Van der Knaap Disease Unveiled: A Radiological-Genomic Journey From Seizure to Diagnosis

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare autosomal recessive leukodystrophy predominantly caused by mutations in the MLC1 gene, characterized by early-onset macrocephaly, progressive neurological deterioration, and distinctive neuroimaging findings. We report this case to highlight a late-onset seizure presentation in a 12-year-old boy with MLC and significant clinico-radiological dissociation. While the patient exhibited pathognomonic MRI findings, including extensive white matter fluid-attenuated inversion recovery (FLAIR) hyperintensity and characteristic subcortical cysts in anterior temporal and occipitoparietal regions, he maintained independent ambulation, which is in striking contrast to the severity of the imaging findings. The corpus callosum, internal capsule, and posterior fossa structures were unaffected. Vasogenic edema was evidenced by elevated apparent diffusion coefficient (ADC) values without diffusion restriction. Whole exome sequencing identified a homozygous frameshift duplication mutation (c.135dup; p.Cys46Leufs*34) in the MLC1 gene, confirming the diagnosis of classical MLC1-related disease. This report underscores the necessity of integrated radiological-genomic assessment to differentiate MLC from other macrocephalic leukodystrophies to enable early diagnosis and initiate appropriate supportive care and genetic counseling. It aids early screening of close family members, facilitating genetic counseling and informed reproductive decision-making for affected families, thereby decreasing the chances of further transfer of the mutant gene in subsequent generations.