eP008: Cystathionine beta synthase deficiency patients are being missed by newborn screening


      Newborn screening for Cystathionine beta Synthase (CBS deficiency, also known as Homocystinuria) was initiated in some states as early as 1968 with the aim of preventing devastating complications from inadequate early treatment. During the 1990s, improvements in technology allowed for CBS deficiency to be detected by mass spectrometry detection of methionine levels from the dried blood spot card. Not until 2009 was CBS deficiency recommended to be universally screened in all US states following its inclusion in the Recommended Uniform Screening Panel (RUSP). Due to the organization of newborn screening laboratories by state, there is not uniformity in cutoffs across states. More recently, some states have started using second-tier screening, where they lower the methionine cutoff, and methionine/phenylalanine ratio and measure total homocysteine for those above the cutoff to decrease false positives.


      HCU Network America, a family support group for individuals with homocystinurias including CBS deficiency, the cobalamin and remethylation disorders, asked its members whether they were being identified by newborn screening, as part of an IRB approved research protocol, after several families had come forward asking about how to obtain their newborn screening results since they thought they had been missed by newborn screening. Through the families, the date of initial newborn screen card collection, date of diagnosis, the state where the newborn screening was done, and, in some cases, the actual newborn screening reports were collected and analyzed.


      Twenty-three individuals were identified to have CBS deficiency whose newborn screening was not flagged positive. These 23 individuals had screening done in approximately 14 different states. Many of the state labs (of those from which we have data) had cutoffs of greater than or equal to 100 μmol/L methionine at the time of newborn screening, although a few had lower methionine cutoffs. Of those with CBS deficiency for whom we have data, many of the individuals had methionine levels in the 30s-60s μmol/L detected from their newborn screening cards.


      Homocystinuria caused by CBS deficiency may not always be detected by newborn screening, especially with our current cutoffs. We recognize that we do not have a complete list of possible false negative CBS deficiency cases, and it unclear whether they are not being reported or whether they are not being diagnosed. Evidence from Europe indicates that up to 50% of cases may be missed with our current newborn screening approaches. Some of this is a consequence of the lower methionine levels seen in individuals with pyridoxine-responsive CBS deficiency, however the cost of missing a diagnosis is significant. Thus, state labs are encouraged to consider a lower methionine cutoff, along with adding methionine/phenylalanine ratio, and to add a second-tier screen for total homocysteine for those who exceed the threshold. Also, clinicians should have a high level of suspicion and should do total homocysteine screening in patients who present with hypermobility, ectopic lentis, tall stature, learning differences/intellectual disability and/or thrombosis. Moreover, awareness throughout the field of genetics that there is a possibility that newborn screening cannot always pick up all the disorders for which individuals are screened should motivate us to continue to collect cases and look for ways to improve screening for health and well-being of our patients.