The neurological form of PDCD contributes to hypotonia, poor feeding, lethargy and structural abnormalities in the brain. However, treatment with dichloroacetate does not improve neurological damage. Corrected and republished in: Mol Genet Metab. features in 371 patients. 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. mutations leading to the deficiency of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). Cells with a normal allele active can metabolize the lactic acid that is released by the PDH deficient cells. Imbard A, Boutron A, Vequaud C, Zater M, de Lonlay P, de Baulny HO, Barnerias 2012 The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Hum Genet. Mol Genet Metab. Patients must be monitored regularly for blood lactate levels, transaminase and plasma ketone levels. 2012 Jul;106(3):384. Aerobic respiration is the process of converting energy in the form of glucose into ATP, the primary currency of energy used by cells to fuel biochemical processes and support growth. 1995 Mar;56(3):558-69. The E1 enzyme, also called pyruvate dehydrogenase, is composed of four parts (subunits): two alpha subunits (called E1 alpha) and two beta subunits (called E1 beta). [14], Direct treatment that stimulates the pyruvate dehydrogenase complex (PDC), provides alternative fuels, and prevents acute worsening of the syndrome. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic abnormality caused by deficiency of the enzyme G6PD. All of these genes, like the PDHA1 gene are responsible for coding for a specific subunit of the pyruvate dehydrogenase complex. Mol Genet Metab. When the body cannot compensate for accelerated loss, anemia develops. Hong YS, Kerr DS, Liu TC, Lusk M, Powell BR, Patel MS. [6] Male infants that reach full term display more severe symptoms than females, and exhibit high mortality within the first few years of life [12][9], Prenatal onset may present with non-specific signs such as low Apgar scores and small for gestational age. This can be explained by x-inactivation, as females carry one normal and one mutant gene. Males with mutations that abolish, or almost abolish, enzyme activity presumably die in utero because brain cells are not able to generate enough ATP to be functionally viable. CNS damage is common and limits a full recovery. This conversion is essential to begin the series of chemical reactions that produce energy for cells. [7], In cases where PDHD is a result of a mutation in a gene other than PDHA1, it is most commonly known to be due to mutations in the following four genes, PDHB, DLAT, PDHX and PDP1. Pyruvate dehydrogenase phosphatase deficiency: [1] The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. Head RA, Brown RM, Zolkipli Z, Shahdadpuri R, King MD, Clayton PT, Brown GK. Pyruvate dehydrogenase deficiency can be diagnosed via the following methods:[14], The differential diagnosis of pyruvate dehydrogenase deficiency can consist of either D-Lactic acidosis or abnormalities associated with gluconeogenesis. Mutations in the genes that provide instructions for E1 beta (the PDHB gene), the E2 enzyme (the DLAT gene), E3 binding protein (the PDHX gene), and pyruvate dehydrogenase phosphatase (the PDP1 gene) have been identified in people with this condition. Mol Genet Metab. PDH is a complex of three primary enzymes— plus a phosphatase, a kinase, and at least one other element of less known function—that combine as a multimer with a very large molecular weight and a number of copies of each enzyme. Aug;58(2):234-41. Jun;6(3):155-9. PDCD is generally presented in one of two forms. Epub Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability. However, males are more severely affected than heterozygous females. 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. [5] Oral citrate is often used to treat acidosis. 2012 Jan;105(1):34-43. doi: 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. The PDHB gene is responsible for the coding of the E1 beta subunit of the pyruvate dehydrogenase complex. Willemsen M, Rodenburg RJ, Teszas A, van den Heuvel L, Kosztolanyi G, Morava 1997 Dec Pyruvate is then transported into mitochondria, where it is converted by the pyruvate dehydrogenase complex into acetyl-CoA, the starting substrate of the Krebs cycle. [2] The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.