Characterization of an MLC patient carrying two MLC1 variants showing radiological improvement

•Here, we identify a new MLC1 patient that show improvement over time, but that carry recessive mutations in MLC1.•Genetic and biochemical studies using peripheral blood leukocytes from the patient indicated that he expresses a small amount of MLC1.•We then suggest that a novel classification of MLC patients, adding a novel group named MLC1B.•We provide a molecular explanation for the reversibility of the phenotype found in some MLC patients, which has implications for MLC therapy. Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy. Approximately 75% of MLC patients have variants in MLC1, while the rest in GLIALCAM, GPRC5B and AQP4. From the GLIALCAM patients, a classical and a benign phenotype can be distinguished, in which a recessive and dominant inheritance is observed, respectively. Here, we report a new MLC patient harboring two variants in MLC1 with radiological improvement. The patient is heterozygous for the variants c.597+37C>G and c.895–1G>T affecting both mRNA splicing, and the latest causes the deletion p.Pro299_Glu353del. By analyzing mRNA and protein obtained from patient's peripheral blood leukocytes, we could demonstrate the expression of a small amount of wild-type MLC1 mRNA and protein in the patient. Thus, we suggest that the improvement of clinical and radiological abnormalities observed in all remitting MLC patients might be due to the presence of residual amounts of MLC1 protein.