NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Oleg A Shchelochkov, MD and Charles Venditti, MD, PhD, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Propionic acidemia is a rare metabolic disorder affecting from 1/20,000 to 1/250,000 individuals in various regions of the world. It is characterized by deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical "building blocks" (amino acids) of 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), dehydration and seizures. Without appropriate treatment, coma and death may result. Rarely, the condition may become apparent later in life and may be associated with less severe symptoms and findings. Propionic acidemia is inherited in an autosomal recessive pattern. Individuals with this condition have to follow a specific diet including a low protein intake and specific food formulas (medical foods). Liver transplant is a surgical option that can help decrease the frequency of acute metabolic episodes (decompensation).
Symptoms most commonly develop during the first weeks of life and may include vomiting, listlessness (lethargy), low muscle tone (hypotonia), failure to grow and gain weight at the expected rate (failure to thrive), and dehydration. Approximately 30% of affected infants may also develop seizures. The recurrence or worsening of symptoms may be associated with an infection, constipation, or consumption of high amounts of protein. In some affected infants, episodes of symptoms may alternate with periods of apparently normal health and development.
Without appropriate treatment, episodes of vomiting, lethargy, dehydration, and accumulation of excessive levels of acids in the blood and bodily tissues (acidosis) may lead to coma and death [1-4].
As patients age, they can experience various symptoms affecting nearly all organ systems. These symptoms include brain damage (encephalopathy), hypotonia, intellectual disability, severe vision problems, inflammation of the pancreas (pancreatitis), recurrent vomiting, chronic renal failure, heart failure (cardiomyopathy), heart rhythm problems (prolonged QTc interval) , and osteoporosis which can lead to fractures. Affected individuals can also have a reduced number of cells in their blood, such as reduced red blood cells (anemia), reduced white blood cells (leukopenia), reduced platelets (thrombocytopenia), or a reduced number of all cell types (pancytopenia). These blood abnormalities can cause various symptoms, such as immune deficiency or bleeding problems. Individuals with propionic acidemia are also at an increased risk of having a stroke as early as a few weeks of age [4-10].
Less commonly, propionic acidemia may become apparent in childhood or later in life [11-13]. These affected individuals may not experience sudden, acute episodes of acidosis and tend to come to medical attention due to neurological symptoms such as intellectual disability or cardiomyopathy.
Propionic acidemia is caused by changes (mutations) in the PCCA and PCCB genes resulting in a deficiency of the enzyme propionyl-CoA carboxylase. This enzyme is required for the proper breakdown of the amino acids isoleucine, valine, threonine, and methionine. These amino acids are needed for proper growth and development. Propionyl-CoA carboxylase is also involved in the breakdown of cholesterol, certain fatty acids, and other substances (metabolites) necessary for metabolic actions or processes. Propionyl-CoA carboxylase deficiency leads to accumulation of toxic chemicals (metabolites). Some of these accumulated chemicals harm the mitochondria (power houses inside cells responsible for energy production). [16-20].
Propionic acidemia is inherited in an autosomal recessive pattern.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal 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 is 25%. The risk is the same for males and females.
Propionic acidemia affects males and females in equal numbers. The prevalence varies among different populations and regions. It affects around 1/100,000 to 1/250,000 individuals in most regions of the world. In the Middle East, where there is a high rate of marriage between blood relatives (consanguineous), around 1/20,000 to 1/45,000 individuals are affected. There are around 1/5,000 to ½,000 individuals with this disease in some Saudi tribes. The highest reported rate of propionic acidemia, with 1/1,000 people, has been reported in Greenlandic Inuits [21-29].
Propionic acidemia can be identified at birth through expanded newborn screening by measuring levels of certain metabolites such a propionylcarnitine and methionine in a blood sample. [9, 30].
Most infants with propionic acidemia are diagnosed in the first weeks of life based upon a thorough clinical evaluation, a detailed patient and family history, and molecular genetic testing.
Propionic acidemia may be diagnosed before birth (prenatally) by screening fetal DNA for disease-causing (pathogenic) mutations in the PCCA and PCCB genes. The diagnosis can also be made by measuring the concentration of 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.
During acute episodes, the treatment of infants with propionic acidemia may require fluid therapy; measures to provide appropriate nutritional intake (e.g., intravenous glucose, with and without intravenous lipids); 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). 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.). Injection of intravenous bicarbonate can also help reduce the acid load in the body. In addition, until the diagnosis is confirmed, physicians may completely eliminate protein from the newborn’s diet and may also administer biotin, a B complex vitamin that plays a role in the metabolism of certain fatty acids and amino acids.
Long-term treatment includes administration of a low-protein diet, possibly in combination with medical formula (medical foods) that are low in certain amino acids (i.e., amino acids which give rise to propionate, 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 L-carnitine (carnitine or levocarnitine). Antibiotic therapy with metronidazole can reduce the burden of propionyl-CoA in the body, as this chemical is produced by some bacteria during fermentation of carbohydrates in our gut.) [4,9,31].
Liver transplant is a potential surgical option for individuals with severe symptoms and frequent recurrent acute episodes (decompensation). Liver recipients generally have a lower risk of decompensation and hospitalization. However, lifelong immunosuppressive therapy is necessary to prevent organ rejection [32-34].
All patients with propionic academia must be followed by dieticians with experience in providing care to metabolic patients.
Some children might need to be in special education classes, as intellectual disability is common with propionic academia.
Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families.
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