Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene

Abstract

ObjectivesTo estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme.Study designMutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems.ResultsPopulation frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40 000, which increased to 1:15 500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired Km for both substrates but resulted from Vmax lowered to 55% of the normal cystathionine beta-synthase enzyme.ConclusionsThe c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.

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].…”

Classical familial homocystinuria in an adult presenting as an isolated lens subluxation

“…The less severe forms, especially the B 6 -responsive ones, which are present in at least 50% of the patients, seem to escape diagnosis by these programs [8]. Increasing numbers of mildly affected adults, previously not diagnosed, are being reported, even patients with negative neonatal screening [21].…”

“…Using the criterion of elevated blood methionine, CBS deficiency has been detected in newborn screening programs in different countries at rates of 1:58,000-1:1,000,000; overall 1:344,000 [5,6]. However, the molecular epidemiology data shows that homocystinuria is not so rare, and the prevalence of certain mutations, such as c.833T[C (p.I278T) or c.1105C[T (p.R369C), is considerably higher among Caucasians in several European countries, with rates of between 0.5 and 1.5% heterozygous, corresponding to an incidence of predicted homozygosity between 1:17,800 and 1:264,000 [7,8].…”

A Rapid Screening Method for the Measurement of Neonatal Total Homocysteine in Dried Blood Spots by Liquid Chromatography-Tandem Mass Spectrometry

“…For example, the incidence ranges between 1:6400 to 1:20,500 in European populations and between 1:1800 to 1:3000 in the Qatari population [2][3][4][5][6][7]. The true worldwide prevalence is likely underestimated because of undiagnosed cases [8].…”