[3]. by protein complementation. Epub 2006 May 19. The pyruvate dehydrogenase complex is made up of multiple copies of several enzymes called E1, E2, and E3, each of which performs part of the chemical reaction that converts pyruvate to acetyl-CoA. Lactate dehydrogenase deficiency is a condition that affects how the body breaks down sugar to use as energy in cells, primarily muscle cells.There are two types of lactate dehydrogenase deficiency: lactate dehydrogenase A deficiency (sometimes called glycogen storage disease XI) and lactate dehydrogenase B deficiency.People with lactate dehydrogenase A deficiency experience … Pyruvate dehydrogenase (PDH) deficiency is a congenital degenerative metabolic disease resulting from a mutation of the pyruvate dehydrogenase complex (PDC) located on the X chromosome. Pyruvate dehydrogenase deficiency (also known as pyruvate dehydrogenase complex deficiency or PDCD) is a rare neurodegenerative disorders associated with abnormal mitochondrial metabolism.PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). To use the sharing features on this page, please enable JavaScript. E. Females with PDHA1 gene mutations: a diagnostic challenge. The activity of pyruvate dehydrogenase is impaired in inborn errors of metabolism, thiamine deficiency and by endotoxin. This enzyme is critical for the proper function of red blood cells: when the level of this enzyme is too low, red blood cells can break down prematurely (hemolysis). Due to the rarity and unfamiliarity of the disease, it is likely underdiagnosed[9] (Shin et al., 2017). Metabolic acidosis in these patients is usually refractory to correction with bicarbonate. pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic Individuals with PDCD beginning prenatally or in infancy usually die in early childhood. Other associated proteins control the activity of the complex: pyruvate dehydrogenase phosphatase turns on (activates) the complex, while pyruvate dehydrogenase kinase turns off (inhibits) the complex. Most have delayed development of mental abilities and motor skills such as sitting and walking. 2011 Genetic Testing Registry: Pyruvate dehydrogenase complex deficiency, Genetic Testing Registry: Pyruvate dehydrogenase E1-alpha deficiency, Genetic Testing Registry: Pyruvate dehydrogenase E1-beta deficiency, Genetic Testing Registry: Pyruvate dehydrogenase E2 deficiency, Genetic Testing Registry: Pyruvate dehydrogenase E3-binding protein deficiency, Genetic Testing Registry: Pyruvate dehydrogenase phosphatase deficiency, Pyruvate dehydrogenase complex deficiency, National Organization for Rare Disorders (NORD), PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY, PYRUVATE DEHYDROGENASE E1-BETA DEFICIENCY, PYRUVATE DEHYDROGENASE E3-BINDING PROTEIN DEFICIENCY, PYRUVATE DEHYDROGENASE PHOSPHATASE DEFICIENCY. In addition, other proteins included in the complex ensure its proper function. Hum Genet. The DLAT gene is responsible for the coding of the E2 subunit, and the PDP1 is responsible for producing the PDH phosphatase catalytic subunit that catalyzes PDH dephosphorylation. Deficiency of Iron overload can occur in people of any age, any ethnicity, or gender; iron overload is a condition of excess (too much) iron in the body. Both patients had abnormal neuromuscular development and lactic acidosis. The lymphocytes had enzyme activity about 10% of normal controls, whereas the activity in cultured skin fibroblasts was normal. See our, URL of this page: https://medlineplus.gov/genetics/condition/pyruvate-dehydrogenase-deficiency/. [5] PDH activity may be enhanced by exercise, phenylbutyrate and dichloroacetate. When the condition is caused by mutations in the PDHA1 gene, it is inherited in an X-linked pattern. [citation needed], The clinical presentation of congenital PDH deficiency is typically characterized by heterogenous neurological features that usually appear within the first year of life. Abnormalities in the membrane and shape of red blood cells (for example, spherocytosis) can lead to increased hemolysis. 2005 10.1016/j.ymgme.2011.09.032. When the condition is caused by mutations in the PDHA1 gene, it is inherited in an X-linked pattern. Genetics Home Reference content now can be found in the "Genetics" section of MedlinePlus. Inherited genetic enzyme disorders, such as glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) or pyruvate kinase deficiency, for example, can lead to increased hemolysis and subsequent elevation in bilirubin levels. 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. 