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NORD is very grateful to Richard E. Frye, MD, PhD, FAAP, Department of Pediatrics, Division of Child Neurology, Arkansas Children's Hospital Research Institute, University of Arkansas, for assistance in the preparation of this report.
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). The age of onset and severity of disease depends on the activity level of the PDC enzymes. Individuals with PDCD beginning prenatally or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have mental retardation and other neurological symptoms and usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. Some affected individuals have rarer forms of the disorder that follow autosomal recessive inheritance.Some individuals have a thiamine responsive form of this disorder.
Common symptoms of PDCD may initially be poor feeding, lethargy and rapid breathing (tachypnea) in an infant. Neurologic symptoms are progressive and usually start in infancy but may even be apparent at birth. These symptoms can include motor delay, poor muscle tone, seizures, incoordination (ataxia), abnormal eye movements and poor visual tracking. Infants with the prenatal onset form may demonstrate brain malformations on neuroimaging. Individuals with the early childhood-onset form of PDCD may have normal neurologic development with intermittent periods of ataxia, often associated with upper respiratory infection or other minor stress. Varying degrees of neurologic deficits and mental retardation may occur in individuals with PDCD.
The pyruvate dehydrogenase complex contains three enzymes identified as E1, E2, and E3. The E1 enzyme contains subunits identified as alpha and beta. The most common form of PDCD is caused by an abnormal gene in the E1 alpha subunit. The gene responsible for this form of PDCD has been located on the short arm of the X chromosome (Xp22.2-Xp22.1) and is known as the E1-alpha subunit pyruvate dehydrogenase gene (PDHA1). There are many different variations (allelic variants) of this gene that can cause pyruvate dehydrogenase deficiency. Most individuals with a PDHA1 gene mutation have a new gene mutation that is not inherited.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off"’ and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. A female carriers of the PDHA1 gene mutation may show symptoms of PDCD. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
Some PDCD cases are caused by a mutation in a gene in another subunit of the pyruvate dehydrogenase complex. One of the genes responsible for this form of PDCD has been mapped to the short arm of the 11th chromosome (11p13) and has been termed PDHX. Others include the PDHB located on the short arm of the 3rd chromosome (3p21.1-p14.2), DLAT on the long arm of the 11th chromosome (11q23.1), PDP1 located on the long arm of the 8th chromosome (8q22.1), and DLD located on the long arm of the 7th chromosome (7q31-q32). The gene mutations in these subunits are usually inherited and follow autosomal recessive inheritance.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Several hundred cases of PDCD have been reported. More males than females have severe disease and early death and progressive neurological symptoms are observed more often in females, although some females have severe symptoms.
Symptoms of the following disorders can be similar to those of pyruvate carboxylase complex deficiency. Comparison may be useful for a differential diagnosis.
Leigh's disease is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh's disease usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh's disease progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function.
There appear to be several different types of genetically determined enzyme defects that can cause Leigh's disease. Most individuals with Leigh’s disease have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh's disease is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information about this disorder, choose "Leigh’s disease" as your search term in the Rare Disease Database.)
Biochemical abnormalities may vary from severe acidosis (due to abnormally high levels of lactic acid) appearing shortly after birth to a mildly elevated level which usually follows a meal high in carbohydrates. In some cases elevation of blood lactate levels is seen only during the acute episodes. Excretion of abnormally large amounts of the amino acid alanine (alaninuria) may occur only during acute episodes. Imaging studies such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may reveal structural brain abnormalities associated with severe disease. A definitive diagnosis can be made by demonstrating abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy.
Some affected individuals respond to treatment with thiamine (vitamin B1), carnitine or lipoic acid. Thiamine may need to be given in high doses to be effective. A diet low in carbohydrates and high in fat (ketogenic diet) has been used to treat the symptoms of PDCD but is not always successful. Oral citrate is often used to treat acidosis
Genetic counseling is recommended for families of children with pyruvate dehydrogenase complex deficiency.
The drug sodium dichloracetate is an investigational treatment for congenital lactic acidosis. Individuals with certain E1 subunit mutations may be more responsive to this treatment. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of congenital lactic acidosis.
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De Meirleir L. Defects of pyruvate metabolism and the Kreb’s cycle. 2002. J Child Neurol Suppl; 3:3S26-33, discussion 3S33-4.
Morten KJ, Beaattie P, Brown GK, et al. Dichloroacetate stabilizes the mutant E alpha subunit in pyruvate dehydrogenase deficiency. 1999. Neurology; 53(3):612-6.
Naito E, Ito M, Yokota I, et al. Thiamine-responsive lactic acidemia: role of pyruvate dehydrogenase complex. 1998. Eur J Pediatr; 157(8):648-52.
Stacpoole PW, Barnes CL, Hurbanis MD, et al. Treatment of congenital lactic acidosis with dichloroacetate. 1997. Arch Dis Child:77(6):535-41.
Wexler ID, Hemalatha SG, McConnell J, et al. Outsome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. 1997. Neurology;49(6);1655-61.
Morris AA, Leonard JV. The treatment of congenital lactic acidosis. 1996. J Inherit Metab Dis 19(4):573-80.
Brown GK, Otero LJ, LeGris M, et al. Pyruvate dehydrogenase deficiency. 1994. J Med Genet; 31(11):875-9.
FROM THE INTERNET
Frye RE and Benke PJ . Pyruvate Dehydrogenase Complex Deficiency. From eMedicine.com, Inc. Last Updated Nov. 6, 2009.
Report last updated: 2010/02/19 00:00:00 GMT+0