Myoadenylate deaminase deficiency
Encyclopedia
Adenosine monophosphate deaminase deficiency type 1 is also called myoadenylate deaminase deficiency. It a recessive
genetic
metabolic disorder that affects approximately 1–2% of populations of European descent. It appears to be considerably rarer in Asian populations. The genetic defect causing this is AMP deaminase
though there is also an acquired form of AMP deficiency.
is an enzyme
that converts adenosine monophosphate
(AMP) to inosine monophosphate (IMP), freeing an ammonia
molecule in the process. It is a part of the metabolic process that converts sugar
, fat
, and protein
into cellular energy. In order to use energy, a cell
converts one of the above fuels into adenosine triphosphate
(ATP) via the mitochondria
. Cellular processes, especially muscle
s, then convert the ATP into adenosine diphosphate
(ADP), freeing the energy to do work.
During heavy or prolonged mild to moderate activity, other enzymes convert two molecules of ADP into one ATP molecule and one AMP molecule, making more ATP available to supply energy. AMP is normally converted into IMP by myoadenylate deaminase — so myoadenylate deaminase deficiency reduces energy that would be available to the cell through the Purine nucleotide cycle
. Normally, excess AMP builds up in the cell and is eventually metabolized in the liver. In persons with a defective enzyme, 5'-nucleotidase removes the ribose and phosphorus from AMP, increasing levels of cellular and circulating adenosine by 16x - 25x.
the AMP molecules has three major effects. First, significant amounts of AMP are lost from the cell and the body. Second, ammonia is not freed when the cell does work. Third, the level of IMP in the cell is not maintained.
, but others have symptoms including early fatigue, muscle pain and muscle cramping.
Fatigue
Muscle pain
Muscle cramping
Muscle weakness
Symptomatic relief from the effects of MADD may sometimes be achieved by administering ribose
orally at a dose of approximately 10 grams per 100 pounds (0.2 g/kg) of body weight per day. and exercise modulation as appropriate. Taken hourly, ribose provides a direct but limited source of energy for the cells. Patients with myoadenylate deaminase deficiency do not retain ribose during heavy exercise, so supplementation may be required to rebuild levels of ATP.
Creatine monohydrate is also helpful for for AMPD patients, as it provides an alternative source of energy for anaerobic muscle tissue.
(cholesterol reducing drugs) will cause myopathy
(muscle weakness) in individuals with MADD.
Anesthesia has the potential to cause malignant hyperthermia
, an uncontrolled increase in body temperature, and permanent muscle damage in patients with MADD. Individuals with MADD are advised to notify their an anesthesiologist about their condition prior to surgery.
In most where myopathy
is present with MADD, a second muscle disease is present and symptoms are worst than either disease in isolation.
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...
genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
metabolic disorder that affects approximately 1–2% of populations of European descent. It appears to be considerably rarer in Asian populations. The genetic defect causing this is AMP deaminase
AMP deaminase
AMP deaminase 1 is an enzyme that in humans is encoded by the AMPD1 gene.Adenosine monophosphate deaminase is an enzyme that converts adenosine monophosphate to inosine monophosphate , freeing an ammonia molecule in the process.-Function:...
though there is also an acquired form of AMP deficiency.
Causes
AMP deaminaseAMP deaminase
AMP deaminase 1 is an enzyme that in humans is encoded by the AMPD1 gene.Adenosine monophosphate deaminase is an enzyme that converts adenosine monophosphate to inosine monophosphate , freeing an ammonia molecule in the process.-Function:...
is an 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...
that converts adenosine monophosphate
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
(AMP) to inosine monophosphate (IMP), freeing an ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
molecule in the process. It is a part of the metabolic process that converts sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
, fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
, and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
into cellular energy. In order to use energy, a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
converts one of the above fuels into adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP) via the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
. Cellular processes, especially 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...
s, then convert the ATP into adenosine diphosphate
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
(ADP), freeing the energy to do work.
During heavy or prolonged mild to moderate activity, other enzymes convert two molecules of ADP into one ATP molecule and one AMP molecule, making more ATP available to supply energy. AMP is normally converted into IMP by myoadenylate deaminase — so myoadenylate deaminase deficiency reduces energy that would be available to the cell through the Purine nucleotide cycle
Purine nucleotide cycle
The Purine Nucleotide Cycle is a metabolic pathway in which fumarate is generated from aspartate in order to increase the concentration of Krebs cycle intermediates. The pathway was first described by John Lowenstein, who demonstrated its role in increasing the rate of oxidative phosphorylation in...
