Exercise Stress Testing in Children with Metabolic or Neuromuscular Disorders

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The role of exercise as a diagnostic or therapeutic tool in patients with a metabolic disease (MD) or neuromuscular disorder (NMD) is relatively underresearched. In this paper we describe the metabolic profiles during exercise in 13 children (9 boys,
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  Hindawi Publishing CorporationInternational Journal of PediatricsVolume 2010, Article ID 254829, 6 pagesdoi:10.1155/2010/254829 Clinical Study  ExerciseStressTestinginChildrenwithMetabolicorNeuromuscularDisorders TimTakken, 1  WimG.Groen, 1 ErikH.Hulzebos, 1 CorneliaG.Ernsting, 2 PeterM.vanHasselt, 3 BerthilH.Prinsen, 4 PaulJ.Helders, 1 andGepkeVisser 3 1 Child Development and Exercise Center, Wilhelmina Children’s Hospital, University Medical Center Utrecht, NL 3508 AB Utrecht, The Netherlands  2 Faculty of Medicine, Vrije University Medical Center, NL 1007 MB Amsterdam, The Netherlands 3 Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, NL 3508 AB Utrecht, The Netherlands 4 Department of Metabolic and Endocrine Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, NL 3508 AB Utrecht, The Netherlands Correspondence should be addressed to Tim Takken, t.takken@umcutrecht.nlReceived 7 January 2010; Revised 10 May 2010; Accepted 15 June 2010Academic Editor: Miles WeinbergerCopyright © 2010 Tim Takken et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited.Theroleofexerciseasadiagnosticortherapeutictoolinpatientswithametabolicdisease(MD)orneuromusculardisorder(NMD)is relatively underresearched. In this paper we describe the metabolic profiles during exercise in 13 children (9 boys, 4 girls, age5–15 yrs) with a diagnosed MD or NMD. Graded cardiopulmonary exercise tests and/or a 90-min prolonged submaximal exercisetest were performed. During exercise, respiratory gas-exchange and heart rate were monitored; blood and urine samples werecollected for biochemical analysis at set time points. Several characteristics in our patient group were observed, which reflectedthe di ff  erences in pathophysiology of the various disorders. Metabolic profiles during exercises CPET and PXT seem helpful in theevaluation of patients with a MD or NMD. 1.Introduction Metabolic diseases (MDs) and Neuromuscular disorders(NMDs) comprise a large heterogeneous group of diseases,that directly (via intrinsic muscle pathology or defectivemetabolic pathways) or indirectly (via nerve pathology),impair muscle function and result in exercise intolerance.Although the value of exercise tests in patients withMD/NMD has been acknowledged for several decades [1–3], the role of exercise stress tests as a diagnostic or evaluativetool in children and adults with MD/NMD is relatively underresearched. Moreover, exercise stress tests are notstandard for most centers to be performed in clinical care[4–7]. In this paper, we provide two standardized exercise tests with preliminary metabolic profiles in children with adiagnosed MD/NMD for this purpose.Exercise stress tests in patients with a metabolic disorderinvolved in ATP synthesis show a clear specific metabolicprofile during exercise [4]. These metabolic profiles can beuseful as a reference for identifying patients for a possibleMD or NMD.Therefore, the aim of the current study was to describethe metabolic profiles during exercise in children with adiagnosed NMD or MD. This information might be helpfulfor clinicians in the diagnosis and follow-up of patients withthese disorders. 2.Methods  2.1. Subjects.  In this retrospective chart review, patients withan established diagnosis involving general ATP synthesis ora dystrophinopathy, who were referred for exercise stresstesting to the Departments of Metabolic Diseases and ChildDevelopmentandExerciseCenter,UniversityMedicalCenterUtrecht, the Netherlands, were included.  