Spotting The Early Signs Of Metachromatic Leukodystrophy (MLD)

Dr. Fumagalli outlines the clinical spectrum of MLD, emphasizing differences between late infantile and juvenile-onset forms. In late infantile MLD, initial motor development may appear normal but is followed by stagnation and regression—often first observed as delayed milestones such as failure to stand or walk independently. Subtle early signs include axial hypotonia, ataxia, and brisk reflexes. Cognitive or behavioral symptoms tend to dominate early in juvenile-onset cases, manifesting as regression in previously acquired skills like toilet training, writing, or speech. Symptoms such as strabismus or gallbladder abnormalities, though non-neurological, can precede clear neurological signs and serve as diagnostic clues.

The discussion includes case studies illustrating the diagnostic delays often caused by misattribution of symptoms to orthopedic or psychological issues. One case describes two siblings: the older child received a late diagnosis after marked regression, while the younger was identified early and successfully treated with gene therapy. Another case involved misdiagnosis as Guillain-Barré Syndrome due to overlapping symptoms such as peripheral neuropathy, highlighting the importance of considering MLD in post-infectious regression scenarios.

Dr. Darling emphasizes the need for multidisciplinary vigilance and timely use of biochemical tests like arylsulfatase A enzyme activity and sulfatide levels, which can support diagnosis before advanced symptoms appear. The presenters stress the utility of dry blood spot testing as a quick and accessible screening tool, especially valuable in contexts where full genetic panels may yield inconclusive results or take weeks.

The session concludes by stressing two red flags for clinicians: in late infantile MLD, developmental stagnation after initially normal progress; and in juvenile MLD, sudden changes in behavior or cognitive skills. Gallbladder anomalies and demyelinating neuropathies should also raise suspicion. Overall, early, accurate diagnosis—especially in the presymptomatic phase—is essential to improving outcomes for children with MLD.