Adenosine monophosphate deaminase deficiency type 1

Adenosine monophosphate deaminase deficiency type 1

Myoadenylate deaminase deficiency (MADD) is a recessive genetic metabolic disorder that affects approximately 1–2% of populations of European descent (making it a not particularly "rare" rare disease). It appears to be considerably rarer in Asian populations. The genetic defect causing MADD is AMPD1 (adenosine monophosphate deaminase type 1)

Causes

Myoadenylate deaminase, also called 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 then 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 cycle. When myoadenylate deaminase is deficient, excess AMP builds up in the cell and is eventually metabolized in the liver. In persons with a defective enzyme are active, AMP is de-phosphorylated to adenosine by 5'-nucleotidase adenosine, increasing levels of circulating adenosine by 16x.

Effects of failure to deaminate the AMP molecules

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.

• 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.

Symptoms

Symptoms of the disease primarily include 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 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. Mild cases of rhabdomyolysis may be mistake for over-exertion and is quite painful.

• Adenosine mediates pain through adenosine receptors. MADD causes a 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 or increased 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 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. Also, patients with myoadenylate deaminase deficiency do not retain ribose during heavy exercise, so supplementation is needed 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 statin (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.

Further reading

• Fischer, H.; Esbjornsson, M.; Sabina, R. L.; Stromberg, A.; Peyrard-Janvid, M.; Norman, B. (2007). "AMP deaminase deficiency is associated with lower sprint cycling performance in healthy subjects". Journal of Applied Physiology. 103 (1): 315–22. doi:10.1152/japplphysiol.00185.2007. PMID 17463303.
• Skalova, K; Luptak, I; Turcani, M; Hulin, I (2002). "Adenosine and cardioprotection: what can we learn from nature's genetic polymorphism?" (PDF). Bratislavske lekarske listy. 103 (6): 187–93. PMID 12448564.