SLC25A12 – Mitochondrial Disease

SLC25A12 is implicated in autosomal recessive mitochondrial disease characterized by early‐onset neurodevelopmental impairment. Four affected individuals from three unrelated families—one child described in NEJM and two siblings in a consanguineous kindred, plus one proband in a multi‐patient cohort—harbor biallelic SLC25A12 variants segregating with disease (PMID:19641205, PMID:24515575, PMID:33629572). Functional assays and animal models provide concordant support for pathogenicity.

Inheritance of SLC25A12‐related mitochondrial disease is autosomal recessive. Homozygous missense mutations c.1769A>G (p.Gln590Arg) and c.1058G>A (p.Arg353Gln) have been reported, with one additional missense allele identified through exome sequencing (PMID:19641205, PMID:24515575, PMID:33629572). Segregation analysis confirmed homozygosity in two affected siblings and absence in unaffected relatives, totaling two additional affected relatives. The variant spectrum to date comprises three missense alleles without observed hypomorphic or splice variants.

Clinically, patients present in infancy with refractory epilepsy, congenital hypotonia, global developmental delay, abnormal myelination (HP:0012447), fluctuating basal ganglia signal, cerebral atrophy (HP:0002059), and reduced brain N-acetylaspartate on spectroscopy (PMID:24515575). Hypomyelination is global, involving both cerebral hemispheres and corpus callosum.

Functional assessment demonstrates that recombinant p.Arg353Gln AGC1 activity is reduced to 15% of wild type, while p.Gln590Arg abolishes carrier function, supporting loss of NADH shuttle activity in neurons (PMID:24515575, PMID:19641205). AGC1‐knockout mice recapitulate hypomyelination and neurofilament accumulation, reversible by pyruvate supplementation (PMID:20015484).

Oligodendrocyte precursor cell (OPC) studies show that AGC1 down‐regulation impairs OPC proliferation and drives precocious differentiation via dysregulated PDGFα and TGFβ signaling, providing mechanistic insight into myelination defects in vivo and in vitro (PMID:31514314).

No conflicting reports have emerged; all identified SLC25A12 variants yield recessive loss‐of‐function and segregate with consistent mitochondrial phenotypes. There is no evidence for heterozygous or dominant‐negative effects in human cohorts.

Integration of genetic and experimental data supports a ClinGen Moderate level of evidence for SLC25A12 in mitochondrial disease. SLC25A12 sequencing should be considered in children with infantile epilepsy, hypotonia, developmental delay, hypomyelination, and reduced brain NAA. Key take‐home: AR SLC25A12 deficiency is a clinically actionable cause of early mitochondrial encephalopathy.

References

• JIMD Reports • 2014 • AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate. PMID:24515575
• The New England Journal of Medicine • 2009 • AGC1 deficiency associated with global cerebral hypomyelination. PMID:19641205
• Journal of pediatric endocrinology & metabolism : JPEM • 2021 • The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum. PMID:33629572
• Biological Psychiatry • 2010 • Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. PMID:20015484
• 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

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