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). Biochim Biophys Acta. Maj MC, MacKay N, Levandovskiy V, Addis J, Baumgartner ER, Baumgartner MR, Structural implications *In less severe cases, signs of lactic acidosis can include ataxia and episodes may only occur when ill, under stress, or after consuming high amounts of carbohydrates. MedlinePlus also links to health information from non-government Web sites. J Clin Endocrinol Metab. [16] Ketogenic baby formulas such as Nutricia KetoCal are available. While defects have been identified in all 3 enzymes of the complex, the E1-α subunit is predominantly the culprit. Pyruvate dehydrogenase E3 binding protein [5][6], More rarely, mutations occur in the E2 (dihydrolipoyl transacetylase) or the E3 (dihydrolipoyl dehydrogenase) subunits of the PDC enzymatic complex, DLAT and DLD genes respectively. 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. U.S. Department of Health and Human Services, intermittent ataxia with pyruvate dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency. This dephosphorylation activates the complex. Ketone bodies serve as an alternate source of energy for the body and the brain. The final gene that could be responsible for this disease is the PDHX gene, which codes for the E3 binding protein which is responsible for binding E3 dimers to the E2 subunit of the complex [8]. [15] However, some correction of acidosis does not reverse all the symptoms. Pyruvate dehydrogenase deficiency is extremely rare, with ~500 reported cases in the medical literature. four families with pyruvate dehydrogenase deficiency. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Any defects of Kreb's cycle or the electron transport chain will cause pyruvate to accumulate. C, Miné M, Marsac C, Saudubray JM, Brivet M. Molecular characterization of 82 A decrease in functional E1 alpha leads to reduced activity of the pyruvate dehydrogenase complex. Conversely, females with little to no enzyme activity will have major structural brain abnormalities and atrophy. Learn more. Pyruvate dehydrogenase deficiency can have different inheritance patterns. Other components of the pyruvate dehydrogenase complex are also involved in pyruvate dehydrogenase deficiency. They cannot, however, supply ATP to these cells and, therefore, phenotype depends largely on the nature/severity of the mutation. In these cases, PDCD displays autosomal recessive inheritance, affecting males and females equally. 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. The most commonly seen form of PDCD is caused by mutations in the X-linked E1 alpha gene, PDHA1,[4] and is approximately equally prevalent in both males and females. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. Epub 2011 Oct 7. Review. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). dihydrolipoamide acetyltransferase (E2) deficiency. What does it mean if a disorder seems to run in my family? [5][11][9], Females with residual pyruvate dehydrogenase activity will have no uncontrollable systemic lactic acidosis and few, if any, neurological symptoms. How can gene mutations affect health and development? [13], The following table lists common symptoms of pyruvate dehydrogenase deficiency.[3]. The excess lactic acid causes lactic acidosis in affected individuals. Two subjects showed very low enzyme activities (0.8 and 2.9 U/g Hb) and were excluded from the analysis because control enzyme activity [hexokinase, glucose-6-phosphate isomerase, triose-phosphate isomerase, pyruvate kinase 0.4, pyruvate kinase 2.0, glyceraldehyde-3-phosphate dehydrogenase, glutathione reductase, glutamic oxaloacetic transaminase (= aspartate … Pyruvate dehydrogenase deficiency can have different inheritance patterns. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Hertecant J, Patel MS, Kerr DS. 2006 [10] Patients may develop seizures and/or neuropathological spasms. What are the different ways in which a genetic condition can be inherited? [16] Preliminary data from PDHD patients on the ketogenic diet indicate that in milder cases, there is a reduction in the frequency of seizures, abnormal EEG readings, ataxia and abnormal sleeping patterns, and extension of remission periods. Pyruvate Dehydrogenase Complex Deficiency. The resources on this site should not be used as a substitute for professional medical care or advice. deficiency. These mutations lead to a shortage of E1 alpha protein or result in an abnormal protein that cannot function properly. 2005 Jul;90(7):4101-7. Dec;104(4):507-16. doi: 10.1016/j.ymgme.2011.08.008. The pyruvate dehydrogenase complex converts a chemical called pyruvate into another chemical … The PDHA1 gene is located on the X chromosome, which is one of the two sex chromosomes. X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. These cases display hydrocephalus, and thinning of the cerebral tissue. 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