Information on the following diseases can be found in the Related Disorders section of this report:

• Leigh Disease

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. 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.

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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, accounting for approximately 25% of cases. The gene responsible for this form of PDCD has been located on the short arm of the X chromosome (Xp22-cen) and is known as the E1-alpha subunit pyruvate dehydrogenase gene (PHE1A). There are many different variations (allelic variants) of this gene that can cause pyruvate dehydrogenase deficiency. Most individuals with a PHE1A gene mutation have a new gene mutation not inherited from parents, and in these cases the recurrence risk is not increased for future children.

Approximately 75% of 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 PDX1. The gene mutations in these subunits are usually inherited and follow autosomal recessive inheritance.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. 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.

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.
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Several hundred cases of PDCD have been reported. PDCD caused by an abnormality in the E1 alpha subunit affects more males than females. 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.
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The following disorder has similar symptoms to Pyruvate Dehydrogenase Deficiency. Comparison can be useful for a differential diagnosis:

Leigh Disease is a genetic metabolic disorder characterized by lesions of the brain, spinal cord, optic nerve, and in some cases, an enlarged heart. Symptoms during infancy may include low body weight, slow growth, tremors, skin changes and interrupted breathing patterns. Progressive neurological disturbances, mental retardation, slurred speech and loss of motor coordination (ataxia) may occur in cases that begin during or after infancy. Abnormalities of eye movement and other vision problems may develop in cases with later onset. This disorder is inherited as a recessive trait. (For more information on this disorder, choose "Leigh" as your search term in the Rare Disease Database.)

Diagnosis
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 in leukocytes, fibroblasts or from a tissue biopsy.

Treatment
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. Some affected individuals respond to treatment with thiamine (vitamin B1), carnitine or lipoic acid.

Genetic counseling will be helpful to families of children with pyruvate dehydrogenase complex deficiency.
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The drug sodium dichloracetate has been approved by the FDA for the treatment of congenital lactic acidosis. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of congenital lactic acidosis.

Researchers at the University of Florida are conducting an ongoing clinical trial to determine whether the drug NTBC (Nitrione, Orfadinin TM) reduces or prevents the undesirable side effects (toxicity) of the investigational drug dichloroacetate (DCA) in patients with congenital lactic acidosis. For more information about this study contact:

Peter W. Stacpoole, Ph.D., M.D.
University of Florida
Box 100226
Gainesville, FL 32610
Tel: (352) 392-2321
Fax: (352) 846-0990
email: stacpool@gcrc.ufl.edu


Researchers at the University of California, San Diego are conducting a study of the use of DCA in the treatment of congenital lactic acidosis. For more information about this study contact:

Richard H. Haas, M.D.
Jan Panyard-Davis, R.N.
UCSD Medical Center
200 West Arbor Street
MC 8467
San Diego, CA 92013
Tel: (619) 294-6104
Email: jpanyard@ucsd.edu
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Frye RE. Pyruvate Dehydrogenase Complex Deficiency. From eMedicine.com, Inc. Last Updated June 20, 2003.

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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.