2 International Journal of Pediatrics Table  1: Cardiopulmonary measurements of patients during the CPET.Patient Diagnosis Determinationof diagnosisAge(years) Sex  Weight(kg)BMI(Z-score)HR  peak  (beats/min) RER  peak  VO 2peak  (L/min)(Z-score)VO 2peak   /kg(mL/min/kg)(Z-score)1 GSD-1a Mutation R570X endelta F327 11.9 M 40 19.3(0.88) 205 1.16 1.99( − 0 . 04)49.7( − 0 . 42)2 GSD-IIIDebranching enzymedeficiency inleucocytes11.9 F 39 19.6(0.71) 182 0 . 92 ∗  1.45( − 1 . 5)37.1( − 1 . 5)3 GSD-7 Phosphofructokinasedeficiency in muscle 12.9 M 32 13 . 1( − 3 . 7) 184 1.0 1.78( − 3 . 55)34.6( − 3 . 24)4 MCADMCAD deficiency inleucocyteshomozygousLys329Glu mutation5.4 F 28 19.4(1.98) 134 0 . 92 ∗  0.55( − 3 . 5)19.5( − 4 . 2)5 MCAD MCAD deficiency inleucocytes 11.4 F 42 18.9(0.59) NA NA NA NA6 SCADSCAD deficiency inleucocytes andfibroblasts; mutation7.0 M 25 14.6(0.70) 173 1.05 1.00( − 0 . 86)40.1( − 1 . 9)7 MADD MADD deficiency infibroblasts 10.2 M 33 16 . 1( − 0 . 23) 195 1.25 1.33( − 1 . 1)40.4( − 1 . 8)8 MADD MADD deficiency infibroblasts 8.6 M 25 14 . 1( − 1 . 35) 180 1.21 1.29(0 . 09)51.5( − 0 . 26)92-Methylacetoacetyl-CoA-thiolasedeficiency 2-Methylacetoacetyl-CoA-thiolasedeficiency infibroblasts8.7 M 30 15 . 5( − 0 . 32) 179 1.20 1.30( − 0 . 69)43.5( − 1 . 4)10Mitochondrialrespiratory chainmyopathy Diminished ATPproduction in freshmuscle biopsy 9.7 M 34 16.9(0.30) 152 1.39 0.63( − 3 . 6)18.5( − 5 . 0)11 M. Beckerdystrophinopathy Duplication exon24-29 dystrophingene10.4 M 25 12 . 4( − 3 . 6) NA NA NA NA12 M. Beckerdystrophinopathy Duplication exon24-29 dystrophingene14.8 M 57 18 . 6( − 0 . 22) 202 1.26 1.57(1.7)62.6(2.7)13 Hypokalemicepisodic paralysisArg1239His mutationin CACNA1S-gene 13.8 F 62 24.5(1.63) 218 1.25 1.20( − 2 . 0)19.4( − 4 . 0)  Abbreviations : BMI: Body Mass Index, HR  peak  : peak heart rate, VO 2peak  : peak O 2  uptake, RER  peak  : peak respiratory exchange ratio,  ∗ : significantly di ff  erentfrom normal, NA: not assessed. Thirteen patients (9  ♂ , 4  ♀ , age 5–15 years) withan established diagnoses were studied in detail. Diagnoseswere Glycogen Storage Disease (GSD) type 1a (1x), GSDtype 3 (1x), GSD type 7 (1x), Medium-Chain Acyl CoAdehydrogenase deficiency (MCAD (2x)), Short-Chain AcylCoA dehydrogenase deficiency (SCAD (1x)), Multiple AcylCoA dehydrogenase deficiency (MADD (2x)), ketothiolasedeficiency (1x), mitochondrial myopathy (1x), Hypokalemicepisodic paralysis (1x), and dystrophinopathy (Becker Mus-cular Dystrophy (BMD) (2x).  2.2. Exercise Tests.  Two exercise stress tests, respectively,a cardiopulmonary exercise test (CPET) and a prolongedexercise ergometry test (PXT) were performed followinga standardized protocol [8]. Blood samples were taken,immediatelybeforeanddirectlyaftertheCPETandPXT,andanalyzed for lactate, creatine kinase (CK), ammonia, acylcar-nitines, and organic acid. Urine samples were collected upto three hours after the exercise test and further analyzedfor creatinine, organic acid, amino acid, tetraglucose, purine,and pyrimidine [8].A CPET (to determine the peak oxygen uptake [VO 2peak  ]and peak workload [W peak  ]) and a submaximal PXT(90 minutes at 30% of W peak  ) were performed in themorning. After a light breakfast, the patients performed asymptom-limited CPET on a bicycle ergometer. Workloadwas increased in constant increments of 10, 15, or 20watts every minute, depending on the patients’ length[9] and was in some conditions adjusted for the physicalcondition of the patient. This protocol was continued  International Journal of Pediatrics 3 Table  2: Biochemical measurements of patients before and after the CPET.PatientLactate CK Ammonia(mmol/L) (U/L) (mmol/L)Before