Exercise efficiency impairment in metabolic myopathies.

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O2 was measured breath-by-breath throughout the incremental test. The ∆V'O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O2/∆Work-Rate slope (mLO2.min-1.W-1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.

Exercise testing-based algorithms to diagnose McArdle disease and MAD defects.

OBJECTIVE: As exercise intolerance and exercise-induced myalgia are commonly encountered in metabolic myopathies, functional screening tests are commonly used during the diagnostic work-up. Our objective was to evaluate the accuracy of isometric handgrip test (IHT) and progressive cycle ergometer test (PCET) to identify McArdle disease and myoadenylate deaminase (MAD) deficiency and to propose diagnostic algorithms using exercise-induced lactate and ammonia variations. METHODS: A prospective sample of 46 patients underwent an IHT and a PCET as part of their exercise-induced myalgia and intolerance evaluation. The two diagnostics tests were compared against the results of muscle biopsy and/or the presence of mutations in PYGM. A total of 6 patients had McArdle disease, 5 a complete MAD deficiency (MAD absent), 12 a partial MAD deficiency, and 23 patients had normal muscle biopsy and acylcarnitine profile (disease control). RESULTS: The two functional tests could diagnose all McArdle patients with statistical significance, combining a low lactate variation (IHT: <1 mmol/L, AUC = 0.963, P < .0001; PCET: <1 mmol/L, AUC = 0.990, P < .0001) and a large ammonia variation (IHT: >100 µmol/L, AUC = 0.944, P = .0005; PCET: >20 µmol/L, AUC = 1). PCET was superior to IHT for MAD absent diagnosis, combining very low ammonia variation (<10 µmol/L, AUC = 0.910, P < .0001) and moderate lactate variation (>1 mmol/L). CONCLUSIONS: PCET-based decision tree was more accurate than IHT, with respective generalized squared correlations of 0.796 vs 0.668. IHT and PCET are both interesting diagnostic tools to identify McArdle disease, whereas cycle ergometer exercise is more efficient to diagnose complete MAD deficiency.

Peripartum anaesthetic management of a patient with Brugada syndrome and myoadenylate deaminase deficiency.

Brugada syndrome is a rare electrophysiological cardiac disease which can result in serious arrhythmias and sudden cardiac death. Peripartum management is centred around avoiding arrhythmogenic drugs, including high doses of sodium channel blocking drugs such as bupivacaine. Myoadenylate deaminase deficiency, also known as adenosine monophosphate deaminase deficiency, is the commonest cause of myopathy in Caucasians. There is evidence that myoadenylate deaminase deficiency can predispose patients to developing malignant hyperthermia when exposed to specific anaesthetic agents. We present a case of a pregnant patient with both Brugada syndrome and myoadenylate deaminase deficiency, in which analgesic and general anaesthetic options for each condition presented potentially conflicting dilemmas for the delivery of intrapartum care.

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

PURPOSE: Current 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. METHODS: From 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. RESULTS: Sixty-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). CONCLUSION: The metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect.

Myoadenylate deaminase deficiency: a frequent cause of muscle pain A case detected by exercise testing.

Myoadenylate deaminase deficit (MAD, MIM#615511) is the most common cause of metabolic myopathies with an estimated prevalence of 1-2% in the general population. We report the case of a 39-year-old man suffering from severe skeletal muscle pain that had developed gradually for 4 years. A moderate increase in creatine kinase (CK) was the only biological sign observed. This study takes a closer look at a common but poorly known pathology and highlights the interest of the dynamic metabolic investigations carried out during exercise stress test with a cycle ergometer. Our non-invasive clinical and biological examination, at the interface between physiology and biology, disclosed the total absence of a physiological increase in plasma ammonia evocative of MAD. However, MAD was later confirmed by histochemistry and molecular studies, which revealed the presence of the recurrent homozygous pathogenic variant affecting the adenosine monophosphate deaminase 1 gene (AMPD1) in most patients with MAD.

AMPD1 polymorphism and response to regadenoson.

