Medium-chain acyl-coenzyme A dehydrogenase deficiency
Encyclopedia
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a fatty acid oxidation disorder associated with inborn errors of metabolism
. It is due to defects in the enzyme
complex known as medium-chain acyl dehydrogenase (MCAD) and reduced activity of this complex. This complex oxidizes medium chain fatty acids (Fatty acids having 6-12 carbons) while reducing FAD to FADH2
It is recognized as one of the more rare causes of sudden infant death syndrome
(SIDS), although it may be better described as a mimic, rather than a cause, of SIDS.
s and wax
es. A triglyceride consists of a three-carbon compound known as glycerol
to which three fatty acids (carboxylic acid
s) are attached by ester
bonds. The length of the fatty acids chains can vary; they may be classified as very long-chain, long-chain, medium-chain or short-chain depending on the number of carbon atoms in the chain.
The fatty acids are broken down in stages by the successive removal of molecules of acetyl-coenzyme A, which contains 2 carbon atoms. Ultimately, under normal conditions, the fatty acids are converted into carbon dioxide
and water
with the liberation of energy during this process. Once a fatty acid molecule is "activated" (attached to coenzyme A), a series of four reactions, each catalyzed by a different enzyme, is required to remove each acetyl-coenzyme A molecule. As the first step involves removal of hydrogen atoms (i.e. an oxidation) from an acyl group
, the enzyme complex is known as an acyl dehydrogenase
. Different enzymes are required to hold fatty acids of different lengths, and the deficiencies connected with these various proteins are:
, hyperammonemia
, and, possibly, sudden death. First symptoms of such an episode, termed a "metabolic crisis," are vomiting and lethargy, and typically present before the onset of hypoglycemia. 20-25% of undiagnosed cases are fatal, and many survivors are left with severe brain damage after particularly severe crises.
The oxidation of fatty acids occurs within mitochondria. Fatty acids from the cytoplasm
are attached to a molecule called carnitine
to transport them across the mitochondrial membrane. The combination of carnitine with a fatty acid is known as an acylcarnitine. In individuals with MCADD, there is an increase in the concentration
of medium-chain acyl carnitines in the cytoplasm of their cells; these acylcarnitines leak into the blood stream. The elevation of specific acylcarnitines, especially octanoyl-carnitine, is a major diagnostic characteristic of MCADD.
, a sample of blood may be taken to measure the concentration of acylcarnitines. MCAD deficiency may be inferred when the levels of acylcarnitines in the blood are raised in a typical pattern.
If the interval between SIDS and post-mortem examination (autopsy
) is not too long, it is sometimes possible to culture cells called fibroblasts from the dermis of a sample of skin
taken during the course of the examination. It is possible to add fatty acids that contain radioactive carbon atoms (carbon-14
) to the culture medium. If the cells oxidise these fatty acids during the course of their metabolism, radioactive carbon dioxide will be produced, which may be detected using suitable apparatus. The rate of production of radioactive carbon dioxide from fatty acid chains of differing lengths may be used as a test to evaluate whether the cells have a deficiency in any of the various acyl dehydrogenases. This type of test may be used to support a diagnosis of MCAD deficiency when it is suspected from the pattern of acylcarnitines in the blood.
The diagnosis of MCAD deficiency should also be considered in the presence of prominent fatty change (also known as steatosis
) within the liver
and proximal renal tubules of the kidney
. However, steatosis is recognised as a non-specific response to a variety of injuries.
Mutations in the ACADM gene
lead to inadequate levels of the medium-chain acyl-coenzyme A dehydrogenase enzyme. This condition is inherited in an autosomal recessive pattern, which means two copies of the faulty gene in each cell are required for the disorder to be inherited. If only one copy of the faulty gene is inherited, the individual is a carrier
, but does not have the disorder.
Many mutations have been identified in affected patients, but by far the most common mutation is the A985G mutation, in which an adenine is replaced with a guanine on position 985 of the cDNA. Even among patients homozygous for this mutation, however, there is a wide spectrum of disease severity, ranging from asymptomatic to lethal. In some instances, asymptomatic parents have been diagnosed with MCAD deficiency after a child's diagnosis.
Inborn error of metabolism
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others...
. It is due to defects in 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...
complex known as medium-chain acyl dehydrogenase (MCAD) and reduced activity of this complex. This complex oxidizes medium chain fatty acids (Fatty acids having 6-12 carbons) while reducing FAD to FADH2
It is recognized as one of the more rare causes of sudden infant death syndrome
Sudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...
(SIDS), although it may be better described as a mimic, rather than a cause, of SIDS.
Overview
Two main types of fat are found in the body: triglycerideTriglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s and wax
Wax
thumb|right|[[Cetyl palmitate]], a typical wax ester.Wax refers to a class of chemical compounds that are plastic near ambient temperatures. Characteristically, they melt above 45 °C to give a low viscosity liquid. Waxes are insoluble in water but soluble in organic, nonpolar solvents...
es. A triglyceride consists of a three-carbon compound known as glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
to which three fatty acids (carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s) are attached by ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
bonds. The length of the fatty acids chains can vary; they may be classified as very long-chain, long-chain, medium-chain or short-chain depending on the number of carbon atoms in the chain.
