Metachromatic Leukodystrophy: Presymptomatic Patients

MLD is a severe autosomal recessive lysosomal storage disorder caused by ARSA gene mutations or, less commonly, activator protein deficiencies. The resulting enzyme deficiency leads to toxic sulfatide accumulation, causing progressive demyelination in both the central and peripheral nervous systems. The disease has varying phenotypes—late infantile, juvenile (early and late), and adult—depending on residual enzyme activity.

Dr. Deodato explains that early symptoms are often nonspecific, including clumsiness, speech delay, learning difficulties, or behavioral changes. Diagnostic delays are common, averaging 1.2 years for late infantile and up to 3.7 years for juvenile forms. MRI findings may be normal early in the disease course, particularly in late infantile MLD, making early diagnosis challenging without targeted testing.

The presentation includes a powerful case study of two siblings: the older sister was diagnosed late with symptomatic MLD after progressive motor decline, despite early warning signs and a normal initial MRI. By the time of diagnosis, she was ineligible for gene therapy and enrolled in a palliative trial. In contrast, her younger sibling was diagnosed through family screening at 11 months—while still asymptomatic—and successfully received gene therapy. Today, that child has normal motor and cognitive development, a stark contrast to her sister’s outcome.

Dr. Deodato outlines the limited therapeutic window for effective intervention and underscores that current gene therapy is only approved for pre-symptomatic or minimally symptomatic patients with late infantile or early juvenile MLD. This makes family screening critical, as newborn screening for MLD is not yet standard due to challenges such as pseudo-deficiency and false positives.

She concludes by advocating for a two-tier newborn screening strategy combining enzyme activity and sulfatide levels with confirmatory genetic testing. Until such screening becomes routine, family screening remains the most effective means to identify treatable patients before irreversible damage occurs.