Myoadenylate deaminase

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

Sabina, R. L. Myoadenylate deaminase deficiency. A common inherited defect with heterogeneous clinical presentation. Neurol. Clin. 18 185-194,2000. 

Myoadenylate deaminase deficiency is a recessive disorder that affects approximately 1 -2% of populations of European descent, but appears considerably rarer in Asian populations. Myoadenylate deaminase, also called adenosine monophosphate (AMP) deaminase, is an enzyme that converts AMP to inosine monophosphate (IMP). Its deficiency results in excess AMP, which is lost by excretion with disturbances in energy generation. Symptoms of severe fatigue and muscle pain can result. 

In relation to the participation of ribose in ribonucleotides, experiments with oral or intravenous administration of this monosaccharide to patients with myoadenylate deaminase... 

In muscle, a unique nucleotide reutilization pathway, known as the purine nucleotide cycle, uses three enzymes myoadenylate deaminase, adenylosuccinate synthetase, and adenylosuccinate lyase. In this cycle, AMP is converted to IMP with formation of NH3, and IMP is then reconverted to AMP. Myoadenylate deaminase deficiency produces a relatively benign disorder of muscle... 

Chapter 21), which is characterized by muscle fatigue following exercise (see Myoadenylate Deaminase Deficiency). 

Several disorders affect purine metabolism. They are gout and the syndromes associated with deficiency of HPRT, APRT, adenosine deaminase, nucleoside phosphorylase, myoadenylate deaminase, and xanthine oxidase. 

Myoadenylate deaminase (or AMP deaminase) deficiency is a relatively benign muscle disorder characterized by fatigue and exercise-induced muscle aches. This disorder is presumably inherited as an autosomal recessive trait. The relationship between the exercise-induced skeletal muscle dysfunction and AMP deaminase deficiency is explained by an interruption of the purine nucleotide cycle. 

Glycogen storage disease Myophosphoiylase Glycerol kinase Lactate dehydrogenase Phospholni inase Phosphoglycerate kinase Myoadenylate deaminase... 

In view of these 18 cases, it seems clear that pristine myoadenylate deaminase deficiency is usually s3nnptomatic, and that the view that symptoms ought not be attributed to the deficiencylO is sorely misguided. The same conclusion was reached by Keleman, et al, who found a 1.5% incidence in the muscle biopsy population, but a 5-6 fold higher incidence in cases coded as exertional myalgias. 

The best available evidence indicates that myoadenylate deaminase deficiency is genetically determined via autosomal recessive inheritance (1) Two affected sibling pairs have now been reported >. (2) Patients with the muscle deficit have normal... 

The prognosis in myoadenylate deaminase deficiency appears to be excellent, with no evidence for progressive debilitation or structural damage in the absence of other disease, and therapy should be aimed at reassurance, and the avoidance of hazardous and ineffective long-term drug treatment. 

Hoffman, R.S. Schoenfeldt, and N. Singh. 1980. Myoadenylate deaminase deficiency. Muscle biopsy and muscle culture in a patient with gout. J. Neurol. Sci. 47 191-202. 

Sabina, R.L., J. L. Swain, B. M. Patten, T. Ashlzawa, W.E. O Brien, and E.W. Holmes. 1980. Disruption of the purine nucleotide cycle. A potential explanation for muscle dysfunction in myoadenylate deaminase deficiency. J. Clin. Invest. 66 1419-1423. 

Mercelis, R., J.J. Martin, I. Dehaene, Th. deBarsy, and G. Van den Berghe. 1981. Myoadenylate deaminase deficiency in a patient with facial and limb girdle myopathy. J. Neurol. 225 157-166. 

Hayes, D.J., B.A. Summers, and J.A. Morgan-Hughes. 1982. Myoadenylate deaminase deficiency or not Observations on two brothers with exercise-induced muscle pain. J. Neurol. Sci. 

Fishbein, W.N., J. I. Davis, K. Nagarajan, J.W. Winkert, and J.W. Foellmer. 1980. Immunologic distinction of human muscle adenylate deaminase from the isozyme(s) in human peripheral blood cells implications for myoadenylate deaminase deficiency. Arch. Biochem. Biophys. 205 360-364. 

Myoadenylate deaminase deficiency verification on repeat biopsy, fresh or frozen, and origin of the residual enzyme. IRCS Med. Sci. 9 103-104. 

Fishbein, W.N., V.W. Armbrustmacher, and J.L. Griffin. 1980. Skeletal muscle adenylate deaminase, adenylate kinase, and creatine kinase in myoadenylate deaminase deficiency and malignant hyperthermia. Clin. Res. 28 288A. 

The case described as case one was discovered during a biochemical study of 36 consecutive muscle biopsies of patients with various complaints. Case 2 and 4 were detected by assaying myoadenylate deaminase in muscle biopsies (partly needle biopsies) of 16 patients with exercise intolerance with muscle pain and/or fatigue. Case 3 was found by screening 12 patients with these complaints with the test on NH3 formation during ischaemic exercise. ... 

MAD deficiencies were detected (patient 2,4). Among 12 patients with these complaints, one showed decreased NH formation during ischaemic exercise. MAD subsequently was found decreased in muscle biopsy (patient 3). MAD deficiency so could be found in these patients in a frequency of about 10%. In consecutive biopsy series from literature, a frequency of about 1,8% can be estimated. Half of the cases in these series display exercise intolerance. However, it is very probable that much less than half of the biopsies in these series come from patients with exercise intolerance. Therefore the available evidence from our study and from literature suggests that myoadenylate deaminase is possibly a rather frequent cause of exercise intolerance. Further research is needed to decide if the occurrence of MAD deficiency together with other often well defined neuromuscular diseases is determined by chance, or if there exists a rather varying clinical expression of the deficiency. 

The broad spectrum of clinical presentation highlights the importance of particular steps in purine and pyrimidine metabolism to different cells and tissues and should have assisted in the development of appropriate treatment. Unfortunately, only three of the nineteen disorders described can be treated successfully hereditary orotic aciduria with life-long uridine, 2,8-di-hydroxyadenine lithiasis with allopurinol. ADA deficiency is treatable by bone marrow transplantation (BHT), or enzyme replacement with polyethylene glycol (PEG)-ADA, but the cost is prohibitive. Er/throcyte-encapsu-lated ADA is effective and less expensive. Oral ribose is reportedly beneficial in myoadenylate deaminase deficiency [1, 4] and also in adenylosucci-nase deficiency [1, 5]. PNP deficiency is also treatable by BMI. 

Zollner N, Reiter S, Pongratz D, Reimers CD, Gerbitz K, Paetzke I, Deufel T, Hubner G. Myoadenylate deaminase deficiency successful symptomatic therapy by high dose oral administration of ribose. Klin Wochenschr 1986 64 1281-1290... 

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