(Dihydro)lipoamide dehydrogenase (LADH) deficiency is an autosomal recessive genetic metabolic disorder. It generally presents with an onset in the neonatal age and premature death. The clinical picture usually involves metabolic decompensation and lactic acidosis that lead to neurological, cardiological, and/or hepatological outcomes. Severity of the disease is due to the fact that LADH is a common E3 subunit to the pyruvate, alpha-ketoglutarate, alpha-ketoadipate, and branched-chain alpha-keto acid dehydrogenase complexes and is also part of the glycine cleavage system; hence, a loss in LADH activity adversely affects several central metabolic pathways simultaneously. The severe clinical manifestations, however, often do not parallel the LADH activity loss, which implies the existence of auxiliary pathological pathways; stimulated reactive oxygen species (ROS) production as well as dissociation from the relevant multienzyme complexes proved to be auxiliary exacerbating pathomechanisms for selected disease-causing LADH mutations. This review provides an overview on the therapeutic challenges of inherited metabolic diseases, structural and functional characteristics of the mitochondrial alpha-keto acid dehydrogenase complexes, molecular pathogenesis and structural basis of LADH deficiency, and relevant potential future medical perspectives.
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Article Synopsis
- - Dihydrolipoamide dehydrogenase (LADH) deficiency is a rare genetic disorder typically manifesting in newborns and often leading to early mortality, especially prevalent among Ashkenazi Jews.
- - The disease causes severe metabolic issues, including lactate acidosis, with significant impacts on neurological, heart, and liver functions due to LADH's role in key metabolic pathways.
- - Recent research sheds light on the complex mechanisms behind the disease, revealing that increased reactive oxygen species and altered interactions with multienzyme complexes may worsen the clinical effects, in addition to the loss of LADH activity.
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