Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinical radiological syndrome with good prognosis that affects mainly children or young adults. We describe two cases of MERS, associated with echovirus 6 and influenza A infection, in two twin sisters, at the age of 4 years. Genetic analysis was performed; next exome sequencing was performed on twins to disclose the eventual causative gene. Two different frameshift mutations in the CD36 gene [NM_000072] were found in both twins and confirmed by Sanger sequencing. To best of our knowledge, we report an association between CD36 mutation and MERS. We think that this relation between CD36 and inflammation has had a crucial role in the same callosal alteration during viral disease in the twin sister with the same gene mutation.