After Before After Before After1 3.5 ∗ 10.3 NA NA 5 4 ∗ 2 2.2 1.6 540 ∗ 597 ∗ NA NA3 0.8 2.4 246 ∗ 273 ∗ 61 ∗ 337 ∗ 7 1.3 7.3 125 146 NA NA8 1.3 6.0 79 89 NA NA9 1.5 4.3 116 121 17 1210 3.1 ∗ 6.9 85 100 8 6 ∗ 12 1.5 13 ∗ 577 ∗ 773 ∗ 34 ∗ 54Normal valuesMean (range)1.56(0.7–2.3)7.0(3.2–11.4)104(45–192)123(51–234)18(9–23)42(10–94) Legend  : NA: not assessed , ∗ : significantly di ff  erent from normal. until the patient stopped due to volitional exhaustion,despite strong verbal encouragement. During the tests, allsubjects breathed through a facemask (Hans Rudolph Inc.,Kansas City, MO), connected to a calibrated respiratory gas analysis system (Oxygen Champion/Pro, Care Fusion,Houten, The Netherlands). This system measured breath-by-breath minute ventilation (VE), oxygen uptake (VO 2 ),and respiratory exchange ratio (RER   =  VCO 2  /  VO 2 ) usingconventional equations. During the maximal exercise test,heart rate (HR) was measured continuously by a bipolarelectrocardiogram. Peak HR (HR  peak  ),VO 2peak  ,VO 2peak   /  kg,and peak RER were taken as the average values over the last30 seconds of the test.A PXT was performed one week after the maximalexercise test to prevent interference from the previous test.The PXT consisted of a 90-minute cycling at a constant work rate of 30% W peak  , as described previously [8].  2.3. Blood and Urine Sampling and Analysis.  Blood sampleswere obtained from an indwelling catheter inserted into avein of the dorsum of the hand. Five milliliters of bloodfrom each sample was placed in lithium-heparin tube,except for determination of FFA and ammonia; respectively,normal blood (without Li-heparin) and EDTA (anotheranticoagulant) blood was used for the analysis [8]. Aftertaking the blood, the tubes were stored in ice and broughtto the laboratory.Blood taken before and after the CPET was analyzed forlactate, creatine kinase (CK), ammonia, acylcarnitines, andorganic acid. Urine samples taken before and after the CPET,were analyzed for creatinine, organic acid, amino acid, andtetraglucose, until three hours after the exercise test.During the PXT, blood samples were taken at regulartime intervals ( t   =  0, 30, 60, 75, 90, 105, and 120 minutesafter the start of the exercise). Concentrations of glucose,lactate, CK, free fatty acids (FFA), ammonia, 3-OH-butyricacid and3-keto-butyric acid,acylcarnitines, andorganicacidwere determined. Before and up to three hours after exercise,urine samples were obtained and analyzed for creatinine,organic acid, amino acid, and tetraglucose.Glucose, lactate, CK, and ammonia were determinedwith a Beckman Coulter DxC chemical analysis machine(Fullerton, USA). Enzymatic method was used for determi-nation of FFA, 3-ketobutyric acid, and 3-OH-butyric acid.After lipoprotein lipase hydrolyzed triglyceride into fat acidsand glycerol, free glycerol was measured colorimetrically.Organic acid concentration in urine and plasma wasdetermined by gas chromatography-mass spectrometry astheir trimethylsilyl derivates (Hewlett Packard 5890 seriesII gas chromatograph linked to a HP 5989B MS-Enginemass spectrometer (Hewlett Packard, Avondale, PA)). Thecoe ffi cients of variation for the various measured organicacids varied between 10%–15%. Analysis of acylcarnitinein plasma as their butyl esters was performed by electro-spray tandem mass spectrometry (ESI-MS-MS; MicromassQuattro Ultima, Micromass Ltd., UK) equipped with anAlliance HPLC system (Waters, Milford, MA, USA). Also forthese analyses the coe ffi cients of variation for the determinedacylcarnitines were 10%–15%. Analysis of amino acids inplasma and urine was done with amino acid analyzer (ion-exchange chromatography-ninhydrin). 3.Results 3.1. CPET.  