The Era of Gene Therapy, Newborn Screening, and Improved Management in the Leukodystrophies: A Shifting Framework With Altered Expectations.

The field of leukodystrophies (LDs) has undergone a paradigm shift in recent decades. Several factors underlie this change: newborn screening, advanced genetic and metabolic testing, improved understanding and medical management of disease, and targeted therapies addressing underlying molecular etiologies. Recent trials as well as regulatory approvals are testimony to the transformative effects of gene therapy. However, the risks of these treatments remain incompletely understood and include malignancies/premalignancies, immune-mediated hepatic injury, and thrombotic microangiopathy, among others. The implementation of newborn screening for individual LDs allows for improved monitoring and earlier treatment but also extends the measured lifespan following diagnosis, skewing survival data compared to historical data based on symptomatic diagnosis. Lastly, population screening leads to identification of genetic variants with milder or uncertain pathogenicity. In this article, we review the shifting framework impacting life expectancy and decision-making in the LDs along with the risks and uncertainties that have arisen in the setting of recent advancements.