engleski

Importance of analyzing amino acid concentrations on tandem mass spectrometer in monitoring the treatment of tyrosinemia type 1

Introduction Tyrosinemia type 1 is an autosomal recessive aminoacidopathy caused by deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme responsible for the final step of tyrosine breakdown. Consequently, tyrosine and its metabolites accumulate, resulting in toxicity to liver and renal cells. Symptoms of the disease begin usually after three weeks of life and include vomiting, failure to thrive, hepatomegaly, jaundice, tendency to bleed and bruise easily, rickets and renal tubular dysfunction. The untreated disease eventually progresses to liver or kidney failure and usually ends fatally in early childhood. In patients who survive, there is an increased risk of hepatocellular carcinoma. Prompt diagnosis is extremely important because early start of treatment may prevent fatal outcome. Subjects and methods A male newborn with positive family history of tyrosinemia type 1 was subjected to a metabolic work-up immediately after birth. Amino acids were quantified by tandem mass spectrometry coupled with high performance liquid chromatography, LC-MS/MS (API 3200, Sciex ; UPLC Nexera, Shimadzu). The results were obtained using aTRAQ™ reagent by Sciex with internal standards of known concentration for each amino acid. DNA analysis of the FAH gene was performed in Sahlgrenska University Hospital in Gothenburg, Sweden. Results At first day of life, patient's plasma amino acid analysis showed increased concentration of tyrosine (169 µmol/L ; normal: 42-135 µmol/L) while urine organic acid analysis detected succinylacetone, a tyrosine metabolite specific for tyrosinemia type 1. The diagnosis was confirmed by patient's DNA sequencing, which revealed a homozygosity for the c.554-1G>T mutation in the FAH gene. As soon as the diagnosis was established, nitisinone treatment, combined with a dietary restriction of tyrosine and phenylalanine, was introduced. Routine measurement of amino acid concentrations continued while a patient has been regularly monitored. Conclusion Regular measurement of the concentration of plasma amino acids using LC-MS/MS enables therapy adjustment and treatment efficiency monitoring in patients with tyrosinemia type 1.

tandem mass spectrometry, tyrosinemia type 1

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