NORD gratefully acknowledges Peter W. Stacpoole, PhD, MD, Professor of Medicine, Biochemistry and Molecular Biology, College of Medicine, University of Florida, for assistance in the preparation of this report.
The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other persons may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.
In some cases (especially those with a severe enzyme defect), symptoms of congenital lactic acidosis develop within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, mental retardation, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood.
Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes within the DNA located within the nucleus (nDNA) or within the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations of nDNA, which occur in cellular chromosomes, can be inherited through different forms of transmission of the mutation, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.
Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.
As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.
Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease of carbohydrate metabolism that is due to a mutation in nDNA. It is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis. PDC deficiency can be inherited as an autosomal recessive or X-linked recessive trait.
Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from the child’s mother. Genetic diseases, due to mutations (changes in genetic information) in the nDNA of a cell, are determined by two genes, one received from the father and one from the mother. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new (spontaneous) mutation in the affected individual. The risk of passing the abnormal gene from the affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
X-linked recessive genetic disorders are conditions caused by an abnormal nDNA 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 mutated 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 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son. Most causes of pyruvate dehydrogenase deficiency are due to mutations in a gene located on the X chromosome.
Although genetic mitochondrial diseases are the commonest causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder. These include biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid).
Congenital lactic acidosis affects males and females in equal numbers. The exact incidence of congenital lactic acidosis is unknown. One estimate places the incidence at 250-300 live births per 1,000 per year in the United States. However, it is likely that many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of congenital lactic acidosis in the general population.
A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted in white blood cells or in skin or muscle cells obtained by biopsy.
There is no proven treatment for any congenital lactic acidosis that is due to a genetic mitochondrial disease. Therefore, treatment is directed toward the specific symptoms and signs that are present in each individual. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine.
For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. However, the long-term safety and effectiveness of ketogenic diets have not been studied in a rigorous fashion.
Dichloroacetate (DCA) has been investigated as a potential therapy for individuals with congenital lactic acidosis. Various studies have shown the drug to be well-tolerated in children and to lead to a reduction in lactic acid levels in many patients with various causes of congenital lactic acidosis. However, the clinical benefit of chronic DCA treatment for any type of congenital lactic acidosis has not yet been demonstrated by controlled clinical trials. In addition, the drug has been shown to worsen or to cause reversible peripheral nerve damage in some individuals with congenital lactic acidosis, especially in older adolescents and adults. Recent studies, however, indicate that this potential side effect may be mitigated or prevented by careful dosing, based on a person’s particular genotype.
Additional therapies for individuals with congenital lactic acidosis are directed at specific complications, such as anti-seizure medications (anti-convulsants) for seizures. Genetic counseling may benefit affected individuals and their families, depending on the underlying cause of the congenital lactic acidosis.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about congenital lactic acidosis:
Peter W. Stacpoole, PhD, MD
Professor of Medicine, Biochemistry and Molecular Biology
College of Medicine
P.O. Box 100226
University of Florida
Gainesville, FL 32610
Clarke JTR, Ed. A Clinical Guide to Inherited Metabolic Disease. Cambridge, MA: Cambridge University Press; 2006:213-214.
Stacpoole PW. The Congenital Lactic Acidoses. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:462-464.
Menkes JH, Pine Jr JW, et al. Eds. Textbook of Child Neurology. 5th ed. Baltimore, MD: Williams & Wilkins; 1995:853-856.
Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;105(1):34-43.
Stacpoole PW, Gilbert LR, Neiberger R, et al. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics. 2008;121:e1223-e1228.
Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006;117:1519-1531.
Gunnerson KJ. Lactic Acidosis.Medscape. http://emedicine.medscape.com/article/167027-overview Updated: Apr 22, 2015. Accessed May 12, 2015.
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