Emerging Knowledge - The Early Indications Of Metachromatic Leukodystrophy (MLD) In Children

MLD is a rare, autosomal recessive lysosomal storage disorder caused by mutations in the ARSA gene or, less commonly, PSAP and SUMF1 genes. The enzyme arylsulfatase A is responsible for the breakdown of sulfatides, and its deficiency leads to sulfatide accumulation in the central and peripheral nervous systems, resulting in progressive demyelination.

Prof. Gissen explains that MLD presents along a clinical spectrum—late infantile, early juvenile, late juvenile, and adult-onset. The earlier the onset, the faster the disease progresses. Clinical features include loss of motor milestones, cognitive decline, psychiatric symptoms, and progressive spasticity. Brain MRI shows characteristic deep white matter changes, such as the “tigroid” or “leopard skin” appearance, though early scans may be normal, particularly in the late infantile form.

He introduces the Gross Motor Function Classification (GMFC) scale, which tracks disease progression and is used in clinical decision-making, particularly for assessing eligibility for emerging treatments. Supportive care, including seizure management, feeding interventions, and physiotherapy, remains essential throughout the disease course.

The webinar highlights the role of hematopoietic stem cell transplantation (HSCT) and, most notably, ex vivo gene therapy (libmeldy). Prof. Gissen reviews data from long-term trials showing that patients treated early—ideally pre-symptomatically—experience significantly improved motor and cognitive outcomes compared to untreated cohorts. Treated children often maintain normal development or show delayed disease progression.

Three patient case studies are presented, demonstrating variable trajectories based on the timing of diagnosis and intervention. These cases underline how subtle early signs—such as clumsiness, decline in school performance, or coordination issues—must not be dismissed.

The session concludes with a call for increased clinical awareness and timely referral. Prof. Gissen stresses that newborn screening or family-based genetic testing are the only ways to diagnose MLD early enough to benefit from gene therapy. He underscores the importance of early enzyme and genetic testing for children showing early neurological or cognitive symptoms.