Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

Abstract

Recent reports suggested that homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a more common inborn error of metabolism than originally thought. In this study we compared the prevalence of homocystinuric alleles ascertained by two different approaches. First, the incidence of homocystinuria estimated by selective biochemical screening in the Czech and Slovak Republics was 1:349,000 (95% CI 1:208,000-1:641,000). The two most common pathogenic mutant alleles found subsequently in these patients, IVS11-2A>C and c.833T>C, had a calculated population prevalence of 0.00042 (95% CI 0.00031-0.00055) and 0.00018 (95% CI 0.00013-0.00023), respectively. Second, to examine the possible negative detection bias of mildly affected patients we determined the prevalence of these two pathogenic mutations in a sample of 1284 unselected newborns. Indeed, the observed prevalence of the c.833T>C allele (0.00195, 95% CI 0.00063-0.00454) was 11x higher than in the previous group suggesting that many homozygotes for the c.833T>C had not been diagnosed by selective biochemical screening. The IVS11-2A>C allele was not detected among 2,568 newborn CBS alleles. The estimated incidence of homocystinuria of 1:83,000, calculated in a combined model, suggests that selective biochemical screening may ascertain only ~25% of all homocystinuric patients. In conclusion, homocystinuria in Central Europe may be sufficiently common to consider sensitive newborn screening programs for this disease.

A common mutation in theCBSgene explains a high incidence of homocystinuria in the Qatari population

“…Considering the very high prevalence of one single disease-causing mutation and the difficulties that are still encountered with selective biochemical screening for this condition (Sokolova et al, 2001), molecular analysis in DNA extracted from dried blood spots may be a suitable method for this purpose. Further studies are under way to establish the sensitivity, specificity and cost-effectiveness of this approach.…”

Cystathionine?-synthase deficiency in Georgia (USA): Correlation of clinical and biochemical phenotype with genotype

“…I278T is a common alteration in homocystinurics from Northern Europe and Australia, and has been observed in some patients from United States Kraus et al, 1999]. Two population-based studies from Denmark and Germany suggest that 1.5% of the population is heterozygous for this mutation, suggesting that the frequency of individuals homozygous for this alteration may be as high as 1 in 20,000, while in the Czech and Slovak republics it was estimated to be 1 in 83,000 Linnebank et al, 2001;Sokolova et al, 2001]. All of the patients in our cohort containing I278T were Caucasian and presumably of FIGURE 1.…”

Acute psychosis in an adolescent with undiagnosed homocystinuria

“…Using blood methionine levels as a hallmark for diagnosis, CBS deficiency has been detected by newborn screening with an incidence rate ranging from 1:58,000 to 1:1, 000,000 of cases and an overall incidence rate of 1:344, 000 of cases [9,10]. Epidemiology data show a variability in the prevalence of different mutations: some mutations, such as c.833 T > C (p.I278T) or c.1105C > T (p.R369C), are frequently found in Caucasians and in several European countries, with heterozygous rates crossing between 0.5 and 1.5 % of the population, corresponding to an incidence of predicted homozygosis rate between 1:17, 800 and 1:264,000 [11][12][13][14]. The late occurrence of psychiatric symptoms has been reported in adults with homocystinuria [4,15,16].…”