Understanding The Diagnostic Journey Of Metachromatic Leukodystrophy

The discussion begins with a scientific overview of MLD, a rare autosomal recessive lysosomal storage disorder caused by mutations in the ARSA gene, leading to sulfatide accumulation and progressive demyelination in the central and peripheral nervous systems. The speakers explain how disease manifestations vary by age of onset, which is categorized into late-infantile, juvenile (early and late), and adult forms.

Professor Gissen outlines the pathophysiological mechanisms, diagnostic tools (including enzyme assays, sulfatide testing, and genetic analysis), and typical neuroimaging findings. He emphasizes the importance of distinguishing true ARSA deficiency from pseudodeficiency and highlights the limitations of relying solely on non-specific whole genome sequencing panels, which can delay diagnosis by months. He presents three illustrative patient cases showing the clinical trajectory and treatment outcomes across MLD subtypes. These cases underscore how delayed recognition of symptoms can severely limit treatment options such as gene therapy or hematopoietic stem cell transplantation.

Dr. Artisone builds on this by presenting her own patient cases, including siblings with early juvenile MLD and a late-infantile case, all highlighting common pitfalls in the diagnostic process. In several cases, cognitive and motor decline were initially attributed to other developmental or behavioral issues, leading to missed opportunities for early intervention. Artisone stresses that delays in specialist referral, limited awareness among general pediatricians, and over-reliance on broad NGS panels are major barriers to timely diagnosis.

The webinar calls for greater awareness among frontline pediatricians, better education on the subtle early signs of MLD, and broader use of rapid biochemical testing. Both speakers advocate for newborn screening as a potential solution, despite current challenges in predicting disease phenotype based solely on genotype. They also highlight the importance of multidisciplinary evaluation and directing patients to reference centers for faster diagnostic confirmation and treatment access.

The session concludes with a discussion of the implications of delayed diagnosis and the importance of early intervention for altering the natural course of this progressive and often fatal disease.