SLC25A1 – Combined D,L-2-Hydroxyglutaric Aciduria

Combined D,L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a severe autosomal recessive neurometabolic disorder characterized by early-onset lactic acidosis, developmental delay, seizures, and distinctive facial dysmorphism. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which transports citrate across the inner mitochondrial membrane. Loss of CIC function leads to accumulation of both D- and L-2-hydroxyglutarate, implicating SLC25A1 deficiency as the molecular basis of D/L-2-HGA.

Initial case studies identified homozygous and compound heterozygous SLC25A1 variants in neonates presenting with lactic acidosis, intracerebral cysts, and complex IV deficiency. A consanguineous patient harbored a homozygous missense variant c.593G>A (p.Arg198His), confirming pathogenicity in substrate-binding site I of CIC (PMID:27306203). A separate report described two siblings compound heterozygous for c.18_24dup (p.Ala9ProfsTer82) and c.134C>T (p.Pro45Leu) with classic D/L-2-HGA and novel facial dysmorphism (PMID:25614306).

A multi-patient cohort study applied a validated functional assay to 17 missense SLC25A1 variants detected in 26 patients, demonstrating graded reductions in citrate transport activity and establishing a genotype–phenotype correlation (PMID:29238895). Transfection of patient fibroblasts with wild-type SLC25A1 restored citrate efflux and normalized intracellular 2-hydroxyglutarate levels, directly proving that CIC deficiency causes D/L-2-HGA.

The variant spectrum includes at least 17 missense substitutions and multiple loss-of-function alleles (e.g., frameshifts), with no clear founder effects reported. All reported cases follow autosomal recessive inheritance with onset in the neonatal period or early infancy, and functional assays consistently recapitulate mitochondrial respiratory deficits.

Mechanistically, SLC25A1 deficiency leads to impaired citrate export, disrupting the tricarboxylic acid cycle and promoting compensatory glycolysis and excess 2-hydroxyglutarate production. Metabolic rescue by citrate supplementation in vivo partially ameliorated lactic acidosis and apneic episodes, underscoring the therapeutic potential of targeted metabolic support.

Together, robust genetic evidence from 26 probands in multiple families, segregation of biallelic variants, and concordant functional studies justify a Strong ClinGen classification for this gene–disease association. SLC25A1 testing should be integrated into diagnostic algorithms for unexplained neonatal lactic acidosis, cystic brain lesions, and combined D/L-2-hydroxyglutaric aciduria.

References

• JIMD Reports • 2016 • Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency PMID:27306203
• JIMD Reports • 2015 • Expanding the Clinical Spectrum of Mitochondrial Citrate Carrier (SLC25A1) Deficiency: Facial Dysmorphism in Siblings with Epileptic Encephalopathy and Combined D,L-2-Hydroxyglutaric Aciduria PMID:25614306
• Journal of Inherited Metabolic Disease • 2018 • An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants PMID:29238895

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