The DLD gene encodes the dihydrolipoamide dehydrogenase enzyme (LADH, E3), common component of the mitochondrial α-keto acid dehydrogenase complexes (the pyruvate dehydrogenase, α-keto(/2-oxo)glutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, α-keto(/2-oxo)adipate dehydrogenase complexes) and the glycine cleavage system that are crucial in cellular metabolism. Upon mutations to the DLD gene, LADH variants with i) reduced stability, ii) decreased catalytic activity, and/or iii) impaired tendency to interact with other subunits/components are expressed leading to dysfunctional multienzyme complexes and impaired metabolism. The above-mentioned multienzyme complexes are affected to various degrees upon each mutation, which explains the broad spectrum of the clinical pictures.
Clinical chemistry (for lactic acidosis, hypoglycaemia, elevated plasma [mostly branched-chain] amino acids, and urine α-keto acids), and functional tests (enzyme activity measurements) on the patient tissue samples can be indicative of the overall complex deficiencies. Definite diagnosis can only be given based on DNA sequencing results.
The relevant clinical literature has hitherto reported 13 missense substitutions (Ile12Thr, Lys37Glu, Gly194Cys, Ile318Thr, Met326Val, Glu340Lys, Ile358Thr, Gly426Glu, Asp444Val, Ile445Met, Arg447Gly, Pro453Leu, Arg460Gly), and one deletion (Gly101del) [mature protein numbering]. Additionally, a nonsense substitution, a mutation causing exon skipping combined with a frame shift, and an intonic mutation at a consensus splice site causing defective splicing and unstable mRNA have also been described; these mutations prevent the expression of the full-length hLADH and therefore they are found exclusively in compound heterozygous states, where likely the other mutations determine the respective disease phenotypes.
DLD