Reduction of false negative results in screening of newborns for homocystinuria.

Background: Mental retardation and other medical problems (including ectopi a lentis, osteoporosis, and thromboembolism) in patients who have homocysti nuria as a result of a deficiency of cystathionine beta-synthase can be pre vented by the screening of newborns with measurement of blood methionine, f ollowed by the early treatment of affected infants. Many infants with this disorder, however, are not identified by screening and have irreversible br ain damage. Methods: We reviewed the results of neonatal screening for homocystinuria o ver a period of 32 years in New England. Additional specimens were requeste d for repeated analysis when blood methionine measurements were at or above the established cutoff level. Homocystinuria due to cystathionine beta-syn thase deficiency was confirmed by quantitative amino acid analyses. Results: For the first 23.5 years of the review period, the blood methionin e cutoff value was 2 mg per deciliter (134 micromol per liter). Among the 2 .2 million infants screened during that period, 8 with homocystinuria were identified (1:275,000). In 1990, the cutoff value was reduced to 1 mg per d eciliter (67 mu mol per liter). Among the 1.1 million infants screened in t he subsequent 8.5 years, 7 with the disorder were identified (1:157,000). D uring the latter period, the specimens were collected from six of the seven infants when they were two days of age or less; five of the six had blood methionine concentrations below 2 mg per deciliter. Use of the reduced cuto ff level increased the false positive rate from 0.006 percent to 0.03 perce nt. Conclusions: A cutoff level for blood methionine of 1 mg per deciliter in n eonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce th e frequency of false negative results. (N Engl J Med 1999;341:1572-6.) (C) 1999, Massachusetts Medical Society.