Propionic acidemia is an inborn error of metabolism: a rare inherited disorder in which the body is unable to break down and use certain proteins properly. As a result, massive amounts of organic compounds (such as propionic acid, ketones, and fatty acids) build up in the blood and urine, interfering with normal body functions and development.
Propionic acidemia, first described in 1961, usually shows up in the first few weeks after birth and, if untreated, results in mental and physical impairment. The disorder can have a broad range of clinical outcomes, ranging from the severe form that is fatal to newborns to the mild, late-onset form associated with periodic attacks of ketoacidosis, when organic compounds build up in the blood and urine. Other names for the disorder include ketotic hyperglycinemia, hyperglycinemia with ketoacidosis and lactic acidosis (propionic type), and propionyl CoA carboxylase (PCC) deficiency, types I and II.
Propionic acidemia can occur in isolation, or it can be a feature of multiple carboxylase deficiency, a condition involving abnormal production of many enzymes—all of which need biotin (a form of vitamin B)—as the result of an abnormality in biotin metabolism. Propionic acidemia is characterized by deficiency of an enzyme, propionyl CoA carboxylase, which the body requires to break down the amino acids isoleucine, valine, threonine, and methionine (chemical building blocks of proteins). The deficiency can be caused by abnormal genes for making propionyl CoA carboxylase (isolated propionic acidemia) or by abnormal genes for metabolizing biotin (propionic acidemia resulting from multiple carboxylase deficiency).
Propionic acidemia is an autosomal recessive disorder; that is, if a man and woman each carry one abnormal gene, then 25% of their children are expected to be born with the disorder. Two genes, PCCA and PCCB, code for the two parts (alpha and beta subunits) of the propionyl CoA carboxylase molecule.
The PCCA gene controls the production of alpha subunit and is on chromosome 13. Alterations in the PCCA gene result in Type I propionic acidemia.
Researchers have identified 19 disease-causing mutations in the PCCA gene. Eight of these mutations result in an incomplete alpha subunit. Six mutations prevent the alpha subunit from binding biotin, which is required for propionyl CoA carboxylase to work properly, and results in multiple carboxylase deficiency. People who inherit two abnormal PCCA genes (homozygotes) produce only 1–5% of the normal amount of propionyl CoA carboxylase. People who inherit one normal and one abnormal PCCA gene (heterozygotes) produce 50% of the normal amount of enzyme.
The PCCB gene, which controls the production of beta subunit, is on chromosome 3. Mutations in this gene are responsible for Type II propionic acidemia.
Twenty-eight disease-causing mutations have been found in the PCCB gene. In people of Caucasian, Spanish, and Latin American heritage, researchers have found the most frequent mutation in about 32% of those with propionic acidemia. In people of Japanese heritage, two other mutations are most prevalent, occurring in 25% and 31% of Japanese patients. Homozygotes for the PCCB gene produce propionyl CoA carboxylase in amounts similar to homozygotes for the PCCA gene, but heterozygotes for the PCCB gene produce nearly normal amounts of propionyl CoA carboxylase. This is probably because many more beta subunits (four to five times more) are produced than alpha subunits, so even with decreased PCCB gene activity, enough beta subunits are available to combine with alpha subunits to make a complete molecule of propionyl CoA carboxylase.
The frequency with which propionic acidemia occurs throughout the world is unknown because it is a rare disorder. Its occurrence does not appear to be specific to any particular population group. Considered to be prevalent among Inuits in Greenland, propionic acidemia has also been identified in other populations, including Austrian, Spanish, Latin American, Saudi Arabian, Amish, and Japanese people. Males and females are equally likely to be affected.
Signs and symptoms
Newborns with propionic acidemia are typically small and pale with poorly developed muscles. Symptoms that usually appear in the first weeks of life include poor feeding, vomiting, listlessness (lethargy), and ketoacidosis. Less often, infants with the disorder
In some patients, the disorder appears later in life. Signs include facial abnormalities, such as puffy cheeks and an exaggerated "Cupid's bow" upper lip. Patients with late-onset propionic acidemia may have acute inflammation of the brain (encephalopathy) or be developmentally delayed. These patients may have periodic attacks of ketoacidosis, usually brought on by eating too much protein, becoming constipated, or having frequent infections.
Patients with propionic acidemia as the result of having multiple carboxylase deficiency often have ketoacidosis and their urine may have a distinct "tom cat's urine" odor. These patients may also have skin rash and loss of hair (alopecia).
Physicians have only a few tests available that allow them to differentiate propionic acidemia from other inborn errors of metabolism. Tests that are absolutely specific for the disorder involve the measurement of propionyl CoA carboxylase and chemicals related to the reactions it affects. These tests are fairly uncommon and do not have published normal values.
Prenatal diagnosis of propionic acidemia is possible using cells obtained by amniocentesis. The cells can be tested for decreased activity of propionyl CoA carboxylase, for their ability to bind propionic acid, or for their methylcitrate levels.
In a newborn child, propionyl CoA carboxylase activity can be measured in white blood cells (leukocytes) from cord blood (blood from the umbilical cord). The infant's blood and urine can be tested for increased levels of propionic acid. These levels are tested as well in older children and adults who are suspected of having the disorder.
Physicians can use genetic tests to analyze DNA and identify the specific gene, PCCA or PCCB, that is abnormal.
Treatment and management
The accepted treatment for propionic acidosis is a low-protein diet. Daily protein intake must be limited to 0.5–1.5 g/kg. Patients should eat frequent meals and avoid fasting, because fasting increases the body's need for propionyl CoA carboxylate.
A low-protein diet keeps the number of ketoacidosis attacks to a minimum; however, such a diet does not prevent attacks. Physicians treat attacks of ketoacidosis by removing all protein from the patient's diet and giving the patient sodium bicarbonate and glucose. If the attack is severe, proteins may be removed from the patient's stomach by peritoneal dialysis.
Some patients may respond to a single oral dose (100 mg/kg) of L-carnitine, an organic compound. Others may be helped by antibiotics, which reduce the number of bacteria that produce propionic acid in the stomach. These are experimental treatments and have not been tested for long-term effects.
Patients with multiple carboxylase deficiency may receive biotin supplements (10 mg daily), which provide immediate, long-lasting improvement. Biotin supplements are not effective, however, for patients with other types of propionic acidemia.
The future of patients with propionic acidemia depends on the severity of the disorder. Left untreated, propionic acidemia in infants results in coma and death. With early diagnosis and treatment, some children are intellectually normal, while others' lives may be complicated by mental retardation and abnormal physical development. Some with popionic acidemia may be identified only during family studies. For patients with late-onset propionic acidemia, the disease can be controlled to some
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Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.
Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. (763) 559-1797. Fax: (863) 694-0017. <http://www.oaanews.org>.
Organic Acidemias UK. 5 Saxon Rd., Ashford, Middlesex, TW15 1QL. UK (178)424-5989.
Propionyl CoA Carboxylase Website. <http://www.uchsc.edu/sm/cbs/pcc/pccmain.htm>.
Linnea E. Wahl, MS