Adenosine Monophosphate Deaminase Deficiency type 1
|Adenosine Monophosphate Deaminase Deficiency type 1|
|Classification and external resources|
Adenosine monophosphate deaminase deficiency type 1 is also called myoadenylate deaminase deficiency (MADD). 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 form is caused by a defect in the gene for AMP deaminase though there is also an acquired form of AMP deficiency.
AMP deaminase 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 muscles, 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. Instead of being converted to IMP, the AMP builds up in the cells of affected individuals, spills into the blood, 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 section does not cite any references or sources. (August 2011)|
This failure to deaminate 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 ribose, a sugar molecule that is also used to make DNA, RNA, and some enzymes. 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 cycle, and it may result in lower levels of nitric oxide (a vasodilator) in the body, reducing blood flow and oxygen 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 acid produced by the muscles, though serum lactate is typically slightly elevated with MADD.
The following is a very simplified model of what may be going on inside a muscle cell with AMPD deficiency. There are two major semi-stable states — one with intra-cellular glycogen available, and one with glycogen exhausted. Both states are modified by how much the citric acid cycle is under-regulated by default.
Let's start from the state where glycogen is available and the citric acid cycle is severely down-regulated. Once the cell has received a non-trivial load, and has expended the phosphocreatine reserve, a small quantity of ATP will become discharged down to AMP. AMP will instantly up-regulate myophosphorylase, which will liberate glucose from glycogen and make it available to the glycolytic pathway, which will eventually recharge AMP back to ATP. Due to the greater availability of pyruvate, the citric acid cycle will also speed up somewhat, but due to AMPD deficiency, its ATP production rate will not be synchronized with ATP demand. Because all pyruvate is not burned down in the citric acid cycle, the excess is converted to lactate and passed into blood.
This state can last for as long as glycogen is available, and can be prolonged by constantly eating carbohydrate-rich food. If the load on muscles is greater, than the body's ability to recycle glycogen back into glucose, lactate will start to build up in the blood. Once lactate reaches its renal re-absorption threshold (5-6 mmol/l), it gets lost to urine, wasting a lot of calories (and producing bright yellow matte specks in urine and irritation from extra acidity). If the muscle load is small, lactate is mostly recycled back into glucose or burned by other cells in the body. However the newly generated glucose is made available to all cells in the body, not just muscle cells. So, ultimately, in this state muscle cells are destined to loose all glycogen. AMP breakdown to adenosine in this state is minor, because the pool of AMP is kept small. Unnoticeable overexertion is possible. Maximum exertion is limited by the burning sensation from lactate accumulation in muscles.
Eventually, all glycogen is exhausted, and the muscle cell enters another semi-stable state. During this transition, a substantial part of the ATP pool is necessarily discharged down to AMP, which allows the citric acid cycle to be sped up by some other mechanism (perhaps by the allosteric mechanism that reacts to the lower concentration of ATP), until ATP production is balanced with ATP consumption. AMP conversion to adenosine, excretion to the blood, further conversion to uric acid and excretion to urine becomes significant for some time, until all AMP is eliminated from the muscle cell. The muscle movements become noticeably less precise. It becomes hard to rapidly increase the load on a muscle, as in McArdle's disease, and such a rapid load increase will dump even more purines into blood and urine (looking like translucent shiny crystals and being highly irritating). On the other hand, unnoticeable overexertion becomes impossible, there will be no lasting muscle pain from lactate, and continuous aerobic activity is possible.
Taking ribose or xylitol in this state delays elimination of AMP, as the body salvages some adenosine back to AMP and returns it to muscle cells.
When a carbohydrate-rich food is eaten before AMP has been eliminated from muscle cells, plenty of glucose becomes available in the blood, is taken up by muscle cells, added to the glycogen store, but then immediately becomes liberated by myophosphorylase. The resulting excess of glucose is metabolized down to lactic acid, recharging all AMP to ATP. The lactate is dumped back into blood and urine. The higher the glycemic index of the food is, the greater proportion of carbohydrates (and calories) is wasted into urine. Once all AMP has been recharged to ATP, and glycogen stores allowed to replenish, the cell transitions back to the unmodified original state.
If carbohydrate-rich food is not consumed in this state, AMP elimination from the cell eventually completes, glycogen stores can be replenished again, and the cell transitions back to the original state but with reduced ATP pool and an up-regulated citric acid cycle.
- 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 rhabdomyolysis, 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.
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 from normal individuals.
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 AMPD patients, as it provides an alternative source of energy for anaerobic muscle tissue. There is also clinical association of various muscular dystrophies with Restless Legs Syndrome (RLS), which needs further clinical study for confirmation.
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.
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