Synonyms of Acidemia, Propionic
- Hyperglycinemia with Ketoacidosis and Lactic Acidosis, Propionic Type
- Ketotic Glycinemia
- PCC Deficiency
- Propionyl CoA Carboxylase Deficiency
- Propionic Acidemia, Type II (PCCB Deficiency)
- Propionic Acidemia, Type I (PCCA Deficiency)
Propionic Acidemia is a rare metabolic disorder characterized by deficiency of propionyl CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical "building blocks" (amino acids) of certain proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), excessive loss of fluids from bodily tissues (dehydration), and episodes of uncontrolled electrical activity in the brain (seizures). Without appropriate treatment, coma and potentially life-threatening complications may result. In rare cases, the condition may become apparent later during infancy and may be associated with less severe symptoms and findings. Propionic Acidemia is inherited as an autosomal recessive trait.
In infants with Propionic Acidemia, symptoms most commonly develop during the first weeks of life. Such abnormalities may include vomiting, listlessness (lethargy), diminished muscle tone (hypotonia), failure to grow and gain weight at the expected rate (failure to thrive), and excessively low levels of bodily fluids (dehydration). Approximately 30 percent of affected infants may also develop seizures. The recurrence or worsening (exacerbation) of symptoms may be associated with infection, constipation, or the consumption of high amounts of protein. In some affected infants, symptom episodes may be separated by periods of apparently normal health and development.
In infants with Propionic Acidemia, episodes are associated with certain characteristic findings that are apparent upon laboratory testing. These findings may include excessive levels of acids in the blood and bodily tissues (acidosis); increased levels of acids in the blood and bodily tissues (acidosis); increased levels of the amino acid glycine in bodily fluids (hyperglycinemia); abnormal accumulations of certain chemical substances (ketone bodies) in bodily tissues and fluids due to excessive breakdown of fats (ketosis); and high levels of ammonia in the blood (hyperammonemia). In addition, there may be low levels of circulating platelets (thrombocytopenia) and certain white blood cells (neutropenia). Without appropriate treatment, episodes of vomiting, lethargy, dehydration, and acidosis and ketosis (ketoacidosis) may lead to a state of unconsciousness (coma) and potentially life-threatening complications.
Less commonly, Propionic Acidemia may become apparent later during infancy. In such cases, affected infants may not experience sudden, acute episodes of ketoacidosis and may tend to come to medical attention due to mental retardation. Because breast milk has a lower, protein content than cow's milk or formulas, some researchers suggest that breastfeeding may contribute to a later onset of symptoms and milder disease in some affected infants.
Propionic Acidemia is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.
In recessive disorders, the condition does not appear unless a person inherits the same defective 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 generally will not show symptoms of the disorder. The risk of transmitting the disease to the children for a couple, both of whom are carriers for a recessive disorder, is 25 percent. On average, fifty percent of their children will be carriers of the disease, while twenty-five percent receive a normal copy from each parent. These risks are the same for each pregnancy.
The symptoms and findings associated with Propionic Acidemia result from deficiency of the enzyme propionyl CoA carboxylase, required for the proper breakdown of the amino acids isoleucine, valine, threonine, and methionine. These amino acids are required for proper growth and development during infancy. Propionyl CoA carboxylase is also involved in the breakdown of cholesterol, certain fatty acids, and other substances (metabolites) necessary for metabolic actions or processes.
The propionyl CoA carboxylase (PCC) enzyme is composed of two subunits, known as alpha and beta. The alpha subunit is regulated (encoded) by a gene known as the PCCA gene, and the beta subunit is encoded by the PCCB gene. (As discussed above, because Propionic Acidemia is transmitted as an autosomal recessive trait, those with the disorder inherit mutated copies of the disease gene from both parents.) The PCCA gene is located on the long arm (q) of chromosome 13 (13q22), and the PCCB gene has been mapped to the long arm of chromosome 3 (3q21-q22).
Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered. )
Propionic Acidemia affects males and females in equal numbers. In most affected individuals, associated symptoms become apparent during the first weeks of life. However, in others with the disorder, symptoms may develop later during infancy.
The prevalence of Propionic Acidemia appears to vary among different geographic populations and regions. According tom some reports, the condition is thought to be particularly frequent in Sandi Arabia, affecting approximately one in 2,000 to 5,000 individuals.