As expected, patients with a MD/NMD showedabnormal results on the CPET (Tables 1 and 2). Patient 2 (GSD-3) stopped the CPET because of myalgia in the lowerlimbs, compared to reference values for healthy children[10, 11], the patients with GSD-3, MCAD, SCAD, and mitochondrial myopathy (patients 4, 6, and 10, resp.) hada significantly reduced HR  peak  .  RER  peak   was significantly lower in the patient with GSD-3 (patient 2) and alsoin the patient with MCAD (patient 4) and surprisingly increased to 1.0 in the patient with GSD-7 (patient 3).VO 2peak   and VO 2peak   /  kg were significantly lower in thepatients 3, 4, 10, and 13. These were patients with GSD-7,  4 International Journal of Pediatrics Table  3: Biochemical measurements of patients during the PXT test.Subject Time(min)Glucose(mmol/L)Lactate(mmol/L)FFA(mmol/L)3-Keto-B(mmol/L)3-OH-B(mmol/L) CK (U/L) Ammonia( µ mol/L)10 4.9 4 . 3 ∗ 0.51 0.14 0.0 11630 4.4 4 . 6 ∗ 0.52 0.13 0.02 11560 5 . 7 ∗ 2 . 8 ∗ 0.489 0.12 0.02 11975 5.6 3 . 1 ∗ 0.536 0.12 0.02 11990 6 . 7 ∗ 2 . 9 ∗ 0.559 0.12 0.02 12115 after 7 . 4 ∗ 4 . 1 ∗ 0.792 0.13 0.04 12130 after 7 . 5 ∗ 4 . 9 ∗ 0.666 0.12 0.04 11830 5.5 1.8 0.08 0.0 0.0 166 2230 5.9 1.2 0.14 0.0 0.0 181 ∗ 60 5 . 8 ∗ 0.8 0.23 0.0 0.0 186 ∗ 75 6 . 9 ∗ 1.2 0.36 0.09 0.04 187 275 ∗ 15 after 6.9 2.3 0.25 0.0 0.03 183 ∗ 30 after 2.0 0.26 0.0 0.0 184 ∗ 144 ∗ 60 4.6 3.2 ∗ 0.268 0.12 0.0 4830 4.6 1.3 0.302 0.1 0.0 4660 4.4 1.4 0.444 0.12 0.0 4815 after 4.6 1.1 0.503 0.13 0.0330 after 4.7 0.9 0.528 0.13 0.03 5170 7.1 1.1 0.76 0.07 0.09 10330 5.6 1.2 0.28 0.0 0.060 4.9 1.0 0.49 0.0 0.0 9875 4.8 1.3 0.88 0.05 0.05 10590 5.5 1.1 1.03 0.10 0.12 11930 after 4.8 1.0 0.93 0.15 0.26 11780 5.2 2.0 0.15 0.0 0.0 5830 4.6 0.9 0.31 0.0 0.060 4.3 0.9 0.62 0.07 0.04 8075 4.4 1.0 0.91 7830 after 4.5 1.2 1.34 0.14 0.24 7890 6.4 1.4 0.22 0.09 0.03 90 1430 4.9 1.4 0.18 0.0 0.0 9360 4.7 1.3 0.21 0.0 0.0 8975 4.4 1.1 0.42 0.0 0.0 99 2290 4.9 1.1 0.64 0.11 0.11 9115 after 4.8 0.8 0.69 0.13 0.18 9230 after 4.6 1.0 0.55 0.14 0.2 92 14100 4.0 2 . 4 ∗ 0.20 0.11 0 . 10 ∗ 138 2030 3 . 7 ∗ 8 . 6 ∗ 0.21 0.11 0 . 11 ∗ 15660 3 . 5 ∗ 9 . 6 ∗ 0.31 0.14 0.13 15175 3 . 6 ∗ 9 . 5 ∗ 0.49 0.16 0.16 156 2090 3 . 6 ∗ 9 . 7 ∗ 0.71 0.16 0.18 15715 after 4.1 7 . 0 ∗ 0.72 0.113 0.29 14530 after 4.0 4 . 7 ∗ 0.73 0.18 0.29 146110 5.9 1.4 0.41 0.0 0.0 5020 ∗ 7.030 4.8 1.4 0.19 0.0 0.0 4975 ∗ 15 after 5.3 1.4 0.57 0.0 0.0 5036 ∗ 30 after 5.2 1.3 0.5 0.0 0.0 18  International Journal of Pediatrics 5 Table  3: Continued.Subject Time(min)Glucose(mmol/L)Lactate(mmol/L)FFA(mmol/L)3-Keto-B(mmol/L)3-OH-B(mmol/L) CK (U/L) Ammonia( µ mol/L)120 5.1 1.1 0.15 0.0 0.0 695 ∗ 33 ∗ 30 5.3 1.2 0.08 0.0 0.0 776 ∗ 60 5 1.2 0.11 0.0 0.0 774 ∗ 75 5.1 1.4 0 . 16 ∗ 0.0 0.0 771 ∗ 51 ∗ 90 5.0 1.7 0.23 0.0 0.0 766 ∗ 15 after 5.1 1.1 0.76 0.0 0.0 755 ∗ Legend  : FFA: free fatty acids, 3-keto-B: 3-ketobutaric acid, 3-OH-B: 3-hydroxybutaric acid , ∗ : significantly di ff  erent from normal. MCAD,mitochondrialmyopathy,andHypokalemicepisodicparalysis, respectively.A remarkably high VO 2peak   /  kg was observed in one of thepatients with BMD (patient 12).The patients with GSD-1a and mitochondrial myopathy (patient 1 and 10, resp.) had significantly increased lactateconcentrations at rest. Patient 2, with GSD-3, had anincreased CK values at rest and after exercise. The 2 patientswith BMD (patients 11 and 12) showed persistently highly elevated CK levels. One patient (patient 13) showed mildly elevated CK. 3.2. PXT.  