia in 1965 in a cohort of children with liver failure, cirrhosis, and renal dysfunction with high levels of tyrosine in their urine and plasma [1]. In 1992, Lindstedt and colleagues reported successful use of the 4-hydroxyphenylpyruvate dioxygenase inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC; nitisinone; brand-names Orfadin or Nityr) in the treatment of 5 patients with TT1 [12] Compared with both late (after one month of age) or no therapy, the Quebec NTBC Protocol showed that early (prior to one month of age) initiation of NTBC eliminated acute manifestations of TT1 and reduced the need for LT with only rare side-effects—most notably, corneal deposits [13]. When 12 children in the UK were tested for TT1 at birth and initiated on NTBC at an average age of four days, none demonstrated laboratory or imaging evidence of liver pathology at 8.5 years follow-up [20]. In Spain, 7/8 patients diagnosed via NBS at an average age of 12.7 days and initiated on NTBC pre-symptomatically remained liver- and renal-disease free at an average. While there was no difference in poor hepatic outcomes between patients diagnosed via NBS and those diagnosed clinically (p-value of 0.06), there was a difference in cognitive outcomes, with the latter group demonstrating lower IQs or psychomotor developmental indices on average (p-value 0.009) [21]
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