DLD – Pyruvate Dehydrogenase E3 Deficiency

Dihydrolipoamide dehydrogenase (encoded by DLD) is the E3 subunit common to pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase complexes. Pathogenic biallelic variants in DLD cause autosomal recessive pyruvate dehydrogenase E3 deficiency (Pyruvate Dehydrogenase E3 Deficiency), a disorder characterized by hepatic failure, lactic acidosis, and variable neurological involvement.

Genetic evidence includes the original identification of two missense mutations (p.Lys37Glu and p.Leu453Val) in a single patient demonstrating only ~6% residual E3 activity (PMID:8506365). Subsequent reports described homozygous p.Gly229Cys in consanguineous families with recurrent liver failure and Reye-like syndrome (PMID:23478190), as well as compound heterozygotes harboring splice-site, nonsense, and frameshift variants in unrelated sibships (PMID:8968745; PMID:39544687). In total, over 50 affected individuals from multiple families have been reported, spanning missense, loss-of-function, and splice variants, with clear genotype–phenotype correlation.

Segregation analysis supports autosomal recessive inheritance with multiple affected siblings in consanguineous pedigrees—most notably a family with five affected siblings demonstrating cosegregation of the p.Gly229Cys variant (PMID:39544687). Enzyme assays in patient fibroblasts and muscle show DLD activity reduced to 2–25% of control levels, with concomitant decreases in pyruvate dehydrogenase activity (PMID:8506365; PMID:8968745).

Functional studies reveal that pathogenic DLD variants disrupt homodimerization and cofactor binding, leading to loss of dehydrogenase activity and, in some cases, gain of proteolytic or ROS-generating functions. Mouse and human enzyme assays confirmed that interface mutations (e.g., p.Asp479Val) both abolish normal activity and enhance cryptic protease activity (PMID:17404228; PMID:21930696). A recent multi-omics analysis of patient fibroblasts compound heterozygous for p.Gly229Cys and a novel p.Gly53Glu variant demonstrated profound mitochondrial dysfunction, altered one-carbon metabolism, and transcriptomic signatures of metabolic stress (PMID:39802097).

Clinically, patients present with early-onset vomiting (HP:0002013), mental deterioration (HP:0001268), fulminant hepatic failure (HP:0004448), lactic acidosis, hypoglycemia, and variable neurodevelopmental delay. Biochemical markers may be intermittent or normal in the well state, necessitating genetic testing in unexplained acute liver failure or Reye-like syndrome.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1993 • Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient. PMID:8506365
• Molecular Genetics and Metabolism • 2013 • Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome. PMID:23478190
• Human Molecular Genetics • 1996 • Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency. PMID:8968745
• JIMD Reports • 2024 • Dihydrolipoamide dehydrogenase deficiency in five siblings with variable phenotypes, including fulminant fatal liver failure despite good engraftment of transplanted liver. PMID:39544687
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • Cryptic proteolytic activity of dihydrolipoamide dehydrogenase. PMID:17404228
• Molecular Genetics and Metabolism Reports • 2025 • In depth profiling of dihydrolipoamide dehydrogenase deficiency in primary patients fibroblasts reveals metabolic reprogramming secondary to mitochondrial dysfunction. PMID:39802097

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