The fatty acids are broken down in stages by the successive removal of molecules of acetyl-coenzyme A, which contains 2 carbon atoms. Ultimately, under normal conditions, the fatty acids are converted into carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
with the liberation of energy during this process. Once a fatty acid molecule is "activated" (attached to coenzyme A), a series of four reactions, each catalyzed by a different enzyme, is required to remove each acetyl-coenzyme A molecule. As the first step involves removal of hydrogen atoms (i.e. an oxidation) from an acyl group
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
, the enzyme complex is known as an acyl dehydrogenase
Dehydrogenase
A dehydrogenase is an enzyme that oxidises a substrate by a reduction reaction that transfers one or more hydrides to an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN.-Examples:...
. Different enzymes are required to hold fatty acids of different lengths, and the deficiencies connected with these various proteins are:
- Very long-chain acyl-coenzyme A dehydrogenase deficiencyVery long-chain acyl-coenzyme A dehydrogenase deficiencyVery long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty acid oxidation disorder which prevents the body from converting certain fats to energy, particularly during periods without food....
(VLCAD deficiency) - Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiencyLong-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiencyLong-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, often shortened to LCHAD deficiency, is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy...
(LCHAD deficiency) - Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)
- Short-chain acyl-coenzyme A dehydrogenase deficiencyShort-chain acyl-coenzyme A dehydrogenase deficiencyShort-chain acyl-coenzyme A dehydrogenase deficiency , also called ACADS deficiency and SCAD deficiency, is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.-Characteristics:Some affected infants...
(SCAD deficiency) - 3-hydroxyacyl-coenzyme A dehydrogenase deficiency3-hydroxyacyl-coenzyme A dehydrogenase deficiency3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to metabolize fats and convert them...
(M/SCHAD deficiency)
Diagnosis
In individuals that have reduced activity of MCAD, there is an impairment of fatty acid oxidation. Under conditions of health this may not cause significant problems. However, when such individuals do not eat for prolonged periods or have increased energy requirements, the impairment of fatty acid oxidation may lead to fatty acid buildup, hypoglycemiaHypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, 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....
, and, possibly, sudden death. First symptoms of such an episode, termed a "metabolic crisis," are vomiting and lethargy, and typically present before the onset of hypoglycemia. 20-25% of undiagnosed cases are fatal, and many survivors are left with severe brain damage after particularly severe crises.
The oxidation of fatty acids occurs within mitochondria. Fatty acids from the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
are attached to a molecule called carnitine
Carnitine
Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
to transport them across the mitochondrial membrane. The combination of carnitine with a fatty acid is known as an acylcarnitine. In individuals with MCADD, there is an increase in the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of medium-chain acyl carnitines in the cytoplasm of their cells; these acylcarnitines leak into the blood stream. The elevation of specific acylcarnitines, especially octanoyl-carnitine, is a major diagnostic characteristic of MCADD.
Treatment
There is no cure for MCADD, but once diagnosed, adverse effects can be prevented by proper management. The most important part of treatment is to ensure that patients never go without food for longer than 10–12 hours (a typical overnight fast). Patients with an illness causing loss of appetite or severe vomiting may need intravenous glucose to make sure that the body is not dependent on fatty acids for energy. Patients also usually adhere to a low-fat diet. Patients may also take daily doses of carnitine, which helps reduce toxic accumulation of fatty acids by forming acylcarnitines, which are excreted in the urine. Severity of symptoms seems to decrease after puberty, but crises may be brought about by particularly long fasts or heavy alcohol consumption.Forensic deliniation
During the course of an investigation of an infant that has died from sudden infant death syndromeSudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...
, a sample of blood may be taken to measure the concentration of acylcarnitines. MCAD deficiency may be inferred when the levels of acylcarnitines in the blood are raised in a typical pattern.
If the interval between SIDS and post-mortem examination (autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
) is not too long, it is sometimes possible to culture cells called fibroblasts from the dermis of a sample of skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
taken during the course of the examination. It is possible to add fatty acids that contain radioactive carbon atoms (carbon-14
Carbon-14
Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon with a nucleus containing 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method pioneered by Willard Libby and colleagues , to date archaeological, geological, and hydrogeological...
) to the culture medium. If the cells oxidise these fatty acids during the course of their metabolism, radioactive carbon dioxide will be produced, which may be detected using suitable apparatus. The rate of production of radioactive carbon dioxide from fatty acid chains of differing lengths may be used as a test to evaluate whether the cells have a deficiency in any of the various acyl dehydrogenases. This type of test may be used to support a diagnosis of MCAD deficiency when it is suspected from the pattern of acylcarnitines in the blood.
The diagnosis of MCAD deficiency should also be considered in the presence of prominent fatty change (also known as steatosis
Steatosis
In cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...
) within the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and proximal renal tubules of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. However, steatosis is recognised as a non-specific response to a variety of injuries.
Genetics
ACADM
ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down a certain group of fats called medium-chain fatty acids. These fatty acids are found in foods such as milk and certain oils, and they are also stored in the...
lead to inadequate levels of the medium-chain acyl-coenzyme A dehydrogenase enzyme. This condition is inherited in an autosomal recessive pattern, which means two copies of the faulty gene in each cell are required for the disorder to be inherited. If only one copy of the faulty gene is inherited, the individual is a carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
, but does not have the disorder.
Many mutations have been identified in affected patients, but by far the most common mutation is the A985G mutation, in which an adenine is replaced with a guanine on position 985 of the cDNA. Even among patients homozygous for this mutation, however, there is a wide spectrum of disease severity, ranging from asymptomatic to lethal. In some instances, asymptomatic parents have been diagnosed with MCAD deficiency after a child's diagnosis.