SLC25A12 – developmental and epileptic encephalopathy, 39

SLC25A12 encodes the mitochondrial aspartate–glutamate carrier isoform 1 (AGC1), a neuron- and muscle-specific component of the malate–aspartate NADH shuttle that exports aspartate to the cytosol, supporting mitochondrial oxidation of cytosolic NADH and providing substrates for myelin synthesis.

AGC1 deficiency manifests as developmental and epileptic encephalopathy 39, characterized by arrested psychomotor development, congenital hypotonia (HP:0001252), seizures (HP:0001250), and global cerebral hypomyelination.

In a single patient, a homozygous missense variant c.1769A>G (p.Gln590Arg) abolished AGC1 transport activity and caused the full clinical phenotype ([PMID:19641205]). In a consanguineous Indian family, two siblings with profound developmental delay, hypotonia, refractory epilepsy, hypomyelination, and reduced N-acetylaspartate harbored a homozygous c.1058G>A (p.Arg353Gln) variant with residual activity of 15% ([PMID:24515575]).

Segregation analysis confirmed homozygosity in all affected relatives (affected_relatives: 2), supporting autosomal recessive inheritance.

Functional assays in patient fibroblasts and reconstituted systems demonstrated absent or markedly reduced AGC1 transport for both variants, validating loss of function as the mechanism ([PMID:19641205], [PMID:24515575]).

AGC1 knock-down in oligodendrocyte precursor cells reduced proliferation and induced precocious differentiation via dysregulation of PDGFα and TGFβ signaling, linking AGC1 deficiency to oligodendrocyte dysfunction and hypomyelination ([PMID:31514314], [PMID:38553684]).

Slc25a12-knockout mice exhibit hypomyelination, neurofilament accumulation, and early lethality; slice culture myelination defects were rescued by pyruvate, underscoring impaired aspartate/N-acetylaspartate metabolism and NADH balance in pathogenesis ([PMID:20015484]).

Collectively, three probands across two families and extensive functional concordance support a Moderate clinical validity for SLC25A12 in developmental and epileptic encephalopathy 39. SLC25A12 sequencing should be considered in children with infantile epilepsy, congenital hypotonia, and hypomyelination.

References

• The New England journal of medicine • 2009 • AGC1 deficiency associated with global cerebral hypomyelination PMID:19641205
• JIMD Reports • 2014 • AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate PMID:24515575
• International Journal of Molecular Sciences • 2019 • Deficiency of Mitochondrial Aspartate-Glutamate Carrier 1 Leads to Oligodendrocyte Precursor Cell Proliferation Defects Both In Vitro and In Vivo PMID:31514314
• Biological Psychiatry • 2010 • Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders PMID:20015484
• Cellular & Molecular Biology Letters • 2024 • Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs) PMID:38553684

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