The neurometabolic disorder ALD is caused by pathogenic variants in the ABCD1 gene. A recent five-year follow-up study of boys identified through newborn screening in Minnesota by Charles J. Billington, Jr. and colleagues shows that C26:0-LPC levels at screening may predict early disease onset in ALD. ALD newborn screening enables early intervention in asymptomatic male newborns, which can prevent irreversible damage. [Click to read more ▼]
In an editorial for JAMA Pediatrics, Marc Engelen and Stephan Kemp discuss these important findings. We discuss that the current screening process also identifies many cases in the “Grey Zone” with borderline elevated C26:0-LPC levels and variants of unknown significance (VUS) in ABCD1. This raises concerns about over-identification and unnecessary follow-up. Recent studies, including those by Billington and by Yorrick Jaspers et al., show a correlation between higher C26:0-LPC levels and early disease manifestations. These findings contradict previous assumptions that very long-chain fatty acid (VLCFA) levels are not correlated with disease severity. These findings may lead to improved newborn screening protocols, likely raising C26:0-LPC cutoff levels to focus on identifying patients who will benefit from early diagnosis and follow-up. However, this effort will require larger, long-term studies and collaboration across U.S. states and countries to validate these newborn screening findings and improve the understanding of the pathogenicity of ABCD1 variants. To this end, the nonprofit organization ALD Connect (aldconnect.org) has initiated the Grey Zone Project, which aims to improve understanding of VUS identified in ABCD1 and determine their potential pathogenicity.