Propionic acidemia
Encyclopedia
Propionic acidemia, also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia, is an autosomal recessive
metabolic disorder, classified as a branched-chain organic acidemia
.
The disorder presents in the early neonatal period with progressive encephalopathy
. Death can occur quickly, due to secondary hyperammonemia
, infection, cardiomyopathy, or basal ganglial stroke.
Propionic Acidemia is a rare disorder that is inherited from both parents. Being autosomal recessive, neither parent shows symptoms, but both carry a defective gene responsible for this disease. It takes two faulty genes to cause PA, so there is a 1 in 4 chance for these parents to have a child with PA.
In many cases, PA can damage the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking. During times of illness the affected person may need to be hospitalized to prevent breakdown of proteins within the body. Each meal presents a challenge to those with PA. If not constantly monitored, the effects would be devastating. Dietary needs must be closely managed by a metabolic geneticist or metabolic dietician.
Mutations in both copies of the PCCA or PCCB gene
s cause propionic acidemia.Barry Lab - Vector and Virus Engineering. Gene therapy for Propionic Acidemia These genes are responsible for the formation of the enzyme
propionyl-CoA carboxylase
, referred to as PCC.
PCC is required for the normal breakdown of the essential amino acids valine
, isoleucine
, threonine
, and methionine
, as well as certain odd-chained fatty-acids. Mutations in the PCCA or PCCB genes disrupt the function of the enzyme, preventing these acids from being metabolized. As a result, propionyl-CoA
, propionic acid
, ketones and other toxic compounds accumulate in the blood
, causing the signs and symptoms of propionic acidemia.
, acidosis
, low muscle
tone (hypotonia
), seizures, and lethargy. The effects of propionic acidemia quickly become life-threatening.
Propionic acidemia is inherited in an autosomal recessive
pattern and is found in about 1 in 35,000 live births in the United States
. The condition appears to be more common in Saudi Arabia
, with a frequency of about 1 in 3,000. The condition also appears to be common in Amish
and Mennonite
populations.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
metabolic disorder, classified as a branched-chain organic acidemia
Organic acidemia
Organic acidemia, also called organic aciduria, is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present....
.
The disorder presents in the early neonatal period with progressive encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
. Death can occur quickly, due to secondary hyperammonemia
Hyperammonemia
Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
, infection, cardiomyopathy, or basal ganglial stroke.
Propionic Acidemia is a rare disorder that is inherited from both parents. Being autosomal recessive, neither parent shows symptoms, but both carry a defective gene responsible for this disease. It takes two faulty genes to cause PA, so there is a 1 in 4 chance for these parents to have a child with PA.
Pathophysiology
In healthy individuals, the enzyme propionyl CoA carboxylase converts proponyl CoA to methylmalonyl CoA. This is one step in the process of converting certain amino acids and fats into sugar for energy. Individuals with PA cannot perform this conversion because the enzyme propionyl CoA carboxylase is nonfunctional. The essential amino acids isoleucine, valine, threonine, and methionine and odd-chain fatty acids are simply converted to propionyl CoA, before the process stops, leading to a buildup of propionyl CoA. Instead of being converted to methylmalonyl CoA, propionyl CoA is then converted into propionic acid, which builds up in the bloodstream. This in turn causes a build-up of dangerous acids and toxins, which can cause damage to the organs.In many cases, PA can damage the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking. During times of illness the affected person may need to be hospitalized to prevent breakdown of proteins within the body. Each meal presents a challenge to those with PA. If not constantly monitored, the effects would be devastating. Dietary needs must be closely managed by a metabolic geneticist or metabolic dietician.
Mutations in both copies of the PCCA or PCCB gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s cause propionic acidemia.Barry Lab - Vector and Virus Engineering. Gene therapy for Propionic Acidemia These genes are responsible for the formation of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
propionyl-CoA carboxylase
Propionyl-CoA carboxylase
Propionyl-CoA carboxylase catalyses the carboxylation reaction of propionyl CoA in the mitochondrial matrix. The enzyme is biotin dependent. The product of the reaction is -methylmalonyl CoA. Propionyl CoA is the end product of metabolism of odd-chain fatty acids, and is also a metabolite of most...
, referred to as PCC.
PCC is required for the normal breakdown of the essential amino acids valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
, isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
, threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
, and methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
, as well as certain odd-chained fatty-acids. Mutations in the PCCA or PCCB genes disrupt the function of the enzyme, preventing these acids from being metabolized. As a result, propionyl-CoA
Propionyl-CoA
Propionyl-CoA is a coenzyme A derivative of propionic acid.-Production:There are several different ways in which it is formed:* It is formed as a product of beta-oxidation of odd-chain fatty acids....
, propionic acid
Propionic acid
Propanoic acid is a naturally occurring carboxylic acid with chemical formula CH3CH2COOH. It is a clear liquid with a pungent odor...
, ketones and other toxic compounds accumulate in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, causing the signs and symptoms of propionic acidemia.
Symptoms
Propionic acidemia is characterized almost immediately in newborns. Symptoms include poor feeding, vomiting, dehydrationDehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
, low muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
tone (hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
), seizures, and lethargy. The effects of propionic acidemia quickly become life-threatening.
Genetic prevalence
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
pattern and is found in about 1 in 35,000 live births in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. The condition appears to be more common in Saudi Arabia
Saudi Arabia
The Kingdom of Saudi Arabia , commonly known in British English as Saudi Arabia and in Arabic as as-Sa‘ūdiyyah , is the largest state in Western Asia by land area, constituting the bulk of the Arabian Peninsula, and the second-largest in the Arab World...
, with a frequency of about 1 in 3,000. The condition also appears to be common in Amish
Amish
The Amish , sometimes referred to as Amish Mennonites, are a group of Christian church fellowships that form a subgroup of the Mennonite churches...
and Mennonite
Mennonite
The Mennonites are a group of Christian Anabaptist denominations named after the Frisian Menno Simons , who, through his writings, articulated and thereby formalized the teachings of earlier Swiss founders...
populations.