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Published on: June 25, 2010
Reduction of false negative results in screening of newborns for homocystinuria
M J Peterschmitt1, J R Simmons, H L Levy
1Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Insights
Newborn screening for homocystinuria using a lower blood methionine cutoff (1 mg/dL) identifies more affected infants. This improved screening helps prevent irreversible brain damage by enabling earlier treatment.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Homocystinuria, caused by cystathionine beta-synthase deficiency, can lead to severe disabilities if not treated early.
- Newborn screening with blood methionine measurement is crucial for early detection and prevention of these disabilities.
- Current screening methods sometimes miss affected infants, resulting in irreversible brain damage.
Purpose of the Study:
- To evaluate the effectiveness of a reduced blood methionine cutoff level in neonatal screening for homocystinuria.
- To assess the impact of this change on the detection rate and false positive rate of the screening test.
Main Methods:
- A retrospective review of 32 years of neonatal screening data for homocystinuria in New England.
- Analysis of blood methionine levels and diagnostic confirmation of homocystinuria.
- Comparison of screening results using two different blood methionine cutoff values (2 mg/dL and 1 mg/dL).
Main Results:
- Reducing the blood methionine cutoff from 2 mg/dL to 1 mg/dL increased the detection rate of homocystinuria from 1:275,000 to 1:157,000.
- The lower cutoff identified infants with only slightly elevated methionine levels, some of whom were missed with the higher cutoff.
- The false positive rate increased from 0.006% to 0.03% with the reduced cutoff.
Conclusions:
- A blood methionine cutoff of 1 mg/dL in neonatal screening for homocystinuria is recommended.
- This lower cutoff improves the identification of affected infants, including those with milder forms of the disorder.
- The revised screening strategy aims to reduce false negative results and prevent developmental disabilities associated with homocystinuria.
Background:
Mental retardation and other disabilities (including ectopia lentis, osteoporosis, and thromboembolism) in patients who have homocystinuria as a result of a deficiency of cystathionine beta-synthase can be prevented by the screening of newborns with measurement of blood methionine, followed by the early treatment of affected infants. Many infants with this disorder, however, are not identified by screening and have irreversible brain damage.
Methods:
We reviewed the results of neonatal screening for homocystinuria over a period of 32 years in New England. Additional specimens were requested for repeated analysis when blood methionine measurements were at or above the established cutoff level. Homocystinuria due to cystathionine beta-synthase deficiency was confirmed by quantitative amino acid analyses.
Results:
For the first 23.5 years of the review period, the blood methionine 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 deciliter (67 micromol per liter). Among the 1.1 million infants screened in the subsequent 8.5 years, 7 with the disorder were identified (1:157,000). During 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 cutoff level increased the false positive rate from 0.006 percent to 0.03 percent.
Conclusions:
A cutoff level for blood methionine of 1 mg per deciliter in neonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce the frequency of false negative results.
