The Importance of Succinylacetone: Tyrosinemia Type I Presenting with Hyperinsulinism and Multiorgan Failure Following Normal Newborn Screening

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.

New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center

“…However, a comparison of published NBS data has to consider differences in absolute results between derivatized and underivatized methods of MSMS [ 1 , 20 ]. Moreover, single cases of biochemically “mild” HT1 have been published which were diagnosed after clinical manifestation with severe liver disease, but showed only milder elevations of succinylacetone in a retrospective analysis of NBS samples between 4.65 and 5.23 µmol/L [ 22 ] or even undetectable succinylacetone in urine with a slight elevation in plasma [ 23 ] (compare Table 2 ). Also, the lower disease range of NBS succinylacetone for patients classified as HT1 in the Region 4S MSMS Collaborative Project comprises cases with succinylacetone as low as 3.8 µmol/L (first percentile of disease range).…”

Secondary Findings of Newborn Screening

“…Detecting SA in such conditions may cause parental anxiety and necessitates molecular testing and prolonged follow-up to rule out tyrosinemia type I. However, missing tyrosinemia type I diagnosis via NBS by using non-specific marker increases the risk of poor outcome with irreversible damage [63].…”

Cardiomyopathy in patients with type 1 tyrosinemia, and the effect of nitisinone treatment on cardiomyopathy

“…Although the incidence of tyrosinemia type 1 is estimated at 1:100,000 worldwide, its exact frequency in Turkey is not known 12 . On the other hand, it has been stated that there would be higher rates of hereditary metabolic diseases with autosomal recessive inheritance due to the relatively high rate of consanguineous marriages 13 .…”

“…This makes early diagnosis of tyrosinemia of utmost importance in Turkey where the incidence of this particular disease is relatively high. For the early diagnosis of tyrosinemia type 1, it is necessary to include it in the national newborn screening program 9,12,16 .…”