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Dihydrolipoamide Dehydrogenase Deficiency.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2014 Jul 17.

Author information

Clinical Lecturer, University of Michigan, Ann Arbor, Michigan
Active Emeritus Professor of Pediatrics, Director, Biochemical Genetics Laboratory, University of Michigan, Ann Arbor, Michigan



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.


Treatment of manifestations: Management of DLD deficiency is difficult due to the various metabolic pathways involved. Management of the early-onset neurologic presentation relies on empiric treatment of the three isolated enzyme complex deficiencies (none of which appear to significantly alter the natural history of the disease): BCKDH complex deficiency: dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring; αKGDH complex: very rare, no recommendations available; PDH complex: ketogenic diet (due to defective carbohydrate oxidation), trial of dichloroacetate (DCA), and thiamine supplementation. Management of the primarily hepatic presentation typically involves supportive therapy during times of acute liver injury or failure, including nutritional support, IV glucose for hypoglycemia, correction of metabolic acidosis, correction of coagulopathy, and avoidance of liver-toxic medications. Prevention of primary manifestations: No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications. Surveillance: Routine monitoring of growth and development; plasma amino acid levels (to guide dietary management). For those receiving DCA, monitoring for the development of peripheral neuropathy. Agents/circumstances to avoid: Fasting, catabolic stressors, liver-toxic medications. Evaluation of relatives at risk: If the DLD pathogenic variants in an affected proband are known, at-risk sibs should undergo molecular genetic testing prenatally or as soon as possible after birth so that those who have inherited both pathogenic variants can receive appropriate interventions and avoid risk factors that may precipitate an acute event.


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 DLD pathogenic variants in the family are known.

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