Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants

Neurology. 2018 Apr 17;90(16):e1395-e1403. doi: 10.1212/WNL.0000000000005334. Epub 2018 Mar 21.


Objective: To provide an overview of clinical and MRI characteristics of the different variants of the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) and identify possible differentiating features.

Methods: We performed an international multi-institutional, cross-sectional observational study of the clinical and MRI characteristics in patients with genetically confirmed MLC. Clinical information was obtained by questionnaires for physicians and retrospective chart review.

Results: We included 204 patients with classic MLC, 187 of whom had recessive mutations in MLC1 (MLC1 variant) and 17 in GLIALCAM (MLC2A variant) and 38 patients with remitting MLC caused by dominant GLIALCAM mutations (MLC2B variant). We observed a relatively wide variability in neurologic disability among patients with classic MLC. No clinical differences could be identified between patients with MLC1 and MLC2A. Patients with MLC2B invariably had a milder phenotype with preservation of motor function, while intellectual disability and autism were relatively frequent. Systematic MRI review revealed no MRI features that distinguish between MLC1 and MLC2A. Radiologic improvement was observed in all patients with MLC2B and also in 2 patients with MLC1. In MRIs obtained in the early disease stage, absence of signal abnormalities of the posterior limb of the internal capsule and cerebellar white matter and presence of only rarefied subcortical white matter instead of true subcortical cysts were suggestive of MLC2B.

Conclusion: Clinical and MRI features did not distinguish between classic MLC with MLC1 or GLIALCAM mutations. Absence of signal abnormalities of the internal capsule and cerebellar white matter are MRI findings that point to the remitting phenotype.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cell Cycle Proteins
  • Cerebral Cortex / diagnostic imaging
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Cysts* / diagnostic imaging
  • Cysts* / genetics
  • Cysts* / physiopathology
  • Female
  • Hereditary Central Nervous System Demyelinating Diseases* / diagnostic imaging
  • Hereditary Central Nervous System Demyelinating Diseases* / genetics
  • Hereditary Central Nervous System Demyelinating Diseases* / physiopathology
  • Humans
  • International Cooperation
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins / genetics*
  • Mutation / genetics*
  • Proteins / genetics*
  • Retrospective Studies
  • Severity of Illness Index
  • Young Adult


  • Cell Cycle Proteins
  • HEPACAM protein, human
  • MLC1 protein, human
  • Membrane Proteins
  • Proteins

Supplementary concepts

  • Megalencephalic leukoencephalopathy with subcortical cysts