Dihydrolipoamide dehydrogenase deficiency

Dihydrolipoamide dehydrogenase deficiency is a severe metabolic condition characterized by life-threatening lactic acid buildup, neurological issues, and potential liver failure.

Overview & Symptoms

Dihydrolipoamide dehydrogenase deficiency is a severe condition that can affect several body systems. Signs and symptoms usually appear shortly after birth and vary widely among affected individuals. Typically, these symptoms occur in episodes triggered by fever, injury, or other stresses on the body, with individuals often being symptom-free between episodes.

Common symptoms and complications include:

• Lactic acidosis: A potentially life-threatening buildup of lactic acid in tissues that can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat.
• Neurological problems: Decreased muscle tone (hypotonia) and extreme tiredness (lethargy) are often the first symptoms in infants. As the condition worsens, infants may experience difficulty feeding, decreased alertness, and seizures.
• Liver problems: Ranging from an enlarged liver (hepatomegaly) to life-threatening liver failure. Liver disease can begin anytime from infancy to adulthood and is often associated with recurrent vomiting and abdominal pain.
• Muscle and heart issues: Weakness of the skeletal muscles (particularly during exercise), droopy eyelids, or a weakened heart muscle (cardiomyopathy).
• Chemical imbalances: Excess ammonia in the blood (hyperammonemia), a buildup of ketones in the body (ketoacidosis), or low blood glucose levels (hypoglycemia).

Many infants with this condition do not survive the first few years of life due to the severity of these episodes. Affected individuals who survive past early childhood often experience delayed growth and ongoing neurological problems, including intellectual disability, muscle stiffness (spasticity), difficulty coordinating movements (ataxia), and seizures.

Frequency

Dihydrolipoamide dehydrogenase deficiency occurs in an estimated 1 in 35,000 to 48,000 individuals of Ashkenazi Jewish descent, a population that typically experiences liver disease as the primary symptom. In other populations, the prevalence of this condition is unknown, but it is likely rare.

Causes

Mutations in the DLD gene cause dihydrolipoamide dehydrogenase deficiency. This gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase (DLD). DLD is a component of three different enzyme complexes that work together to convert energy from food into a form cells can use:

• Branched-chain alpha-keto acid dehydrogenase (BCKD): Involved in breaking down the amino acids leucine, isoleucine, and valine.
• Pyruvate dehydrogenase (PDH)
• Alpha-ketoglutarate dehydrogenase (αKGDH)

Mutations in the DLD gene impair the function of the DLD enzyme, preventing these three complexes from functioning properly. This leads to a buildup of unprocessed molecules and their byproducts, damaging tissues and causing lactic acidosis and other chemical imbalances. It also diminishes cellular energy production, which particularly impacts the brain and liver. The degree of impairment of each complex contributes to the variability of the condition's features.

Learn more about the gene associated with Dihydrolipoamide dehydrogenase deficiency

• DLD

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Dihydrolipoyl dehydrogenase deficiency
• DLD deficiency
• E3 deficiency
• Lactic acidosis due to LAD deficiency
• Lactic acidosis due to lipoamide dehydrogenase deficiency
• Lipoamide dehydrogenase deficiency
• Maple syrup urine disease, type III