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In this webinar, Dr. Lucia Laugwitz from the University of Tübingen provides a comprehensive update on newborn screening for Metachromatic Leukodystrophy (MLD). The session focuses on the importance of early identification and the implications for timely treatment. It uses a compelling sibling case study to highlight diagnostic strategies, therapeutic windows, and screening challenges.
The webinar begins with a case of a boy diagnosed at age seven with early cognitive and behavioral symptoms misattributed to ADHD. Only after a decline in IQ and abnormal MRI findings was MLD considered. Biochemical and genetic diagnostics confirmed the diagnosis. His younger sister, although still asymptomatic, underwent early testing and was found to have the same pathogenic ARSA gene mutations. She was diagnosed in a pre-symptomatic phase and became the first child in Tübingen to receive gene therapy for MLD.
Dr. Laugwitz explains the biology of MLD, a lysosomal storage disorder caused by arylsulfatase A (ARSA) deficiency, which leads to sulfatide accumulation and CNS demyelination. She emphasizes the "window of opportunity" for effective treatment—before the onset of neurodegeneration—and explains that both gene therapy and hematopoietic stem cell transplantation (HSCT) are most effective in pre-symptomatic or early symptomatic stages.
The session outlines the rationale and methodology for newborn screening. A two-tier strategy is recommended: first testing dried blood spots for sulfatides and ARSA enzyme activity, followed by genetic sequencing for confirmation. This approach helps differentiate between true MLD cases, pseudodeficiency, and heterozygous carriers. Dr. Laugwitz discusses technical limitations and the need for more biomaterial and standards to refine thresholds and reduce false positives.
She also explores biomarkers like neurofilament light chain and N-acetyl aspartic acid, noting that while useful for monitoring, they are not sensitive enough for predicting onset in newborns. MRI, MRS, and neurophysiology are similarly helpful for surveillance but limited for early detection.
Dr. Laugwitz concludes by stressing the need for international consensus on monitoring and treating screen-positive newborns. A European project is underway to establish shared protocols. She underscores that screening and intervention should begin as soon as one child in a family is diagnosed, to maximize treatment outcomes for siblings.