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Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus
Anne Fogli1, Kondi Wong, Eleonore Eymard-Pierre
1Institut National de la Santé et de la Recherche Médicale UMR 384, Facultéde Médecine, Clermont-Ferrand, France.
Insights
Cree leukoencephalopathy, a fatal infantile disorder, is linked to mutations in the eukaryotic translation initiation factor 2B (eIF2B) gene. Researchers identified a specific homozygous missense mutation in epsilon-eIF2B in affected individuals.
Area of Science:
- Neurogenetics
- Molecular Biology
- Pediatric Neurology
Background:
- Cree leukoencephalopathy is a rare, fatal, autosomal recessive leukodystrophy affecting infants in North American indigenous populations.
- The condition is characterized by white matter abnormalities and is clinically similar to central hypomyelination syndrome/vanishing white matter disease.
- Vanishing white matter disease is known to be caused by mutations in genes encoding subunits of the eukaryotic translation initiation factor 2B (eIF2B).
Purpose of the Study:
- To investigate the genetic cause of Cree leukoencephalopathy.
- To identify the specific molecular mechanisms underlying this rare neurological disorder.
Main Methods:
- Neuropathological examination of affected individuals' brains to identify characteristic cellular phenotypes.
- Genetic analysis, including sequencing of eIF2B family genes, to identify mutations in affected patients.
Main Results:
- Brain tissue analysis revealed foamy cells with an oligodendroglial phenotype, consistent with central hypomyelination syndrome/vanishing white matter disease.
- A homozygous missense mutation (R195H) in the epsilon-eIF2B subunit of the eukaryotic translation initiation factor 2B was identified in three patients from two Cree families.
Conclusions:
- The identified homozygous missense mutation in epsilon-eIF2B is the likely cause of Cree leukoencephalopathy.
- This finding establishes a genetic link between Cree leukoencephalopathy and mutations in the eIF2B complex, expanding the known spectrum of vanishing white matter disease.
Abstract:
Cree leukoencephalopathy is a rapidly fatal infantile autosomal recessive leukodystrophy of unknown cause observed in the native North American Cree and Chippewayan indigenous population. We found in the brain of affected individuals the typical foamy cells with the oligodendroglial phenotype described in central hypomyelination syndrome/vanishing white matter, a syndrome related to mutations in the genes encoding the five subunits of the eucaryotic translation initiation factor eIF2B. In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B.