Homocystinuria (HCU), a group of inherited disorders, causes symptoms ranging from failure to thrive and developmental delays in infants or young children to abnormal blood clots with onset in adults.1 Approximately 1 in 200,000 to 335,000 people have HCU globally.2
Various clinical settings use the dried blood spot (DBS) for sample collection methods such as newborn screening tests for HCU. Due to the complex chemistry of homocysteine (Hcy), which is elevated in people with HCU, and known interferences, labs cannot screen DBS for this biomarker in primary-tier newborn screening assays. Instead, labs use methionine as a surrogate marker for dysfunction in the Hcy metabolic pathway, although methionine has poor sensitivity and specificity for HCU. This impacts false positive rates, causing parental anxiety and unnecessary burden for follow up teams, and false negative rates which increase the morbidity and mortality of newborns with HCU. There are reports of HCU cases having been missed.3 Another approach uses second-tier screening following the primary assay to test presumed positive specimens with elevated methionine for Hcy after a chromatographic separation step. This also has disadvantages in that specimens may not exceed the methionine cutoff to receive second-tier screening and added time (+1-5 days) before referral affects treatment delivery.
CDC has developed a workflow to selectively convert Hcy to a derivative using a maleimide reagent in a sample matrix. The process allows accurate quantification by shifting Hcy’s mass, thus, removing any undesired interferences. The specific derivative agent, N-ethylmaleimide, is widely available and has a very low price. CDC’s method screens Hcy during primary newborn screening from the DBS, along with dozens of other newborn screening biomarkers without adding substantial time or efforts to the screening process. No currently reported methods use this workflow to screen for Hcy in DBS. Current commercial products cannot screen for Hcy from DBS in areas of newborn screening and other clinical sciences that desire to quantify Hcy as a biomarker. This technology can potentially revolutionize HCU screening via DBS in newborns globally. DBS is also becoming more widely adopted as a sample collection method in other clinical areas. Eventually, clinical labs may begin to screen Hcy as a risk for cardiometabolic diseases/disorders and can benefit from the new workflow. CDC has demonstrated the workflow in DBS from HCU positive, presumptive normal, and those with reported administration of total parenteral nutrition.
- 1. https://rarediseases.info.nih.gov/diseases/10770/homocystinuria
- 2. https://medlineplus.gov/genetics/condition/homocystinuria/
- 3. Bowron et al. Clinical Chemistry. 51, No.1, 2005.