Pyruvate dehydrogenase complex deficiency

Alternate names

Pyruvate dehydrogenase deficiency; PDHC; PDH; PDH deficiency; PDC deficiency

Definition

Pyruvate dehydrogenase complex (PDC) deficiency is a type of metabolic disease. This means that the body is not able to efficiently break down nutrients in food to be used for energy.

Onset

Symptoms usually begin in infancy, but signs can first appear at birth or later in childhood. Symptoms may be especially apparent during times of illness, stress, or after meals with high amounts of carbohydrates.

Epidemiology

Pyruvate dehydrogenase deficiency is believed to be a rare condition; however, its prevalence is unknown.

Cause

• 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.

Inheritance

• Pyruvate dehydrogenase deficiency can have different inheritance patterns. When the condition is caused by mutations in the PDHA1 gene, it is inherited in an X-linked pattern. The PDHA1 gene is located on the X chromosome, which is one of the two sex chromosomes.
• In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
• In females, who have two copies of the X chromosome, one altered copy of the PDHA1 gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all.
• However, many females with one altered copy of this gene have pyruvate dehydrogenase deficiency similar to affected males because the X chromosome with the normal copy of the PDHA1 gene is turned off through a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells).
• X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body cells. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.
• Research shows that females with pyruvate dehydrogenase deficiency caused by mutation of the PDHA1 gene often have skewed X-inactivation, which results in the inactivation of the X chromosome with the normal copy of the PDHA1 gene in most cells of the body. This skewed X-inactivation causes the chromosome with the mutated PDHA1 gene to be expressed in more than half of cells.

• When caused by mutations in other genes, pyruvate dehydrogenase deficiency 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.

Signs and symptoms

• Signs that may be apparent in pregnancy include poor fetal weight gain and low levels of estriol in the mother’s urine. Some babies with the disease may have brain abnormalities seen on ultrasound. 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.
• 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).
• 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.
• PDC deficiency affects both males and females. However, males are more likely to have severe forms of the disease than females.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Feeding difficulties in infancy
• Lethargy
• Muscular hypotonia(Low or weak muscle tone)

30%-79% of people have these symptoms

• Abnormal pyramidal sign
• Abnormality of eye movement(Abnormal eye movement)
• Aplasia/Hypoplasia of the corpus callosum
• Ataxia
• Choreoathetosis
• Dysarthria(Difficulty articulating speech)
• Gait disturbance(Abnormal gait)
• Global developmental delay
• Intrauterine growth retardation(Prenatal growth deficiency)
• Microcephaly(Abnormally small skull)
• Osteolytic defects of the middle phalanx of the 4th toe
• Seizure
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Tachypnea(Increased respiratory rate or depth of breathing)
• Tremor

5%-29% of people have these symptoms

• Cerebral palsy
• Dyspnea(Trouble breathing)
• Dystonia
• Epicanthus(Eye folds)
• Frontal bossing
• High palate(Elevated palate)
• Hypertelorism(Wide-set eyes)
• Long philtrum
• Multiple lipomas(Multiple fatty lumps)
• Narrow face(Decreased breadth of face)
• Pectus excavatum(Funnel chest)
• Trigonocephaly(Triangular skull shape)
• Upslanted palpebral fissure(Upward slanting of the opening between the eyelids)
• Ventriculomegaly
• Wide nasal bridge(Broad nasal bridge)

1%-4% of people have these symptoms

• Abnormal facial shape(Unusual facial appearance)

Diagnosis

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.

Treatment

• 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.

Prognosis

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.

NIH genetic and rare disease info

• NIH info on Pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex deficiency is a rare disease.

Pyruvate dehydrogenase complex deficiency Resources
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