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Disease Profile

Pyruvate dehydrogenase complex deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Childhood

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ICD-10

E74.4

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Pyruvate dehydrogenase deficiency; PDHC; PDH;

Categories

Metabolic disorders

Summary

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. Symptoms of PDC deficiency include signs of metabolic dysfunction such as extreme tiredness (lethargy), poor feeding, and rapid breathing (tachypnea). Other symptoms may include signs of neurological dysfunction such as developmental delay, periods of uncontrolled movements (ataxia), low muscle tone (hypotonia), abnormal eye movements, and seizures. 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.[1]

The most common form of PDC deficiency is caused by genetic changes (mutations or pathogenic variants) in the PDHA1 gene. These pathogenic variants are inherited in an X-linked manner.[2] Pathogenic variants in other genes including PDHB, DLAT, PDHX, DLD, and PDP1 can also cause PDC deficiency. These pathogenic variants are inherited in an autosomal recessive manner.[2][3] PDC deficiency is diagnosed based on laboratory tests including blood tests, analysis of the urine, and brain MRI. The diagnosis can be confirmed by analyzing the pyruvate dehydrogenase enzyme.[1][2] Treatment for PDC deficiency includes dietary supplementation with carnitine, thiamine, and lipoic acid.[1]

Symptoms

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]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Feeding difficulties in infancy
0008872
Lethargy
0001254
Muscular hypotonia
Low or weak muscle tone
0001252
30%-79% of people have these symptoms
Abnormal pyramidal sign
0007256
Abnormality of eye movement
Abnormal eye movement
Abnormal eye movements
Eye movement abnormalities
Eye movement issue

[ more ]

0000496
Aplasia/Hypoplasia of the corpus callosum
0007370
Ataxia
0001251
Choreoathetosis
0001266
Dysarthria
Difficulty articulating speech
0001260
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Global developmental delay
0001263
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation

[ more ]

0001511
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Osteolytic defects of the middle phalanx of the 4th toe
0100453
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Tachypnea
Increased respiratory rate or depth of breathing
0002789
Tremor
0001337
5%-29% of people have these symptoms
Cerebral palsy
0100021
Dyspnea
Trouble breathing
0002094
Dystonia
0001332
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Frontal bossing
0002007
High palate
Elevated palate
Increased palatal height

[ more ]

0000218
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Long philtrum
0000343
Multiple lipomas
Multiple fatty lumps
0001012
Narrow face
Decreased breadth of face
Decreased width of face

[ more ]

0000275
Pectus excavatum
Funnel chest
0000767
Trigonocephaly
Triangular skull shape
Wedge shaped skull

[ more ]

0000243
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Ventriculomegaly
0002119
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
1%-4% of people have these symptoms
Abnormal facial shape
Unusual facial appearance
0001999
Percent of people who have these symptoms is not available through HPO
Agenesis of corpus callosum
0001274
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils

[ more ]

0000463
Apneic episodes precipitated by illness, fatigue, stress
0002872
Basal ganglia cysts
0006799
Cerebral atrophy
Degeneration of cerebrum
0002059
Chronic lactic acidosis
0004925
Decreased activity of the pyruvate dehydrogenase complex
0002928
Episodic ataxia
0002131
Flared nostrils
0000454
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Hyperalaninemia
Increased blood alanine
Increased serum alanine

[ more ]

0003348
Increased CSF lactate
0002490
Increased serum lactate
0002151
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Psychomotor retardation
0025356
Ptosis
Drooping upper eyelid
0000508
Severe lactic acidosis
0004900
Small for gestational age
Birth weight less than 10th percentile

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.[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]

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:[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]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    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.[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]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • Genetics Home Reference (GHR) contains information on Pyruvate dehydrogenase complex deficiency. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Pyruvate dehydrogenase complex deficiency. Click on the link to view a sample search on this topic.

            References

            1. Frye RE and Benke PJ. Pyruvate Dehydrogenase Complex Deficiency. Medscape. February 18, 2016; https://emedicine.medscape.com/article/948360-overview.
            2. Frye RE. Pyruvate Dehydrogenase Complex Deficiency. National Organization for Rare Disorders. 2010; https://rarediseases.org/rare-diseases/pyruvate-dehydrogenase-complex-deficiency/.
            3. Pyruvate dehydrogenase deficiency. Genetics Home Reference. July 2012; https://ghr.nlm.nih.gov/condition/pyruvate-dehydrogenase-deficiency.
            4. Brown GK, Otero LJ, LeGris M, and Brown RM. Pyruvate dehydrogenase deficiency. Journal of Medical Genetics. 1994; 31:875-879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1016663/pdf/jmedgene00001-0059.pdf.
            5. Brown G. Pyruvate dehydrogenase deficiency. Orphanet. April 2012; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=765.
            6. Shin HK, Grahame G, McCandless SE, Kerr DS, and Bedoyan JK. Enzymatic testing sensitivity, variability, and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Molecular Genetics and Metabolism. November 2017; 122(3):61-66. https://www.ncbi.nlm.nih.gov/pubmed/28918066.
            7. Jauhari P, Sankhyan N, Vyas S, and Singhi P. Thiamine Responsive Pyruvate Dehydrogenase Complex Deficiency: A Potentially Treatable Cause of Leigh’s Disease. Journal of Pediatric Neurosciences. July-September 2017; 12(3):265-267. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696666/.
            8. Pyruvate Dehydrogenase Complex Deficiency (PDCD/PDH). United Mitochondrial Disease Foundation. https://www.umdf.org/types/pyruvate-dehydrogenase-complex-deficiency/. Accessed 2/13/2018.

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