AIMS:  AMPD1 c.34C > T (rs17602729) polymorphism results in AMPD1 deficiency. We examined the association of AMPD1 deficiency and variability of hemodynamic response to regadenoson. SUBJECTS & METHODS: Genotyping for c.34C>T was performed in 267 patients undergoing regadenoson cardiac stress testing. RESULTS: Carriers of c.34C >T variant exhibited higher relative changes in systolic blood pressure (SBP) compared with wild-type subjects ([%] SBP change to peak: 12 ± 25 vs 5 ± 13%; p = 0.01) ([%] SBP change to nadir: -3 ± 15 vs -7 ± 11%; p = 0.04). Change in heart rate was similar between groups, but side effects were more common in carriers of the variant (+LR = 4.2; p = 0.04). CONCLUSION: AMPD1 deficiency may be involved in the modulation of regadenoson's systemic effects.

CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity.

Erythrocytes are the key target in 5'-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3(-/-) mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH. The affinity of mammalian hemoglobin for oxygen is thought to be regulated primarily by 2,3-BPG levels and pH (the Bohr effect). However, our results show that increased endogenous levels of ATP and ADP, but not AMP, directly increase the p50 value of hemoglobin. Additionally, the rise in erythrocyte p50 directly correlates with an enhanced capability of systemic metabolism.

Diagnostic Algorithm for Glycogenoses and Myoadenylate Deaminase Deficiency Based on Exercise Testing Parameters: A Prospective Study.

AIM: Our aim was to evaluate the accuracy of aerobic exercise testing to diagnose metabolic myopathies. METHODS: From December 2008 to September 2012, all the consecutive patients that underwent both metabolic exercise testing and a muscle biopsy were prospectively enrolled. Subjects performed an incremental and maximal exercise testing on a cycle ergometer. Lactate, pyruvate, and ammonia concentrations were determined from venous blood samples drawn at rest, during exercise (50% predicted maximal power, peak exercise), and recovery (2, 5, 10, and 15 min). Biopsies from vastus lateralis or deltoid muscles were analysed using standard techniques (reference test). Myoadenylate deaminase (MAD) activity was determined using p-nitro blue tetrazolium staining in muscle cryostat sections. Glycogen storage was assessed using periodic acid-Schiff staining. The diagnostic accuracy of plasma metabolite levels to identify absent and decreased MAD activity was assessed using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: The study involved 51 patients. Omitting patients with glycogenoses (n = 3), MAD staining was absent in 5, decreased in 6, and normal in 37 subjects. Lactate/pyruvate at the 10th minute of recovery provided the greatest area under the ROC curves (AUC, 0.893 ± 0.067) to differentiate Abnormal from Normal MAD activity. The lactate/rest ratio at the 10th minute of recovery from exercise displayed the best AUC (1.0) for discriminating between Decreased and Absent MAD activities. The resulting decision tree achieved a diagnostic accuracy of 86.3%. CONCLUSION: The present algorithm provides a non-invasive test to accurately predict absent and decreased MAD activity, facilitating the selection of patients for muscle biopsy and target appropriate histochemical analysis.

A diagnostic approach to recurrent myalgia and rhabdomyolysis in children.

Episodic myalgia is a common complaint in children and young adults. While many cases remain idiopathic even after extensive investigation, myalgia can be the first symptom of an underlying serious neuromuscular condition, and can be associated with an increased risk of such serious complications as rhabdomyolysis and malignant hyperthermia. We review and highlight the metabolic myopathies and other increasingly recognised muscle disorders that may present to paediatricians with episodic myalgia or isolated episodes of rhabdomyolysis, and propose a diagnostic algorithm for investigation of these complaints.

Effect of AMP-deaminase 3 knock-out in mice on enzyme activity in heart and other organs.

