Loss-of-function mutations in DLD cause MSUD3/DLDD

Stable Identifier
R-HSA-9907570
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Loss-of-function mutations in DLD cause MSUD3/DLDD
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Mutations in the dihydrolipoyl dehydrogenase (DLD) gene are associated with dihydrolipoyl dehydrogenase deficiency (DLDD), an autosomal recessive disorder characterized by lactic acidosis and neurological deterioration (reviewed in Quinonez et al, 2021). DLDD is sometimes referred to as Maple Syrup Urine Disease 3 due to its effects on BCKDH function, but the phenotype is distinct due to the involvement of DLD in multiple protein complexes (reviewed in Strauss et al, 2020).
DLD encodes the shared E3 component of the multiprotein mitochondrial enzymes BCKDH (branched-chain amino acid dehydrogenase), KGDH (alpha-ketoglutarate deydrogenase) and PDH (pyruvate dehydrogenase). In consequence mutations in DLD have pleiotropic effects and manifest with a range of clinical outcomes, including increased urinary excretion of alpha-keto acids and accumulation of pyruvate and plasma branched-chain amino acids in plasma (reviewed in Quinonez and Thoene, 2021). Mutations in DLD often occur as compound heterozygotes complicating the assignment of pathogenic effect. Moreover, the severity of phenotypic effects displayed in vivo does not correlate linearly with the extent of residual DLD enzymatic activity in vitro (Shany et al, 1999; Cameron et al, 2006; Quinonez et al, 2013; reviewed in Quinonez and Thoene, 2021).
Literature References
PubMed ID Title Journal Year
16770810 Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity

Renaud, DL, Robinson, BH, Elpeleg, O, Feigenbaum, A, Cameron, JM, Clarke, JT, MacKay, N, Raiman, J, Levandovskiy, V

Am J Med Genet A 2006
23290025 Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency

Bedoyan, JK, Thoene, JG, Martin, DM, Quinonez, SC, Leber, SM

Pediatr Neurol 2013
10448086 Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain

Elpeleg, ON, Shany, E, Hershkovitz, E, Saada, A, Shaag, A, Landau, D

Biochem Biophys Res Commun 1999
25032271 Dihydrolipoamide Dehydrogenase Deficiency

Thoene, JG, Quinonez, SC

2014
20301495 Maple Syrup Urine Disease

Puffenberger, EG, Strauss, KA, Carson, VJ

2006
Participants
Events
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as an event of
Disease
Name Identifier Synonyms
maple syrup urine disease DOID:9269 dihydrolipoamide dehydrogenase deficiency
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-04-12)
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