Acidemia, Propionic

Acidemia, Propionic

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Acidemia, Propionic is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • PCC Deficiency
  • Propionyl CoA Carboxylase Deficiency
  • Ketotic Glycinemia
  • Hyperglycinemia with Ketoacidosis and Lactic Acidosis, Propionic Type

Disorder Subdivisions

  • Propionic Acidemia, Type I (PCCA Deficiency)
  • Propionic Acidemia, Type II (PCCB Deficiency)

General Discussion

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.

Symptoms

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.

Causes

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. )

Affected Populations

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.

Standard Therapies

Diagnosis

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).



Treatment

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.

Investigational Therapies

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.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: W.B. Saunders Company; 2000:360-61.



Buyse ML. Birth Defects Encyclopedia. Dover, Mass: Blackwell Scientific Publications, Inc; 1990:22-23.



Stanbury JB, et al., eds. Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw Hill; 1983:2063-064.



JOURNAL ARTICLES

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

Propionic acidemia

http://ghr.nlm.nih.gov/condition=propionicacidemia



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.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



Organic Acidemia Association

P.O. Box 1008

Pinole, CA 94564

USA

Tel: (763)559-1797

Fax: (763)694-0017

Email: carolbarton@oaanews.org

Internet: http://www.oaanews.org/index.htm



Organic Acidaemias UK

5, Saxon Road

Ashford

Middlesex, TW15 1QL

United Kingdom

Tel: 4401784245989

Email: info.oauk@gmail.com

Internet: http://myweb.tiscali.co.uk/priddy/



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



Propionic Acidemia Foundation

1963 McCraren Rd

Highland Park, IL 60035

USA

Tel: (877)720-2192

Tel: (877)720-2192

Email: paf@pafoundation.com

Internet: http://www.pafoundation.com



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



For a Complete Report

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