Recent findings suggest that inhibition of AMP-deaminase (AMPD) could be effective therapeutic strategy in heart disease associated with cardiac ischemia. To establish experimental model to study protective mechanisms of AMPD inhibition we developed conditional, cardiac specific knock-outs in Cre recombinase system. AMPD3 floxed mice were crossed with Mer-Cre-Mer mice. Tamoxifen was injected to induce Cre recombinase. After two weeks, hearts, skeletal muscle, liver, kidney, and blood were collected and activities of AMPD and related enzymes were analyzed using HPLC-based procedure. We demonstrate loss of more than 90% of cardiac AMPD activity in the heart of AMPD3-/-mice while other enzymes of nucleotide metabolism such as adenosine deaminase, purine nucleoside phosphorylase were not affected. Surprisingly, activity of AMPD was also reduced in the erythrocytes and in the kidney by 20%-30%. No change of AMPD activity was observed in the skeletal muscle and the liver.

AMP deaminase 3 deficiency enhanced 5'-AMP induction of hypometabolism.

A hypometabolic state can be induced in mice by 5'-AMP administration. Previously we proposed that an underlying mechanism for this hypometabolism is linked to reduced erythrocyte oxygen transport function due to 5'-AMP uptake altering the cellular adenylate equilibrium. To test this hypothesis, we generated mice deficient in adenosine monophosphate deaminase 3 (AMPD3), the key catabolic enzyme for 5'-AMP in erythrocytes. Mice deficient in AMPD3 maintained AMPD activities in all tissues except erythrocytes. Developmentally and morphologically, the Ampd3(-/-) mice were indistinguishable from their wild type siblings. The levels of ATP, ADP but not 5'-AMP in erythrocytes of Ampd3(-/-) mice were significantly elevated. Fasting blood glucose levels of the Ampd3(-/-) mice were comparable to wild type siblings. In comparison to wild type mice, the Ampd3(-/-) mice displayed a deeper hypometabolism with a significantly delayed average arousal time in response to 5'-AMP administration. Together, these findings demonstrate a central role of AMPD3 in the regulation of 5'-AMP mediated hypometabolism and further implicate erythrocytes in this behavioral response.

Miopatía por deficiencia de mioadenilato desaminasa desencadenada por el tratamiento con atorvastatina / Myopathy due to deficiency of desaminase myoadenilate induced by atorvastatine

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Metabolic disorders of purine metabolism affecting the nervous system.

The purines are a group of molecules used by all cells for many vital biochemical processes including energy-requiring enzymatic reactions, cofactor-requiring reactions, synthesis of DNA or RNA, signaling pathways within and between cells, and other processes. Defects in some of the enzymes of purine metabolism are known to be associated with specific clinical disorders, and neurological problems may be a presenting sign or the predominant clinical problem for several of them. This chapter describes three disorders for which the clinical features and metabolic basis are well characterized. Deficiency of adenylosuccinate-lyase (ADSL) causes psychomotor retardation, epilepsy, and autistic features. Lesch-Nyhan disease is caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and is characterized by hyperuricemia, motor and cognitive disability, and self-injurious behavior. Deficiency of myoadenylate deaminase (mAMPD) is associated with myopathic features. In addition to these disorders, several other disorders are briefly summarized. These include defects of phosphoribosylpyrophosphate synthase, adenosine deaminase (ADA), purine nucleoside phosphorylase (PND), deoxyguanosine kinase (dGK), or IMP dehydrogenase (IMPDH). Each of these disorders provides an unusual window on the unique importance of purine metabolism for function of different parts of the nervous system.

AMP deaminase 3 plays a critical role in remote reperfusion lung injury.

Remote reperfusion lung injury following skeletal muscle ischemia and reperfusion accounts for high morbidity and mortality. AMP deaminase (AMPD), a key enzyme for nucleotide cycle, has been implicated in the regulation of this phenomenon. However, the function of Ampd2 and Ampd3 subtype has not been elucidated in remote reperfusion rodent lung injury. We utilized AMPD3 and AMPD2-deficient mice. The two types of AMPD-deficient mice and wild-type (WT) littermates were subjected to ischemia-reperfusion injury. After 3h bilateral hind-limb ischemia and reperfusion, AMPD3 mRNA, AMPD activity and inosine monophosphate (IMP) increased significantly in WT and AMPD2-deficient mice lungs, while they did not show significant alterations in AMPD3-deficient mice lungs. Genetic inactivation of Ampd3 resulted in markedly accelerated myeloperoxidase (MPO) activity along with exaggerated neutrophils infiltration and hemorrhage in the lungs compared to WT and AMPD2-deficient mice, furthermore, IMP treatment significantly attenuated MPO activity and neutrophils infiltration in WT and the two types of AMPD-deficient mice lungs after 3h reperfusion. These findings demonstrate for the first time in AMP-deficient mice models that AMPD3 plays a critical role in remote reperfusion lung injury via generation of IMP and validate the potential to use IMP into the clinical arena to attenuate remote ischemia-reperfusion lung injury.

