PMID 25032271


The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset isolated liver involvement. Early-onset DLD deficiency typically manifests as a hypotonic infant with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes patients frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease. The diagnosis of DLD deficiency is suspected in a proband with a characteristic clinical history and biochemical evidence of defective function of three mitochondrial enzyme complexes (branched chain alpha-ketoacid dehydrogenase [BCKDH] complex, α-ketoglutarate dehydrogenase [αKGDH] complex, and pyruvate dehydrogenase [PDH] complex). These may manifest as lactic acidosis, elevated α-ketoglutarate in the urine, the presence of branched chain keto-acids in the urine, elevated plasma levels of branched chain amino acids (leucine, isoleucine, and valine), and the presence of allo-isoleucine in plasma. Of note, these biochemical changes may be absent or intermittent. The diagnosis is confirmed by the presence of biallelic pathogenic variants in DLD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the