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Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature
Emma M J Passchier1,2, Quinty Bisseling1,2, Guy Helman3
1Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam Neuroscience, Amsterdam, Netherlands.
Abstract:
The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white matter. With delayed onset, patients typically experience motor problems, epilepsy and slow cognitive decline. No treatment is available. Classic MLC is caused by bi-allelic recessive pathogenic variants in MLC1 or GLIALCAM (also called HEPACAM). Heterozygous dominant pathogenic variants in GLIALCAM lead to remitting MLC, where patients show a similar phenotype in early life, followed by normalization of white matter edema and no clinical regression. Rare patients with heterozygous dominant variants in GPRC5B and classic MLC were recently described. In addition, two siblings with bi-allelic recessive variants in AQP4 and remitting MLC have been identified. The last systematic overview of variants linked to MLC dates back to 2006. We provide an updated overview of published and novel variants. We report on genetic variants from 508 patients with MLC as confirmed by MRI diagnosis (258 from our database and 250 extracted from 64 published reports). We describe 151 unique MLC1 variants, 29 GLIALCAM variants, 2 GPRC5B variants and 1 AQP4 variant observed in these MLC patients. We include experiments confirming pathogenicity for some variants, discuss particularly notable variants, and provide an overview of recent scientific and clinical insight in the pathophysiology of MLC.
Insights
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare brain disorder. This study updates genetic variants in MLC patients, identifying new mutations and providing insights into disease mechanisms.
Area of Science:
- Neurogenetics
- Molecular Medicine
- White Matter Disorders
Background:
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC) presents with macrocephaly and chronic white matter edema.
- Classic MLC results from recessive variants in MLC1 or GLIALCAM; remitting MLC involves dominant GLIALCAM variants.
- Recent studies identified rare variants in GPRC5B and AQP4 associated with MLC phenotypes.
Purpose of the Study:
- To provide an updated overview of genetic variants associated with Megalencephalic leukoencephalopathy with subcortical cysts (MLC).
- To report novel and published variants from a large cohort of genetically confirmed MLC patients.
- To offer insights into the pathophysiology of MLC based on variant analysis and recent research.
Main Methods:
- Genetic analysis of 508 patients with MRI-confirmed MLC.
- Compilation of variants from a dedicated database and published literature.
- Inclusion of pathogenicity confirmation experiments for select variants.
Main Results:
- Detailed characterization of genetic variants in MLC1 (151 unique), GLIALCAM (29), GPRC5B (2), and AQP4 (1).
- Analysis of variants from 258 patients in a private database and 250 patients from 64 published reports.
- Identification and discussion of notable variants and their potential impact on MLC pathophysiology.
Conclusions:
- This study presents the most comprehensive variant landscape for MLC to date, expanding the known genetic basis of the disorder.
- The findings contribute to a better understanding of genotype-phenotype correlations in MLC.
- Updated genetic information is crucial for diagnosis, genetic counseling, and future therapeutic strategies for MLC.
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