Correspondence

Prevalence of Congenital Homocystinuria in Denmark

N Engl J Med 1999; 340:1513May 13, 1999

Article

To the Editor:

Homocystinuria due to a deficiency of cystathionine β-synthase has been reported to occur with a cumulative overall frequency of 1 in 344,000 worldwide, a value that ranges from 1 in 58,000 to 1 in 1,000,000 in countries that systematically screen newborns.1 Overall, 50 percent of persons with untreated homocystinuria have a thromboembolic event before the age of 30 years, and dislocation of the lens occurs in 50 percent by the age of 8.1 Among mutations causing cystathionine β-synthase deficiency, the 833T→C mutation2 is geographically widespread. We determined the prevalence of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of an infant's blood collected on filter paper). A frequent genetic insertion variant, 844ins68, was simultaneously sought by polymerase-chain-reaction amplification of exon 8 of the cystathionine β-synthase gene in genomic DNA isolated from the Guthrie cards, followed by incubation of the polymerase-chain-reaction products with the restriction enzyme BsrI.3

A surprisingly high prevalence of the 833T→C mutation (1.4 percent) was detected among newborns who did not carry the 844ins68 variant (Table 1Table 1Prevalence of the Cystathionine b-Synthase 833T→C Mutation and of the 844ins68 Variant among 500 Danish Newborns.). Assuming that there is no selection against heterozygotes for the mutation, we estimate the incidence of homocystinuria due to homozygosity for this mutation to be at least 1 per 20,500 live births, which is much higher than that previously reported.1 Cases of cystathionine β-synthase deficiency caused by other, albeit less frequent, genetic defects should be considered in the overall estimation of the incidence of the disease. The cystathionine β-synthase 844ins68 variant was present in 10 percent of the Danish newborns. It seems to be a neutral variant that is deleted from messenger RNA during splicing.4

Early diagnosis is essential in preventing the clinical manifestations of homocystinuria. We strongly recommend routine measurement of plasma homocysteine levels in cases of thrombophilia, severe myopia in childhood, and other conditions associated with complications of homocystinuria.

Mette Gaustadnes, M.Sc.
Jørgen Ingerslev, M.D.
Niels Rütiger, Ph.D.
Aarhus University Hospital at Skejby, 8200 Aarhus N, Denmark

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