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Alpha-ketoglutarate dehydrogenase (OGDH) catalyzes the decarboxylation of 2-oxoglutarate in the mitochondrial TCA cycle. Biallelic pathogenic variants in OGDH have been identified in individuals with autosomal recessive oxoglutaricaciduria, presenting with neonatal lactic acidosis, hypotonia, and progressive neurologic deterioration. Genetic and experimental data collectively establish a robust gene–disease relationship supporting clinical genetic testing.
Early evidence from three affected siblings born to consanguineous parents documented severe hypotonia, metabolic acidosis, and hyperlactatemia immediately after birth, with death by 30 months (3 probands) (PMID:1640293). This first report defined the clinical phenotype of OGDH deficiency in humans.
In 2021, whole exome sequencing identified two individuals harboring a homozygous missense variant c.959A>G (p.Asn320Ser) in OGDH, who presented with global developmental delay, ataxia, seizures, and elevated lactate (PMID:32383294). Fibroblast assays showed reduced OGDH protein and enzyme activity, and Drosophila models failed to rescue lethality when expressing the mutant protein, confirming pathogenicity.
A 2023 study described four additional unrelated consanguineous families with three novel homozygous OGDH variants: c.566C>T (p.Pro189Leu), c.890C>A (p.Ser297Tyr), and c.935G>A (p.Arg312Lys) (4 probands) (PMID:36520152). Segregation analysis in each family and in silico and cellular assays demonstrated decreased protein stability and impaired function. A splice impact of c.935G>A was confirmed by mini-gene assay.
Functional studies across patient fibroblasts, HEK293 transfection, and Drosophila rescue consistently show loss of OGDH protein function and enzyme activity, establishing a loss-of-function mechanism. Rescue of developmental lethality by wild-type but not mutant OGDH in flies, and restoration of enzyme activity by wild-type cDNA in patient cells, provide concordant experimental support.
No conflicting reports have been documented. The collective genetic and functional evidence fulfills ClinGen criteria for a Strong gene–disease association. Biallelic OGDH variants cause an autosomal recessive oxoglutaricaciduria characterized by congenital lactic acidosis, neurodevelopmental impairment, and hypotonia.
Key take-home: Genetic testing for OGDH should be included in diagnostic panels for neonatal lactic acidosis and neurodevelopmental disorders to guide management and genetic counseling.
Gene–Disease AssociationStrongNine probands including three siblings and four unrelated families; supportive segregation and concordant functional assays Genetic EvidenceStrongIdentification of five distinct biallelic variants in nine probands; segregation in consanguineous families Functional EvidenceStrongConsistent reduction of OGDH protein/activity in patient fibroblasts, HEK293 assays, and Drosophila rescue models demonstrating loss-of-function |