Pyruvate dehydrogenase complex deficiency

What causes pyruvate dehydrogenase complex (PDC) deficiency?

Pyruvate dehydrogenase complex (PDC) deficiency is caused by having low levels of one or more enzymes that are needed for an important chemical reaction that takes place in the cells of the body. These enzymes are part of a group of three enzymes called the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex converts a chemical called pyruvate into another chemical called acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA is an important compound that helps the body make energy through a cycle known as the citric acid cycle. This cycle allows the body to get energy from proteins, carbohydrates, and fats.

When the pyruvate dehydrogenase complex is not working properly, pyruvate can’t be converted to acetyl-CoA. This causes pyruvate to build up in cells. The pyruvate instead is turned into lactic acid, which is toxic to the body in large amounts and causes lactic acidosis. When pyruvate isn’t converted into acetyl-CoA, the body also can’t go through the citric acid cycle. Therefore, enough energy is not made for the body to function properly. The brain is a part of the body that requires a lot of energy, so the symptoms that are first seen when energy is lacking often affect the brain. The signs and symptoms of PDC deficiency are variable because the amount of enzyme that is available to create energy varies in different people with the disease.

PDC deficiency is caused by genetic changes (mutations or pathogenic variants) in any of the genes that provide instructions for the body to make the enzymes of the pyruvate dehydrogenase complex. Genes in which pathogenic variants are known to cause PDC deficiency include: PDHA1 , PDHB , DLAT , PDHX , DLD , and PDP1.

Last updated on 05-01-20

How is pyruvate dehydrogenase complex (PDC) deficiency diagnosed?

Pyruvate dehydrogenase complex (PDC) deficiency is suspected in people who have lactic acidosis or signs of early-onset neurological disease such as seizures, lethargy, and poor feeding. A doctor may wish to order more tests including:

  • Brain MRI to check for brain damage
  • Blood test to measure levels of lactic acid or pyruvate
  • Tests to measure levels of lactic acid or pyruvate in the fluid surrounding the brain and spinal cord (cerebrospinal fluid)
  • Blood test or urine test to analyze levels of the amino acid alanine

A diagnosis of PDC deficiency can be confirmed by testing the activity of the pyruvate dehydrogenase complex and the activity of all of the specific enzymes within the complex. This can be completed by sampling the blood, skin (fibroblast), or muscle. Genetic testing may be used to confirm the diagnosis.

Last updated on 05-01-20

How is pyruvate dehydrogenase complex (PDC) deficiency inherited?

Pyruvate dehydrogenase complex (PDC) deficiency can be inherited in an X-linked manner or in an autosomal recessive manner depending on the gene that has a change (mutation or pathogenic variant).

The most common cause of PDC deficiency is pathogenic variants in PDHA1, which is located on the X chromosome. PDC deficiency caused by pathogenic variants in PDHA1 is therefore inherited in an X-linked manner. Most people have two sex chromosomes; males have one X chromosome and one Y chromosome, and females have two X chromosomes. Males therefore have one copy of the PDHA1 gene and females have two copies. Males or females with a change in one copy of the PDHA1 gene can have signs or symptoms of PDC deficiency. However, because females have another copy of the PDHA1 gene __ that is producing the enzyme of the pyruvate dehydrogenase complex, some females may have less severe symptoms of the disease.

In some cases, people who have a pathogenic variant in PDHA1 are the first people in the family with the genetic change. This is because many people with pyruvate dehydrogenase complex (PDC) deficiency pass away before they have children. Genetic changes that are new in a person are called de novo. In some cases, people who have a pathogenic variant in PDHA1 inherited the genetic change from their mother. The mother may have less severe symptoms of PDC deficiency or no symptoms at all. In these situations, each future child of that woman will have a 50% chance to inherit the pathogenic variant that causes the disease.

The other genes that cause PDC deficiency are not located on the sex chromosomes, so they are called autosomal genes. We inherit one copy of every autosomal gene from our mother and the other from our father. People with changes in both copies of the autosomal genes that cause PDC deficiency have symptoms of the disease. This is called autosomal recessive inheritance. People who have only one changed copy of an autosomal gene that causes PDC deficiency are known as carriers. Carriers typically do not have signs or symptoms of the disease. When two carriers of PDC deficiency have children together, for each child there is a:

  • 25% chance that the child will inherit both changed copies of the gene, so he or she has PDC deficiency
  • 50% chance that the child will inherit only one changed copy of the gene, so he or she is a carrier of the disease like each of the parents
  • 25% chance that the child will inherit both working copies of the gene, so he or she does not have PDC deficiency and is not a carrier of the disease

Last updated on 05-01-20

What is the long-term outlook for people with pyruvate dehydrogenase complex (PDC) deficiency?

Unfortunately, the long-term outlook for people with pyruvate dehydrogenase complex (PDC) deficiency is poor. People who show signs and symptoms early in life may pass away from complications of the disease in the first years of life. If people with the disease survive, they may be affected with complications including intellectual disability. People who have symptoms of PDC deficiency beginning in late childhood may survive longer because they have higher levels of functioning enzymes in the body. However, these individuals can still have complications of the disease.

Last updated on 05-01-20

How might pyruvate dehydrogenase complex (PDC) deficiency be treated?

The goal of the treatment for pyruvate dehydrogenase complex (PDC) deficiency is to stimulate the pyruvate dehydrogenase complex to produce as much energy as possible. This can prevent immediate worsening of the disease. Treatment options typically include supplementing cofactors including carnitine, thiamine, and lipoic acid. These are substances in the body that help the chemical reactions in the cells occur. Certain genetic changes (mutations or pathogenic variants) that cause PDC deficiency may be more responsive to thiamine treatment than others.

A medication called dichloroacetate may help treat some people with PDC deficiency. Doctors may also recommend a diet that is high in fats and low in carbohydrates (ketogenic diet). This can help prevent lactic acidosis but typically does not stop neurological symptoms. Medications to help prevent seizures may be recommended for some people with PDC deficiency.

Last updated on 05-01-20

Name: Metabolic Support UK 5 Hilliards Court Sandpiper Way
Chester Business Park
Chester, CH4 9QP, United Kingdom
Phone: 0845 241 2173 Toll Free: 0800 652 3181 Email: https://www.metabolicsupportuk.org/contact-us Url: https://www.metabolicsupportuk.org
Name: United Mitochondrial Disease Foundation 8085 Saltsburg Road, Suite 201
Pittsburgh, PA, 15239 , United States
Phone: +1-412-793-8077 Toll Free: 1-888-317-8633 Fax : +1-412-793-6477 Email: info@umdf.org Url: https://www.umdf.org
Name: Epilepsy Foundation 8301 Professional Place East Suite 230
Landover, MD, 20785, United States
Phone: +1-301-459-3700 Toll Free: 800-332-1000 (24/7 Helpline) Fax : +1-301-577-2684 Email: contactus@efa.org Url: https://www.epilepsy.com/ en Español 1-866-748-8008
Name: PDCD Parents & Friends Url: https://www.facebook.com/groups/pdcdkids/
Name: PDCD Parents and Guardians Url: https://www.facebook.com/groups/866318513458303/

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