OP3 – 2232: Phenotype and genotype in 212 patients with megalencephalic leukoencephalopathy with subcortical cysts: New insights in the disease spectrum

Abstract

Objective Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by white matter oedema. The disease starts with macrocephaly, generally followed by neurological deterioration. Patients with recessive MLC1 or GLIALCAM mutations have the classic, deteriorating phenotype while patients with dominant GLIALCAM mutations show remarkable recovery. Our aim was to better delineate the phenotypic spectrum and identify potential discriminating clinical and MRI features in patients with different genetic defects. Methods We performed a multi-institutional cross-sectional observational study of the clinical, radiological and genotypic characteristics of the genetically confirmed MLC patients in our database. Results Pathogenic mutations were found in 212 patients (183 families). Recessive MLC1 mutations were present in 80% of patients; GLIALCAM mutations were recessive in 7% and dominant in 13%. The median age at the latest clinical observation was 5 years (range 7 months–56 years). Seven patients were deceased (age range 3–56 years). Epilepsy was common and usually well controlled. Few patients however, had refractory epilepsy and some had status epilepticus, sometimes fatal. Interestingly, we found that also within the group of patients with recessive mutations, there were oligosymptomatic and improving cases. Several patients with the classic phenotype were sensitive to mild head trauma, leading to seizures or prolonged unconsciousness. This was not the case for patients with dominant mutations. Systematic MRI review revealed that autosomal dominant improving MLC could be distinguished from classical MLC on the basis of absence of cerebellar white matter abnormalities at any stage. Furthermore, autosomal dominant patients were more likely to only show rarefied subcortical white matter instead of actual subcortical cysts. Conclusion MLC is a well recognisable disease associated with three different gene defects. We studied a relatively large cohort of patients and provided new insights in the phenotypic characteristics.