AMPD3-deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency.

AMP deaminase (AMPD) catalyzes AMP to IMP and plays an important role in energy charge and nucleotide metabolism. Human AMPD3 deficiency is a type of erythrocyte-specific enzyme deficiency found in individuals without clinical symptoms, although an increased level of ATP in erythrocytes has been reported. To better understand the physiological and pathological roles of AMPD3 deficiency, we established a line of AMPD3-deficient [A3(-/-)] mice. No AMPD activity and a high level of ATP were observed in erythrocytes of these mice, similar to human RBC-AMPD3 deficiency, while other characteristics were unremarkable. Next, we created AMPD3 and pyruvate kinase (PK) double-deficient [PKA(-/-,-/-)] mice by mating A3(-/-) mice with CBA-Pk-1slc/Pk-1slc mice [PK(-/-)], a spontaneous PK-deficient strain showing hemolytic anemia. In PKA(-/-,-/-) mice, the level of ATP in red blood cells was increased 1.5 times as compared to PK(-/-) mice, although hemolytic anemia in those animals was not improved. In addition, we observed osmotic fragility of erythrocytes in A3(-/-) mice under fasting conditions. In contrast, the ATP level in erythrocytes was elevated in A3(-/-) mice as compared to the control. In conclusion, AMPD3 deficiency increases the level of ATP in erythrocytes, but does not improve anemia due to PK deficiency and leads to erythrocyte dysfunction.

Proteinuria in AMPD2-deficient mice.

The AMPD2 gene, a member of the AMPD gene family encoding AMP deaminase, is widely expressed in nonmuscle tissues including kidney, although its functions have not been fully elucidated. In this study, we studied the function of the AMPD2 gene by establishing AMPD2-deficient model animal. We established AMPD2 knockout mice by using gene transfer and homologous recombination in murine ES cells and studied phenotypes and functions in the kidneys of these animals. AMPD activity was decreased from 22.9 mIU/mg protein to 2.5 mIU/mg protein in the kidneys of AMPD knockout mice. In addition to changes in nucleotide metabolism in the kidneys, proteinuria was found in 3-week-old AMPD2 knockout mice, followed by a further increment up to a peak level at 6 weeks old (up to 0.6 g/dL). The major protein component in the urine of AMPD2 knockout mice was found to be albumin, indicating that AMPD2 may have a key role in glomerular filtration. Indeed, an ultrastructure study of glomerulus specimens from these mice showed effacement of the podocyte foot processes, resembling minimal-change nephropathy in humans. Based on our results, we concluded that AMPD2 deficiency induces imbalanced nucleotide metabolism and proteinuria, probably due to podocyte dysfunction.

Right ventricular obstructive hypertrophic cardiomyopathy in primary myo-adenylate deaminase deficiency.

MyoAdenylate Deaminase Deficiency (MADD) is a relatively common metabolic disorder of the skeletal muscle. Patients with MADD usually show an impaired bioenergetic production and a clinical spectrum with either exercise-induced muscle pain, fatigue and/or rhabdomyolysis. Left ventricular hypertrophy as well as other types of cardiac involvement have been reported in patients with primary MADD. We describe herein a case of a 61-year-old woman with biochemical and genetic evidence of Myo-Adenylate Deaminase deficiency, in whom we found a right ventricular hypertrophic cardiomyopathy leading to severe outflow tract dynamic obstruction.