Biochemical profiles of the MD/NMD patientsduring the PXT varied with the disorder (Table 3). Twopatients, one with GSD-1a and the other with mitochondrialmyopathy (resp., patient 1 and 10), showed significantly increased concentrations of blood lactate at all time points.The patient, with GSD-7 had significantly increased ammo-nia concentrations with no rise in lactate during exercise.During and after exercise, the CK value of the patientwith GSD-7 (patient 3) was significantly increased as well asin the 2 patients with BMD (patients 11 and 12).Acylcarnitines C6, C8, C10, C12, and C14:1 were allincreased in two patients with MADD (patients 7 and 8) inrest as well as during exercise. The patient with ketothiolasedeficiency (patient 9) had increased C5:1 and C5-OH acyl-carnitine during rest and exercise, as well as several increasedorganic acids in the urine. In the patient with mitochondrialmyopathy (patient 10), C5 carnitine was increased in theurine during and after exercise. In the patient with SCAD(patient 6), there was no C4 carnitine found. In all otherMD/NMD patients, no altered acylcarnitines, carnitines, fororganic acids concentrations could be observed in plasma orurine (data not shown). 4.Discussion The purpose of this study was to describe metabolic profilesduring exercise using CPET and PXT including extensiveblood and urine analyses in children with a diagnosedMD/NMD. This information might be helpful for cliniciansin the diagnosis and follow-up of these disorders. Becauseof the heterogeneity of the disorders, there was a largevariation in the CPET and PXT results between patients.These di ff  erences reflect the di ff  erent pathophysiology of the various disorders (e.g., defects in di ff  erent metabolicpathways) and heterogeneity within disorders.Metabolic profiling might be helpful in the furtherworkup towards a diagnosis. For example, a low rise inlactate after CPET is suggestive for a GSD, and a very highincrease in lactate, combined with a very low VO 2peak  , mightbe suggestive for a mitochondrial myopathy. Further studiesshoulddevelopanalgorithmfortheinterpretationofexercisedata in MD/NMD patients, comparable to the interpretativealgorithms for cardiac and pulmonary limitations duringexercise [12, 13]. The diagnostic yield of exercise stress testing in childrenwith unexplained exercise intolerance seems relatively low.Among 29 patients referred for exercise intolerance of unknown srcin, only 3 patients could be diagnosed witha MD/NMD: 2 patients with a Becker Muscular Dys-trophinopathy and one patient with a hypokalemic episodicparalysis. However, many of these patients have undergoneextensive medical screening before they were referred forexercise testing. Ten percent is therefore a reasonable yield. Itis our opinion that the expense of exercise testing includingextensive blood and urine analyses is justified because itcould be useful for guiding the diagnostic workup and candi ff  erentiate between patients with medically unexplainedexercise intolerance and patients with a MD/NMD. Inpatients with a MD involved in ATP synthesis, only duringcertain periods of metabolic stress (e.g., exercise, fasting,or illness), abnormal quantities of metabolites in bloodand urine can be found, and symptoms are present. Thesedefects can only be indentified using standardized tests. Thecurrent paper provides two standardized exercise tests withpreliminary metabolic profiles for this purpose.Furthermore, several of the tested MD/NMD patients(patients 3, 7, 8, and 10) were referred for exercise testing toassess their exercise capacity for physical activity recommen-dations. Based on their exercise results, an advice regardingappropriatelevelsofphysicalactivitywasprovided.Su ffi cientamounts of physical activity are necessary for an optimalphysical, psychosocial, and emotional development in chil-dren [14].In addition, for patient 12, we gave an exercise restrictionbased on the findings. This patient was a talented cyclist witha very high VO 2peak   for his age. However, during several raceshe developed myoglobinuria, and he had quite high restingvalues of CK. A muscle biopsy in the workup after the tests
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