Myoadenylate Deaminase Activity Research Articles

Effects of AMPD1 common mutation on the metabolic-chronotropic relationship: Insights from patients with myoadenylate deaminase deficiency.

PurposeCurrent evidence indicates that the common AMPD1 gene variant is associated with improved survival in patients with advanced heart failure. Whilst adenosine has been recognized to mediate the cardioprotective effect of C34T AMPD1, the precise pathophysiologic mechanism involved remains undefined to date. To address this issue, we used cardio-pulmonary exercise testing data (CPX) from subjects with myoadenylate deaminase (MAD) defects.MethodsFrom 2009 to 2013, all the patients referred in our laboratory to perform a metabolic exercise testing, i.e. a CPX with measurements of muscle metabolites in plasma during and after exercise testing, were prospectively enrolled. Subjects that also underwent an open muscle biopsy for diagnosis purpose were finally included. The metabolic-chronotropic response was assessed by calculating the slope of the linear relationship between the percent heart rate reserve and the percent metabolic reserve throughout exercise. MAD activity was measured using the Fishbein’s technique in muscle biopsy sample. The common AMPD1 mutation was genotyped and the AMPD1 gene was sequenced to screen rare variants from blood DNA.ResultsSixty-seven patients were included in the study; 5 had complete MAD deficiency, 11 had partial MAD deficiency, and 51 had normal MAD activity. Compared with normal MAD activity subjects, MAD deficient subjects appeared to have a lower-than-expected metabolic-chronotopic response during exercise. The metabolic-chronotropic relationship is more closely correlated with MAD activity in skeletal muscle (Rs = 0.57, p = 5.93E-7, Spearman correlation) than the presence of the common AMPD1 gene variant (Rs = 0.34, p = 0.005). Age-predicted O2 pulse ratio is significantly increased in MAD deficient subjects, indicating a greater efficiency of the cardiovascular system to deliver O2 (p < 0.01, Scheffé’s post hoc test).ConclusionThe metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect.

Myoadenylate-deaminase gene mutation associated with left ventricular hypertrabeculation/non-compaction

Background — Left ventricular hypertrabeculation (LVHT)/non-compaction, a rare myocardial abnormality and frequently associated with neuromuscular disorders, has not been reported in primary myoadenylate-deaminase (MAD) deficiency (MADD).Case report — In a 53-year-old man with easy fatigability and myalgia since boyhood, primary MADD was diagnosed based upon slightly, but recurrently elevated creatine-kinase, absent staining for MAD on muscle biopsy, markedly reduced MAD activity in the muscle homogenate, and the C34T mutation within exon 2 of the AMPD1 gene. An ambulatory ECG showed nocturnal sinus bradycardia and echocardiography thickening of the interventricular septum (20 mm) and the posterior wall (16 mm) and additionally LVHT. Cardiac MRI confirmed myocardial thickening and LVHT. Myocardial thickening and LVHT were regarded as causally related to the C34T mutation.Conclusion — Cardiac involvement in MADD may manifest as left ventricular myocardial thickening and LVHT. MADD should be included in the list of neuromuscular disorders which are associated with LVHT.

Phenotype modulators in myophosphorylase deficiency

Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p < 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease.

Exertional Myalgia Syndrome Associated with Diminished Serum Ammonia Elevation in Ischemic Exercise Testing

A 36-year-old man with chronic severe exertional myalgias had a normal serum lactate elevation and diminished serum ammonia elevation on an ischemic forearm exercise test (IFET). The IFET is commonly performed in the evaluation of patients with complaints of exertional myalgias, cramps, and rhabdomyolysis. The finding of a normal serum lactate elevation and a diminished serum ammonia elevation after ischemic exercise is usually considered indicative of myoadenylate deaminase deficiency. However, myoadenylate deaminase activity was normal in this man's muscle biopsy specimen. This case suggests that a diminished serum ammonia elevation in the IFET is not always indicative of myoadenylate deaminase deficiency, a disorder of ammonia production. A diminished serum ammonia elevation in the IFET could also reflect an impairment of net ammonia efflux from muscle into blood.

Purine Nucleotides and AMP Deamination During Maximal and Endurance Swimming Exercise in Heart and Skeletal Muscle of Rats

The purine nucleotides, phosphocreatine (PCr), ammonia, and lactic acid were investigated in skeletal muscles of rats with prominent type I, type IIa, type IIb fibers, and the heart after exhaustive and endurance swimming tests. ATP, ADP, AMP, IMP, and PCr were determined by HPLC with UV detection in controls after maximal and endurance training for 6 weeks with or without a respective final test and also after final exhaustive or endurance test without preceding training. The swimming time in these tests was longer with than without training. A pronounced ATP decrease and a large increase in IMP, up to 4.9 mumol/g wet weight, were found in type IIb fibers after the maximal final test without preceding training. Compared with skeletal muscle, the IMP concentration in the heart was significantly lower after all exercise bouts, even though after maximal exercise AMP augmentation was highest, ATP reduction was greatest, and energy charge was lowest. The difference between the heart and skeletal muscle in the production of IMP indicates that despite AMP and ADP accumulation, myoadenylate deaminase (MAD) activity in the heart is considerably lower than in skeletal muscle, especially in type IIb fibers. The smaller amount of MAD per tissue, and also the different MAD isozyme pattern of the heart as reported in the literature, may be attributed to lower activation. The difference between MAD activation of the soleus muscle and of the iliacus muscle, both consisting predominantly of type I fibers, suggests that MAD activity may be influenced by biochemical demand and oxygen supply, varying with the anatomical localization. Even though ammonia and lactic acid were highly correlated, it is questionable whether the H+ ion increase due to the lactate accumulation itself triggers MAD activation, as has been found for AMP and ADP in skeletal muscle.

Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies.

A histochemical assay was routinely performed of myoadenylate deaminase (MAD) in muscle biopsy specimens. MAD was absent in 13 cases, i.e. 2.9% of the specimens. In 10 cases the deficiency was confirmed biochemically. The diagnoses in the 13 patients were: polyneuropathy (n = 5), infantile spinal muscular atrophy (n = 3), congenital myopathy with type 2 fibre atrophy, facioscapulohumeral myopathy, polymyositis, myotonic dystrophy and hyperornithinaemia with gyrate atrophy of the retina. In contrast, 35 unrelated patients presenting with exercise-related muscle cramps or pains showed normal histochemical MAD activity. The biopsy specimens in all of these patients were essentially normal and in none of them was the diagnosis of a neuromuscular disease made. The results failed to confirm the association of MAD deficiency with aches, cramps and pains or exertional myalgia.

Myoadenylate deaminase deficiency or not?: Observations on two brothers with exercise-induced muscle pain

This paper describes 2 brothers with increasingly severe exercise-induced muscle pain and stiffness, beginning in adolescence. Histochemical studies showed that myoadenylate deaminase activity was absent in the propositus, but present in his younger brother. Biochemical examination of muscle homogenates confirmed these findings, with enzyme activity approximately 60% of the mean control value in the younger sibling. Red cell adenylate deaminase activity was normal in both cases. The possible relationship between the clinical and biochemical findings in these patients is discussed.