Diagnosis and the importance of early treatment of tyrosinemia type 1: A case report

Abstract

Tyrosinemia type 1 is an autosomal recessive aminoacidopathy caused by fumarylacetoacetate hydrolase (FAH) deficiency. Consequently, tyrosine and its metabolites accumulate, resulting in liver and kidney toxicity. Symptoms of the disease usually manifest after three weeks of life and include vomiting, failure to thrive, hepatomegaly, jaundice, bleeding diathesis, rickets and renal tubular dysfunction. Untreated, the disease eventually progresses to liver or kidney failure and generally results in a fatal outcome. Expedient diagnosis is critical because an early start of treatment can increase the likelihood of a positive outcome. Here, we report on a male newborn with a family history positive for tyrosinemia type 1 who was subjected to a metabolic work-up immediately after birth. Amino acids were quantified by tandem mass spectrometry coupled with ultra performance liquid chromatography. Urinary organic acids were analyzed on capillary gas chromatography coupled with mass spectrometry. DNA analysis of the FAH gene was performed by Sanger sequencing. On the first day of life, the patient's plasma amino acids showed an increased tyrosine concentration, while urine organic acids detected succinylacetone, a tyrosine metabolite specific for tyrosinemia type 1. The patient's DNA analysis revealed homozygosity of the c.554-1G > T mutation in the FAH gene, which was consistent with the diagnosis. Nitisinone treatment, combined with a dietary restriction of tyrosine and phenylalanine, was introduced immediately. Regular visits and measurement of amino acid concentrations, which enables therapy adjustment and treatment efficiency monitoring in patients with tyrosinemia type 1, has continued over the past 4+ years, and is expected to continue.

Keywords: BSTFA+1%TCMS, N,O-Bis (trimethylsilyl)trifluoroacetamide with 1% trimethylchlorosilane 99:1; CE, collision energy; CXP, collision cell exit potential; DBS, dried blood spot; DP, declustering potential; EP, entrance potential; ESI, electrospray ionization; FAA, fumarylacetoacetate; FAH, fumarylacetoacetate hydrolase; GC MS, capillary gas chromatography coupled with mass spectrometry; GS1, nebulizer gas; GS2, heater gas; HCl, hydrochloric acid; LC-MS/MS, tandem mass spectrometry coupled with ultra performance liquid chromatography; MRM, multiple reaction monitoring; NBS, newborn screening; NTBC, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione; PFBO, O-(2,3,4,5,6-Pentafluorobenzyl)hydroxylamine hydrochloride; Q1, first quadrupole; Q3, third quadrupole; RCF, Relative Centrifugal Force; RP, reverse phase; SUAC, succinylacetone; TIC, Total Ion Chromatogram; TYRSN1, tyrosinemia type 1; Tyr, tyrosine; Tyr_IS, tyrosine internal standard.

Fig. 1

Total Ion Chromatogram-TIC of a TYRSN1 patient compared with the TIC of a healthy individual. Plasma amino acid chromatograms show a high intensity peak of tyrosine (Tyr) in the TYRSN1 patient (A) compared to the chromatogram of a healthy individual (B).