Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1

Abstract

Hereditary tyrosinemia type 1 (HT1) (OMIM 276700) is a severe inherited metabolic disease affecting mainly hepatic and renal functions that leads to a fatal outcome if untreated. HT1 results from a deficiency of the last enzyme of tyrosine catabolism, fumarylacetoacetate hydrolase (FAH). Biochemical findings include elevated succinylacetone in blood and urine; elevated plasma concentrations of tyrosine, methionine and phenylalanine; and elevated tyrosine metabolites in urine. The HT1 frequency worldwide is about 1 in 100,000 individuals. In some areas, where the incidence of HT1 is noticeably higher, prevalence of characteristic mutations has been reported, and the estimated incidence of carriers of a specific mutation can be as high as 1 out of 14 adults. Because the global occurrence of HT1 is relatively low, a considerable number of cases may go unrecognized, underlining the importance to establish efficient prenatal and carrier testing to facilitate an early detection of the disease. Here we describe the 95 mutations reported so far in HT1 with special emphasis on their geographical and ethnic distributions. Such information should enable the establishment of a preferential screening process for mutations most predominant in a given region or ethnic group.

Fig. 1

Location of the 95 mutations identified on the fah gene. Among the known HT1 alleles causing mutations, 45 are missense mutations, 23 are splicing mutations, 13 are nonsense mutations, 10 are deletions and 4 are frameshift. Intronic mutations are illustrated at the bottom of the figure

Fig. 2

Geographical distribution of the most common HT1 alleles causing mutations worldwide. Pie chart representing distribution of ethnic groups in HT1 alleles. Where the patient provenance was not clear, the mutation is included in the continent of origin, i.e. undefined (un) on graphic. The top three mutations and the total number of alleles for each continent are reported. There are more than 894 HT1 alleles reported worldwide. The most frequent HT1 mutation encountered is the IVS12+5G>A splice mutation, which accounts for 33.7% of all HT1 alleles, followed by the IVS6-1G>T mutation (16.4%). The French Canadian population alone accounts for as much as a third of all HT1 alleles reported. Both mutations are the most reported globally