Pyruvate dehydrogenase complex deficiency

The signs and symptoms of pyruvate dehydrogenase complex (PDC) deficiency can begin at any time between birth and late childhood, but they most commonly begin in infancy. Signs that may be apparent in pregnancy include poor fetal weight gain and low levels of estriol in the mother’s urine.^[4] Some babies with the disease may have brain abnormalities seen on ultrasound.^[1] Babies with PDC deficiency may have low scores measuring a baby’s health after birth (Apgar scores). A low birth weight is common. Some features that may be characteristic of PDC deficiency include a narrow head, prominent forehead (frontal bossing), wide nasal bridge, long philtrum, and flared nostrils. However, these features are not present in all babies with PDC deficiency.^[2]

Most commonly, babies with PDC deficiency develop symptoms soon after birth. Babies may have high levels of lactate in the bloodstream (lactic acidosis). Some babies with severe lactic acidosis may have high levels of ammonia in the blood (hyperammonemia). Other symptoms of PDC deficiency can include having low muscle tone (hypotonia), poor feeding, extreme tiredness (lethargy), rapid breathing (tachypnea), abnormal eye movements, and seizures. Symptoms that later develop may include having a small head (microcephaly), intellectual disability, blindness, and tight muscles (spasticity).^[1][4] 

There is a wide range of severity of symptoms associated with PDC deficiency. In some cases, the disease is less severe, and episodes of lactic acidosis only occur when a person is ill, under stress, or eats a high amount of carbohydrates. In these situations, signs of lactic acidosis may include abnormal muscle movements (ataxia). In some cases, people with PDC deficiency that begins in childhood may have normal development of the brain.^[2]

PDC deficiency affects both males and females. However, males are more likely to have severe forms of the disease than females.^[2]

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.^[1]

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.^[1]

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.^[2][3]

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).^[1] 

The most common cause of PDC deficiency is pathogenic variants in PDHA1, which is located on the X chromosome.^[1][3] 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.^[1]

In some cases, people who have a pathogenic variant in PDHA1 are the first people in the family with the genetic change.^[5] 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.^[2]

The other genes that cause PDC deficiency are not located on the sex chromosomes, so they are called autosomal genes.^[1][3] 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

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:^[1]

• 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.^[6] Genetic testing may be used to confirm the diagnosis.^[1]

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.^[1][4] 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.^[1] Certain genetic changes (mutations or pathogenic variants) that cause PDC deficiency may be more responsive to thiamine treatment than others.^[7]

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.^[1] Medications to help prevent seizures may be recommended for some people with PDC deficiency.^[8] 

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.^[1][4] 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.^[1]