The Unique Spectrum of Mutations in Patients with Hereditary Tyrosinemia Type 1 in Different Regions of the Russian Federation

Abstract

Background: Hereditary tyrosinemia (HT1) is an autosomal recessive disorder characterized by impaired tyrosine catabolism because of fumarylacetoacetate hydrolase deficiency. HT1 is caused by homozygous or compound heterozygous mutations in the FAH gene. The HT1 frequency worldwide is 1:100,000-1:120,000 live births. The frequency of HT1 in the Russian Federation is unknown. Aim: To estimate the spectrum of mutations in HT1 in several ethnic groups of the Russian Federation. Materials and methods: From 2004 to 2017, 43 patients were diagnosed with HT1. The analysis of amino acids and succinylacetone was performed using NeoGram Amino Acids and Acylcarnitines Tandem Mass Spectrometry Kit and a Sciex QTrap 3200 quadrupole tandem mass spectrometer. Bi-directional DNA sequence analysis was performed on PCR products using an ABI Prism 3500. Results: In the Russian Federation, the most common mutation associated with HT1 (32.5% of all mutant alleles) is c.1025C>T (p.Pro342Leu), which is typical for the Chechen ethnic group. Patients of the Yakut, the Buryat, and the Nenets origins had a homozygous mutation c.1090G>C (p.Glu364Gln). High frequency of these ethnicity-specific mutations is most likely due to the founder effect. In patients from Central Russia, the splicing site mutations c.554-1G>T and c.1062+5G>A were the most prevalent, which is similar to the data obtained in the Eastern and Central Europe countries. Conclusion: There are ethnic specificities in the spectrum of mutations in the FAH gene in HT1. The Chechen Republic has one of the highest prevalence of HT1 in the world.

The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1)

“…To date, over 900 mutations of FAH have been identified. Among them, around 100 variants were reported to be associated with HT1 (Table S1) (Angileri et al, 2015; Angileri, Bergeron, et al, 2014; Angileri, Morrow, et al, 2014; Awata et al, 1994; Baydakova et al, 2019; Bergman et al, 1998; Couce et al, 2011; Dursun et al, 2011; Forget et al, 1999; Gokay et al, 2016; Ibarra‐González et al, 2019; Imtiaz et al, 2011; Introne, 2021; Kawabata et al, 2022; Luijerink et al, 2004; Maiorana et al, 2014; McKiernan et al, 2015; Morrow et al, 2017; Morrow et al, 2019; Nakamura et al, 2007; Pérez‐Carro et al, 2014; Ploos van Amstel et al, 1996; Van Dyk et al, 2010; van Spronsen et al, 1994; Wu & Hurst, 2016). It was worth noting that the most frequent FAH mutation to cause HT1 is c.1062+5G>A (IVS12+5G>A) (32.3%), followed by c.554‐1G>T (IVS6‐1G>T) (16.4%) and c.786G>A (p.W262X) (5.6%) (Angileri, Bergeron, et al, 2014).…”

“…Insights on the relationship between gene polymorphisms and amino acid metabolism have helped target FAH mutation‐mediated tyrosinemia processes underlying renal dysfunction (Angileri, Bergeron, et al, 2014; Dursun et al, 2011; Morrow et al, 2017). Up to now, approximately 100 pathogenic FAH variants have been reportedly associated with HT1, and despite numerous studies, no clear genotype–phenotype map has been established (Angileri, Bergeron, et al, 2014; Baydakova et al, 2019; Ibarra‐González et al, 2019). For children with atypical clinical manifestations, the identification of biallelic pathogenic FAH variants using molecular genetic testing should be combined, especially for prenatal diagnoses.…”

“…numerous studies, no clear genotype-phenotype map has been established (Angileri, Bergeron, et al, 2014;Baydakova et al, 2019;Ibarra-González et al, 2019). For children with atypical clinical manifestations, the identification of biallelic pathogenic FAH variants using molecular genetic testing should be combined, especially for prenatal diagnoses.…”

Tyrosinemia type 1 in a child, experience of a hematologist. Clinical case

“…ŬƂƊƈƁƂƇſƆƟƙ ƌƂƉ I (ŧŬ-1) -ƊƟžƄƟƋƇſ ƋƉźž-Ƅƈżſ ƁźƏżƈƊƘżźƇƇƙ, ƋƉƊƂƑƂƇſƇſ ƉƈƊƍƒſƇƇƙƆ źƆƟƇƈƄƂƋƅƈƌƇƈŽƈ ƈŻƆƟƇƍ, Ɖƈż'ƙƁźƇſ Ɓ žſƎſƄƌƈƆ ƈŻƆƟƇƍ ƊſƑƈżƂƇ Ɵ ƉƈƊƍƒſƇƇƙƆ ƆſƌźŻƈƅƟƁƆƍ ƌƂƊƈƁƂƇƍ, Ɠƈ ƉƊƂƁżƈžƂƌƖ žƈ ƉſƑƟƇƄƈżƈƠ Ƈſžƈ-ƋƌźƌƇƈƋƌƟ ƟƁ ƋƍƉƍƌƇƟƆƂ ƁźƏżƈƊƘżźƇƇƙƆƂ ƇƂƊƈƄ Ɵ ƇſƊżƈżƈƠ ƋƂƋƌſƆƂ [1,5,20,21] [5,7]. ŭ 37% ƏżƈƊƂƏ, ƙƄƟ ż ƆƂƇƍƅƈƆƍ ƉſƊſƀƂƅƂ Ɗƍƃ-ƇƟżƇƟ ƍƋƄƅźžƇſƇƇƙ HT-1, żƂƇƂƄźƘƌƖ ŽſƉźƌƈƆƂ, Ɠƈ ƑźƋƌƈ ƌƊźƇƋƎƈƊƆƍƘƌƖƋƙ ż ŝŰŤ [29].…”