. Normally, excess AMP builds up in the cell and is eventually metabolized in the liver. In persons with a defective enzyme, 5'-nucleotidase removes the ribose and phosphorus from AMP, increasing levels of cellular and circulating adenosine by 16x - 25x.
Effects of failure to deaminate the AMP molecules
This failure to deaminateDeamination
Deamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...
the AMP molecules has three major effects. First, significant amounts of AMP are lost from the cell and the body. Second, ammonia is not freed when the cell does work. Third, the level of IMP in the cell is not maintained.
- The first effect—the loss of AMP—is mostly significant because AMP contains riboseRiboseRibose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
, a sugar molecule that is also used to make DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, RNARNARibonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, and some enzymeEnzymeEnzymes 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...
s. Though the body can manufacture some ribose and obtain more from RNA-rich sources such as beans and red meat, this loss of ribose due to MADD is sometimes sufficient to create a shortage in the body, resulting in symptoms of severe fatigue and muscle pain. This outcome is especially likely if the individual regularly exercises vigorously or works physically over a period of weeks or months.
- The second effect, the absence of ammonia, is not well understood. It may result in a reduction of the amount of fumarate available to the citric acid cycleCitric acid cycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
, and it may result in lower levels of nitric oxideNitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(a vasodilator) in the body, reducing blood flow and oxygenOxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
intake during vigorous exercise, though this may be offset by increased levels of adenosine, another vasodilator.
- The third effect, the reduction in IMP, is also not well understood. It may somehow result in a reduction in the amount of lactic acidLactic acidLactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
produced by the muscles, though serum lactate is typically slightly elevated with MADD.
Symptoms
The majority of people with the AMPD gene are asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, but others have symptoms including early fatigue, muscle pain and muscle cramping.
Fatigue
- MADD lowers aerobic power output, so increased anaerobic power is needed to perform the same amount of work.
- Without myoadenlyate deaminase, heavy activity causes adenosine to be released into the cell or perfused into the surrounding tissues. Fatigue and sedation after heavy exertion can be caused by excess adenosine in the cells which signals muscle fiber to feel fatigued. In the brain, excess adenosine decreases alertness and causes sleepiness. In this way, adenosine may play a role in fatigue from MADD.
- Recovery from over-exertion can be hours, days or even months. In cases of rhabdomyolysisRhabdomyolysisRhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, which is the rapid breakdown of muscle fibers, time to recovery is dependent on duration and intensity of original activity plus any excess activity during the recovery period.
Muscle pain
- Muscle pain from MADD is not well understood, but is partially due to high levels of lactate. Increased levels of free adenosine temporarily decrease pain, allowing over exertion without awareness. The over exertion can cause mild to severe cases of rhabdomyolysis which is painful.
- Adenosine mediates pain through adenosine receptors. MADD causes an increase of free adenosine during heavy activity which may cause exercise-induced muscle pain. Over time, excess free adenosine down-regulates primary A1 adenosine receptors, leading to increased muscle pain. Secondary receptors (A3) increase peripheral inflammation which also increases pain.
Muscle cramping
- Cause of cramping is unknown, but may be related to elevated lactate, increased calcium signaling across the sarcoplasmic reticulum caused by membrane instability from reduced levels of ATP, or increased levels of free adenosine.
Muscle weakness
- Muscle weakness is not a major symptom, though the progressive effects of chronic muscle damage from rhabdomyolysis will eventually cause significant weakness. Similarly, the long-term metabolic effects may result in nerve damage.
Treatment
It is important for MADD patients to maintain strength and fitness without exercising or working to exhaustion. Learning this balance may be more difficult than normally, as muscle pain and fatigue may be perceived differently than normal individuals.Symptomatic relief from the effects of MADD may sometimes be achieved by administering ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
orally at a dose of approximately 10 grams per 100 pounds (0.2 g/kg) of body weight per day. and exercise modulation as appropriate. Taken hourly, ribose provides a direct but limited source of energy for the cells. Patients with myoadenylate deaminase deficiency do not retain ribose during heavy exercise, so supplementation may be required to rebuild levels of ATP.
Creatine monohydrate is also helpful for for AMPD patients, as it provides an alternative source of energy for anaerobic muscle tissue.
Potential Complications
There is an increased risk that statinStatin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
(cholesterol reducing drugs) will cause myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
(muscle weakness) in individuals with MADD.
Anesthesia has the potential to cause malignant hyperthermia
Malignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
, an uncontrolled increase in body temperature, and permanent muscle damage in patients with MADD. Individuals with MADD are advised to notify their an anesthesiologist about their condition prior to surgery.
In most where myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
is present with MADD, a second muscle disease is present and symptoms are worst than either disease in isolation.