Classic homocystinuria (HCU) was added to newborn screening (NBS) by Robert Guthrie a few years after the disorder was first described. The justification for NBS was similar to that for PKU, that presymptomatic identification and early dietary treatment would prevent the clinical consequences, which, for HCU, are mental deficiency, ectopia lentis, skeletal abnormalities, and thromboembolism. It was assumed that identifying increased methionine in the screening blood specimen would identify all affected neonates. However, it is now clear that many with HCU are missed by NBS, mainly because the methionine level in the first days of life is normal or below the cutoff level in the NBS program. This includes virtually all of those with B6-responsive HCU. Thus, a more effective method of NBS for HCU should be considered. Included among the possibilities are decreasing the methionine cutoff level, requiring an increase in the Met/Phe ratio if the methionine level is not at or greater than the cutoff level, using methionine as the primary screen with homocysteine as a second-tier test, or replacing methionine with homocysteine as the primary screen. Homocysteine is the primary metabolite that increases in HCU, while the methionine increase is secondary, so homocysteine is usually increased before the increase in methionine, almost always during the first few days of life. Finally, targeted gene screening might be considered. All of these possibilities would impose added expense and labor to NBS, so meeting these challenges would likely require a regional or national effort.
Keywords: CBS; HCU; NBS; cystathionine b-synthase; false negative; homocysteine; homocystinuria; methionine; missed cases; newborn screening.