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DLD gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

DLD gene

The DLD gene provides instructions for making an enzyme essential for cellular energy production, and mutations in this gene can lead to severe metabolic and neurological conditions.

Normal Function

The DLD gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase. This enzyme forms one part (subunit), called the E3 component, of several groups of enzymes that work together (enzyme complexes). These complexes are essential for the breakdown of certain molecules to produce energy in cells.

Branched-chain alpha-keto acid dehydrogenase, or BCKD, is one of the enzyme complexes that include dihydrolipoamide dehydrogenase. The BCKD enzyme complex performs one step in the breakdown of three protein building blocks (amino acids): leucine, isoleucine, and valine. These amino acids are obtained from the diet, particularly from protein-rich foods such as milk, meat, and eggs. The breakdown of these amino acids produces molecules that can be used for energy.

Dihydrolipoamide dehydrogenase is also part of the pyruvate dehydrogenase (PDH) complex. This complex plays an important role in the production of energy for cells by converting pyruvate—formed from the breakdown of carbohydrates—into acetyl-CoA. Dihydrolipoamide dehydrogenase performs one step of this chemical reaction, which is essential to begin the series of reactions that ultimately produces adenosine triphosphate (ATP), the cell's main energy source.

Additionally, dihydrolipoamide dehydrogenase is part of a third enzyme complex involved in cellular energy production called alpha-ketoglutarate dehydrogenase (αKGDH). This complex converts α-ketoglutarate to succinyl-CoA, with further steps generating ATP for cells to use as energy.

Health Conditions Related to Genetic Changes

Dihydrolipoamide dehydrogenase deficiency

At least 17 mutations in the DLD gene have been found to cause dihydrolipoamide dehydrogenase deficiency. This severe condition presents with widely varying signs and symptoms, most commonly including:

  • A potentially life-threatening buildup of lactic acid in the tissues (lactic acidosis)
  • Neurological problems
  • Liver disease

Most DLD mutations change single amino acids in the enzyme, preventing the BCKD, PDH, and αKGDH enzyme complexes from functioning normally. Impairment of these complexes leads to the toxic accumulation of amino acids and pyruvate, reduced energy production, and subsequent damage to energy-demanding tissues, particularly the brain and liver.

Leigh syndrome

The DLD gene is also associated with Leigh syndrome, a rare inherited neurometabolic disorder.

Frequently Asked Questions

cute decompensations are typically provoked by periods of catabolic stress, including common viral infections, febrile illnesses, prolonged fasting, gastrointestinal illnesses with dehydration, or strenuous exertion. During these states, the body attempts to break down muscle protein and glycogen for energy, which overwhelms the defective mitochondrial energy pathways and causes a rapid accumulation of toxic organic acids and lactate, leading to lethargy, vomiting, liver failure, or encephalopathy.
While a ketogenic diet is sometimes used to treat isolated pyruvate dehydrogenase (PDH) deficiency (by bypassing glycolysis), it is strictly contraindicated in DLD deficiency. The impaired alpha-ketoglutarate dehydrogenase and branched-chain alpha-keto acid dehydrogenase complexes prevent normal processing of acetyl-CoA and ketone oxidation within the tricarboxylic acid (TCA) cycle. Imposing a high-fat, low-carbohydrate load forces the body to rely on pathways that cannot function efficiently, worsening metabolic acidosis and potentially triggering fatal metabolic collapse.
Because the DLD gene encodes the shared E3 subunit for three distinct mitochondrial enzyme complexes, DLD deficiency causes a combined biochemical defect. Unlike isolated MSUD—which only affects the branched-chain alpha-keto acid dehydrogenase complex—DLD deficiency disrupts branched-chain amino acid metabolism while simultaneously impairing pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (αKGDH). As a result, blood and urine testing reveals not only elevated branched-chain amino acids (leucine, isoleucine, valine) and alloisoleucine, but also severe lactic acidosis, elevated pyruvate, and marked excretion of alpha-ketoglutarate, which does not occur in classic MSUD.
During acute intercurrent illness, patients must immediately transition to an emergency sick-day management plan. This centers on suppressing catabolism by providing high-caloric non-protein nutrition, usually through intravenous infusion of high-concentration dextrose (10% or higher) with appropriate electrolytes, along with insulin if needed to control hyperglycemia. Fasting must be completely avoided, oral protein intake should be temporarily halted for 24 to 48 hours, and laboratory parameters (blood lactate, venous blood gas, ammonia, and liver enzymes) must be monitored closely in an intensive care or metabolic unit.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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