Symptoms of the following disorders may be similar to those of Propionic Acidemia. Comparisons may be useful for a differential diagnosis:
Ketotic Hyperglycinemia is a group of hereditary protein metabolism disorders. In each case, a defective enzyme prevents the breakdown of certain amino acids and lipids. High levels of the amino acid glycine and ketones accumulate in the blood and urine. Clinically, affected infants have feeding difficulties and developmental, neurological, digestive, and metabolic problems, as well as increased susceptibility to infections. Often, complications can be avoided with early treatment. The disorders are very rare, with only a few individual cases reported. Methylmalonic Acidemias are a form of Ketotic Hyperglycinemia.
Methylmalonic Acidemias are one type of organic academia. All known organic acidemias are inherited as autosomal recessive traits. They are caused by an enzyme defect in the breakdown (metabolism) of one amino acid. This results in an abnormally high level of acid in the blood and body tissues, which can cause metabolic acidosis. Drowsiness, coma, and seizures are symptoms of metabolic acidosis. Mental retardation is a long-term consequence. The disorders may be caused by either a deficiency of the enzyme methylmalonyl CoA mutase, methylmalonyl racemase, or of adenosylcobalamin synthetic enzymes. Excretion of methylmalonate (a product of amino acid metabolism) in the urine is abnormally high in people affected by Methylmalonic Acidemias. ((For more information on this disorder, choose "Methylmalonic Acidemia" as your search term in the Rare Disease Database.)
In some cases, Propionic Acidemia may be diagnosed before birth (prenatally) by measuring the concentration of the characteristic metabolites in amniotic fluid or the activity of the propionyl CoA carboxylase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. This disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.
In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm deficient activity of the propionyl CoA carboxylase enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis); increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria); high levels of ammonia in the blood (hyperammonemia); and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia).
During acute episodes, the treatment of infants with Propionic Acidemia may require fluid and electrolyte therapy; measures to ensure appropriate nutritional and caloric intake (e.g., parenteral hyperalimentation); administration of certain medications to prevent or treat bacterial infection; and other supportive measures as required. In infants with severe disease (e.g., severe acidosis, hyperammonemia), treatment may require procedures that remove excess waste products from the blood (hemodialysis or peritoneal dialysis). During hemodialysis, waste products are removed by filtering the blood through an artificial kidney machine. Peritoneal dialysis is a technique during which the peritoneum is used as a natural filtering membrane. (The peritoneum is the two-layered membrane that lines the abdominal wall and covers abdominal organs.) In addition, until the diagnosis is confirmed, physicians may administer biotin, a B complex vitamin that plays a role in the metabolism of certain fatty and amino acids.
Long-term treatment includes administration of a low-protein diet, possibly in combination with artificial (synthetic) proteins that are low in certain amino acids (i.e., propionate precursors, e.g., isoleucine, valine, threonine, and methionine). Infants and children with the disorder may develop secondary deficiency of carnitine, a substance that plays a role in metabolism and the proper use of fatty acids. In such cases, therapy includes administration of the amino acid derivative L-carnitine.
Early intervention may be important in ensuring that children with Propionic Acidemia reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
Genetic counseling will also be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
This disease entry is based upon medical information available through August 2007. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.
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Acidemia, Propionic Resources
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Stanbury JB, et al., eds. Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw Hill; 1983:2063-064.
Campeau E, et al. Structure of the pcca gene and distribution of mutations causing propionic acidemia. Mol Genet Metab. 2001;74:238-47.
Ravn K, et al. High incidence of propionic acidemia in Greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet. 2000;67:203-06.
Ugarte M, et al. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Hum Mutat. 1999;14:275-82.
Nyhan WL, et al. Neurologic nonmetabolic presentation of propionic acidemia. Arch Neurol. 1999;56:1143-47.
Campeau E, et al. Coding sequence mutations in the alpha subunit of propionyl-CoA carboxylase in patients with propionic acidemia. Mol Genet Metab. 1999;67:11-22.
Richard E, et al. Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. Biochim Biophys Acta. 1999;1453:351-58.
Al Essa M, et al. Infectious complications of propionic acidemia in Saudia (sic) Arabia. Clin Genet. 1998;54:90-94.
Richard E, et al. Three novel splice mutations in the PCCA gene causing identical exon skipping in propionic acidemia patients. Hum Genet. 1997;101:93-96.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University. Entry No: 606054; Last Update: 6/22/01. Entry No: 232000; Last Update 9/10/01. Entry No: 232050; Last Update 9/10/01.
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