Early-Onset Clinical Manifestations Of Metachromatic Leukodystrophy

MLD is a progressive lysosomal storage disorder caused by arylsulfatase A deficiency, leading to sulfatide accumulation and subsequent demyelination in both the central and peripheral nervous systems. While children with MLD typically appear normal at birth, disease onset occurs after a period of normal development, followed by stagnation and then regression of motor and cognitive skills.

Dr. Zambon categorizes MLD into late infantile, early juvenile, and late juvenile forms and explains how the early symptoms vary by age group. In late infantile cases (onset before 30 months), early red flags include hypotonia, delayed motor milestones, abnormal reflexes, ataxia, and foot deformities such as retrocurved knees. Around 50% of these children never achieve independent walking.

Early and late juvenile forms may present more subtly, with behavioral changes, cognitive decline, inattention, or decreased school performance preceding clear neurological signs. Symptoms such as ataxia, fine motor impairment, spasticity, and urinary incontinence may also appear. Because of these non-specific features, MLD is frequently misdiagnosed or diagnosed late.

Dr. Zambon highlights diagnostic tools including brain MRI, EMG, and enzyme assays. He warns that early MRI scans may appear normal due to incomplete myelination and urges clinicians to refer to expert centers for proper interpretation. He also describes electrophysiological findings and gallbladder ultrasound abnormalities as potential early indicators.

The session stresses the necessity of early diagnosis to enable access to gene therapy, which is only available for pre-symptomatic or minimally symptomatic patients. Early identification also supports timely family counseling and the possibility of screening siblings, who may benefit from early intervention.

Dr. Zambon concludes with a powerful message: while MLD is rare, awareness of its early signs can change outcomes dramatically. Pediatricians should not delay referral when developmental stagnation or regression is observed, especially in combination with neurological or behavioral red flags.