Dihydrolipoamide dehydrogenase deficiency

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Reviewed September 2014

What is dihydrolipoamide dehydrogenase deficiency?

Dihydrolipoamide dehydrogenase deficiency is a severe condition that can affect several body systems. Signs and symptoms of this condition usually appear shortly after birth, and they can vary widely among affected individuals.

A common feature of dihydrolipoamide dehydrogenase deficiency is a potentially life-threatening buildup of lactic acid in tissues (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Neurological problems are also common in this condition; the first symptoms in affected infants are often decreased muscle tone (hypotonia) and extreme tiredness (lethargy). As the problems worsen, affected infants can have difficulty feeding, decreased alertness, and seizures. Liver problems can also occur in dihydrolipoamide dehydrogenase deficiency, ranging from an enlarged liver (hepatomegaly) to life-threatening liver failure. In some affected people, liver disease, which can begin anytime from infancy to adulthood, is the primary symptom. The liver problems are usually associated with recurrent vomiting and abdominal pain. Rarely, people with dihydrolipoamide dehydrogenase deficiency experience weakness of the muscles used for movement (skeletal muscles), particularly during exercise; droopy eyelids; or a weakened heart muscle (cardiomyopathy). Other features of this condition include excess ammonia in the blood (hyperammonemia), a buildup of molecules called ketones in the body (ketoacidosis), or low blood sugar levels (hypoglycemia).

Typically, the signs and symptoms of dihydrolipoamide dehydrogenase deficiency occur in episodes that may be triggered by fever, injury, or other stresses on the body. Affected individuals are usually symptom-free between episodes. Many infants with this condition do not survive the first few years of life because of the severity of these episodes. Affected individuals who survive past early childhood often have delayed growth and neurological problems, including intellectual disability, muscle stiffness (spasticity), difficulty coordinating movements (ataxia), and seizures.

How common is dihydrolipoamide dehydrogenase deficiency?

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

What genes are related to dihydrolipoamide dehydrogenase deficiency?

Mutations in the DLD gene cause dihydrolipoamide dehydrogenase deficiency. This gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase (DLD). DLD is one component of three different groups of enzymes that work together (enzyme complexes): branched-chain alpha-keto acid dehydrogenase (BCKD), pyruvate dehydrogenase (PDH), and alpha (α)-ketoglutarate dehydrogenase (αKGDH). The BCKD enzyme complex is involved in the breakdown of three protein building blocks (amino acids) commonly found in protein-rich foods: leucine, isoleucine, and valine. Breakdown of these amino acids produces molecules that can be used for energy. The PDH and αKGDH enzyme complexes are involved in other reactions in the pathways that convert the energy from food into a form that cells can use.

Mutations in the DLD gene impair the function of the DLD enzyme, which prevents the three enzyme complexes from functioning properly. As a result, molecules that are normally broken down and their byproducts build up in the body, damaging tissues and leading to lactic acidosis and other chemical imbalances. In addition, the production of cellular energy is diminished. The brain is especially affected by the buildup of molecules and the lack of cellular energy, resulting in the neurological problems associated with dihydrolipoamide dehydrogenase deficiency. Liver problems are likely also related to decreased energy production in cells. The degree of impairment of each complex contributes to the variability in the features of this condition.

How do people inherit dihydrolipoamide dehydrogenase deficiency?

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.

Where can I find information about diagnosis or management of dihydrolipoamide dehydrogenase deficiency?

These resources address the diagnosis or management of dihydrolipoamide dehydrogenase deficiency and may include treatment providers.

You might also find information on the diagnosis or management of dihydrolipoamide dehydrogenase deficiency in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about dihydrolipoamide dehydrogenase deficiency?

You may find the following resources about dihydrolipoamide dehydrogenase deficiency helpful. These materials are written for the general public.

MedlinePlus - Health information (4 links)
Educational resources - Information pages
Orphanet
Patient support - For patients and families (4 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary
Genetic Testing Registry - Repository of genetic test information (1 link)
OMIM - Genetic disorder catalog

What other names do people use for dihydrolipoamide dehydrogenase deficiency?

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

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about dihydrolipoamide dehydrogenase deficiency?

Ask the Genetic and Rare Diseases Information Center

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding dihydrolipoamide dehydrogenase deficiency?

acidosis ; acids ; ammonia ; Ashkenazi Jewish ; ataxia ; autosomal ; autosomal recessive ;breakdown ; cardiomyopathy ; cell ; decreased muscle tone ; deficiency ; dehydrogenase ; disability ;enzyme ; fever ; gene ; hyperammonemia ; hypoglycemia ; hypotonia ; inherited ; injury ; isoleucine ;lactic acid ; lactic acidosis ; lethargy ; leucine ; liver failure ; muscle tone ; neurological ; population ;prevalence ; protein ; recessive ; spasticity ; symptom ; valine

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References (6 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.