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In this comprehensive webinar, Dr. Dipak Ram presents an overview of Metachromatic Leukodystrophy (MLD), focusing on its natural history, clinical phenotypes, progression patterns, and emerging treatment options—especially gene therapy. Through real-life case studies, Dr. Ram illustrates the wide clinical spectrum of MLD, emphasizing the contrasting progression between late-infantile and juvenile forms of the disease.
Late-infantile MLD typically presents in children under 30 months with rapid regression in motor and cognitive functions. Dr. Ram highlights a case where a child, initially evaluated for clumsiness, deteriorated swiftly—losing speech and ambulation within weeks. MRI revealed hallmark white matter changes, confirming the diagnosis. This phenotype is associated with aggressive neurodegeneration and early mortality.
Juvenile MLD, by contrast, has a more insidious onset. Symptoms may include subtle behavioral changes, clumsiness, or cognitive difficulties, often misdiagnosed as dyspraxia or learning disorders. Progression occurs over months to years, and early MRI may appear normal, complicating diagnosis. Enzyme testing for ARSA levels and nerve conduction studies can reveal the diagnosis even in the absence of imaging abnormalities.
Dr. Ram outlines the current diagnostic approach—favoring early enzyme testing over MRI due to its faster turnaround and diagnostic reliability. He stresses that identifying MLD early, particularly in siblings of affected children, is essential to access gene therapy before symptoms develop.
Therapeutically, early attempts with enzyme replacement and bone marrow transplantation showed limited success. While HSCT partially protected the CNS, it failed to halt peripheral nerve damage. Gene therapy, specifically Libmeldy (atidarsagene autotemcel), has transformed outcomes. Using the patient’s own stem cells modified to express high levels of ARSA enzyme, this approach has dramatically improved survival and functional outcomes when administered pre-symptomatically.
Dr. Ram presents data showing that most treated children maintain ambulation and cognitive function years after therapy. However, the process takes time to manufacture the therapy, making early identification critical. Strict eligibility criteria—such as preserved ambulation and IQ in juvenile MLD, or complete pre-symptomatic status in infantile cases—remain key to effective intervention.
The webinar concludes with a call to action: pediatricians should prioritize enzyme testing when MLD is suspected and screen siblings of affected children early. Ongoing newborn screening initiatives and international collaboration are vital for expanding timely access to treatment.