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AGC1 deficiency associated with global cerebral hypomyelination
Rolf Wibom1, Francesco M Lasorsa, Virpi Töhönen
1Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
The New England Journal of Medicine
|July 31, 2009
Summary
Mitochondrial aspartate-glutamate carrier 1 (AGC1) deficiency, caused by an SLC25A12 mutation, leads to neurodevelopmental issues. Impaired aspartate transport disrupts energy metabolism and myelin formation in the brain.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) is crucial for neuronal energy metabolism via the malate-aspartate shuttle.
- AGC1 facilitates aspartate transport, supporting cytosolic NADH oxidation in mitochondria, vital for central nervous system energy supply.
Observation:
- A novel syndrome of arrested psychomotor development, hypotonia, and seizures was identified in a child.
- The child presented with a homozygous missense mutation in the SLC25A12 gene, encoding the AGC1 protein.
Findings:
- Functional analysis revealed abolished activity of the mutant AGC1 protein.
- The patient exhibited global hypomyelination in the cerebral hemispheres, indicating impaired myelin formation.
Implications:
- This suggests that impaired aspartate efflux from neuronal mitochondria due to AGC1 deficiency hinders normal myelin development.
- AGC1 deficiency represents a newly identified genetic disorder with significant neurological consequences.
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