Homocystinuria (HCU) is an inborn error of the metabolism that affects an estimated 1 in 200,000 newborns in the US, though due to issues with the newborn screening test the number may be much higher. Once patients are diagnosed, they are treated with a combination of B6, folic acid, B12, betaine, medical formula, and usually a low protein diet. Patients who are undiagnosed and/or untreated are at high risk for progressive nearsightedness, lens dislocation, scoliosis, osteoporosis, strokes and blood clots. Since our organization was founded in 2016, we have frequently heard from patients (or their caregivers) who were missed by newborn screening. A recent report published by Orphan Technologies confirmed what we had been hearing – i.e. that based on medical claims data, there are over 12,000 patients with a diagnosis of classical homocystinuria in the US alone, many detected through an elevated blood test that was ordered due to clinical issues such as blood clots or strokes. This analysis would suggest that over 85% of patients were not diagnosed through newborn screening 1. This is why we are asking you for help!
What’s the problem? Why are so many patients missed?
Massachusetts led the way with newborn screening for homocystinuria by adding it to their newborn screening panel in 1968. Slowly many other states joined the ranks, but it wasn’t until 2009, after the Newborn Screening Saves Lives Act of 2007, that homocystinuria officially became part of the Recommended Uniform Screening Panel (RUSP). Between 1968 and 2009 many changes took place in newborn screening, and mass spectrometry became the new standard for screening. Because of the complexity of the homocysteine test, labs test the metabolite methionine as their primary biomarker instead.
Here is where the problem starts. Methionine (MET) is not as sensitive a biomarker as homocysteine (HCY) would be. In many cases, patient levels for methionine, an essential amino acid, do not elevate during the 24 to 48-hour period when the heel prick test for newborn screening is performed. There is also no standard cut-off level for methionine. Every state sets their own cut-offs, which range from 45 umol/L to 100 umol/L across the US. There are many known cases of classical HCU that were diagnosed by NBS programs with a lower cut-off that would have been missed by states with higher cut-offs. Higher levels are often set to minimize the number of false positives, as there can be other causes of elevated methionine.
Is there a better approach?
Experts in NBS for HCU in the US and internationally have recommended a revised process that includes a lower cut-off for methionine (such as 40 or 45 umol/L) or a corresponding Met/Phe ratio, with a second-tier test for homocysteine using the same dried blood spot 2. This lowers the number of false positives and increases the likelihood of diagnosing newborns with classical homocystinuria 3, 4. (Note that the algorithm recommended also increases the diagnosis of related disorders such as methylation and certain cobalamin disorders.) There are several states now utilizing this approach in the US, and the second tier test can be outsourced if needed. The CLIR tools (Collaborative Laboratory Integrated Reports) that are available free via Mayo Clinic are also being utilized by some states which enhance the specificity and ability to interpret data. The CDC is finalizing a second-tier assay that will be made available to the state labs. Another step some states have taken is to perform a second Met test (along with other analytes) a few weeks after birth, which may pick up additional cases. Both later testing and lower Met cutoffs together with a second tier for HCY could greatly help with more effective diagnosis.
What can you do?
An important component of HCU Network America’s mission is to support the advancement of diagnosis for HCU and related disorders. Since 2019, we have given testimony before the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC), spoken with leaders of many newborn screening programs, and engaged key opinion leaders in the realm of newborn screening. While we are making tremendous strides, we need your help to solve this issue.
Please share our newborn screening survey with your clinic!
Were you or your child missed by newborn screening? Please review the table before to see when newborn screening was implemented in your state. If you or your child were missed after that date, please forward this survey to your clinic!
You don't fit the criteria? That's okay - still forward the survey to your metabolic team to make sure they are aware of the survey!
For Geneticists, Metabolic Clinicians, and others involved in treating HCU Patients
Can we ask you to contact your state or region’s newborn screening lab and engage them in the conversation on newborn screening for HCU, and advocate for an improved process?
What should I talk to them about?
- What is your state’s methionine cut-off?
- Have you considered the benefits of using a lower MET cut-off (if higher than the recommended levels, e.g. 40 to 45 umol/L)
- Do the cut offs vary by weight, length or gestation period? Male or female?
- Does your state use a methionine/phenylalanine ratio?
- Are there other biomarker/analytes that you are looking at when diagnosing HCU?
- Does your state have a 2nd newborn screening test?
- When is the test administered?
- Are the cut-offs the same?
- Does your state have a 2nd tier test for Homocystinuria?
- Does it include total homocysteine?
- If so, what cut off do you use?
- Would you advocate to change the process to ensure we are diagnosing as many HCU patients at birth as possible?
- Would they like to talk to one of the experts who is recommending or implementing the recommended two-tier process? If so, please contact HCU Network America’s Executive Director, Danae Bartke, at email@example.com
- Would they be willing to outsource the second tier test if resources are not available?
- Does it include total homocysteine?
For Newborn Screening Program or Lab leaders:
We are asking you to evaluate your current process and consider lowering the MET cut-off if higher than recommended and instituting the second-tier test for HCY. The full process and rationale and benefits are described in the publications noted in footnote 1. Also, if laboratory resources are not available to implement a second-tier test, HCU Network America is compiling a list of potential labs to which you could consider outsourcing. You can find a list of 2-tier NBS labs at: https://hcunetworkamerica.org/2-tier-nbs-labs/ . We will continue to update this list and encourage you to let us know if you are aware of any others. Check our website under the resources tab for the most updated listing.
We urge you to alter your process even if you believe you have not missed any HCU patients, as we know they are out there and that states do not have the reporting systems and “closed loops” to ensure that there is a full accounting of patients who may have been missed by NBS. Your willingness to take action proactively could lead to improved lives for many HCU patients and their families.
1Sellos-Moura, M., Glavin, F., Lapidus, D. et al. Prevalence, characteristics, and costs of diagnosed homocystinuria, elevated homocysteine, and phenylketonuria in the United States: a retrospective claims-based comparison. BMC Health Serv Res 20, 183 (2020). https://doi.org/10.1186/s12913-020-5054-5
2 Keller, R, Chrastina, P, Pavlíková, M, et al. Newborn screening for homocystinurias: Recent recommendations versus current practice. J Inherit Metab Dis. 2019; 42: 128– 139. https://doi.org/10.1002/jimd.12034
3Matern, D, Tortorelli, S, Oglesbee, D, et al. Reduction of false-positive rate in newborn screening by implementation of MS/MS-based second-tier tests: The Mayo Clinic experience (2004-2007). J Inherit Metab Dis. 2007; 30:585-592
4Chace, D, Hannon, W. Impact of Second-Tier Testing on the Effectiveness of Newborn Screening. Clinical Chemistry. 2010; 56:11: 1653-1655 https://doi.org/10.1373/clinchem.2010.153494