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Metabolic MyopathiesMark A. Tarnopolsky, MD, PhD

ABSTRACTPurpose of Review: Metabolic myopathies are genetic disorders that impair intermediarymetabolism in skeletal muscle. Impairments in glycolysis/glycogenolysis (glycogen-storagedisease), fatty acid transport and oxidation (fatty acid oxidation defects), and the mito-chondrial respiratory chain (mitochondrial myopathies) represent the majority of knowndefects. The purpose of this review is to develop a diagnostic and treatment algorithm forthe metabolic myopathies.Recent Findings: The metabolic myopathies can present in the neonatal and infant periodas part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy;however, most cases present in childhood or in adulthood with exercise intolerance (oftenwith rhabdomyolysis) and weakness. The glycogen-storage diseases present during briefbouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrialmyopathies present during a long-duration/low-intensity endurance-type activity or duringfasting or another metabolically stressful event (eg, surgery, fever). The clinical examinationis often normal between acute events, and evaluation involves exercise testing, bloodtesting (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids(ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastruc-ture, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing.Summary: Accurate and early identification of metabolic myopathies can lead to ther-apeutic interventions with lifestyle and nutritional modification, cofactor treatment, andrapid treatment of rhabdomyolysis.

Continuum (Minneap Minn) 2016;22(6):1829–1851.

INTRODUCTIONMetabolic myopathies are genetic skele-tal muscle disorders that impact en-zymes and proteins involved inintermediary metabolism of glucoseand free fatty acids. Although aminoacids are part of intermediary metabo-lism and can be oxidized to a smallextent by skeletal muscle,1 the aminoacid oxidation defects do not result inmyopathy but rather present withneurocognitive delay or regression ininfancy or childhood. Although someexperts have considered myoadenylatedeaminase deficiency to be part of thegroup of metabolic myopathies,2,3 it isnot directly involved in intermediarymetabolism, and its role in causing ametabolic defect in muscle is seriouslyquestioned. First, the prevalence ofhomozygous mutations is approximately2% in the general population,4 muscle

blood flow appears to be enhanced inmyoadenylate deaminaseYdeficient pa-tients with no significant lowering ofpower,5 and Tarnopolsky and col-leagues6 have shown that homozygousmyoadenylate deaminaseYdeficient indi-viduals do not show alterations incellular energy charge in response tohigh-intensity exercise nor do any of theproposed pathophysiologic mechanismsof the supposed energy deficit appearvalid.6 Consequently, myoadenylate de-aminase will not be further consideredin this review.

Structural myopathies such as Beckermuscular dystrophy (dystrophin), limb-girdle muscular dystrophy (SGCA, SGCB,SGCD, ANO5, and DYSF mutations), andmalignant hyperthermia (RYR1 andCACNA1S mutations) can present withsymptoms triggered by exercise andthus mimic the metabolic myopathies;

Address correspondence toDr Mark A. Tarnopolsky,Division of Neuromuscularand Neurometabolic Disorders,McMaster University, 1200Main St W, HSC-2H26,Hamilton,ON L8N 3Z5, Canada,[email protected].

Relationship Disclosure:Dr Tarnopolsky has receivedpersonal compensation as aspeaker and consultant forSanofi Genzyme and hasreceived research fundingfrom the Canadian Institutesof Health Research, ExerkineCorporation, and MitoCanada.Dr Tarnopolsky is also ashareholder and stockholderfor Exerkine Corporation.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Tarnopolsky discusses theunlabeled/investigational useof triheptanoin, which isunder license and investigationby Ultragenyx Pharmaceutical,Inc, to treat fatty acidoxidation defects.

* 2016 American Academyof Neurology.

1829Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

these have been referred to as thepseudometabolic myopathies.7Y9 Theaforementioned myopathies often ini-tially present with hyperCKemia andexercise-induced cramps, myalgia, orrhabdomyolysis, and may progress to afixed muscle weakness after manyyears. A key to considering a pseudo-metabolic myopathy is the persistenceof creatine kinase (CK) elevation beyond10 days after a bout of rhabdomyolysis,although the CK often normalizes inmalignant hyperthermia. Statins canalso present with a pseudometabolicpattern.10,11 For example, exercisingwhile taking a statin leads to a greaterincrease in CK (likely reflective of greatermuscle damage) than the same exer-cise in those not taking a statin.10,11

Statins can lead to myalgia in up to10% of individuals, and rhabdomyolysisand autoimmune myopathies may oc-cur in a small fraction of patientstreated with statins.12Y14 Statins are alsocontextually relevant in that they canunmask a metabolic myopathy as hasbeen described in fatty acid oxidationdefects, glycogen-storage disease, andmitochondrial cytopathies.15

The current review focuses on themetabolic myopathies associated withglycogen-storage diseases, fatty acid ox-idation defects, and mitochondrial my-opathies (Table 4-1).

For a true clinical understanding ofthe metabolic myopathies, it is firstnecessary to review the metabolic path-ways in the context of exercise andphysiologic stress.

SKELETAL MUSCLE METABOLISMThe rest-to-exercise transition initiatesan immediate mass action effect ofADP + ADP 9 ATP + AMP through theadenylate kinase reaction, where ADPis adenosine diphosphate, ATP is aden-osine triphosphate, and AMP is adeno-sine monophosphate. The flux ismaintained in the forward direction bymyoadenylate deaminase, which cataly-ses the deamination of AMP to inosine

monophosphate, which, through a se-ries of reactions, culminates in the enzy-matic (xanthine oxidase) conversion ofxanthine to uric acid under anaerobicconditions. Although this pathway isactive in normal muscle contraction, it isaccentuated in glycogen-storage disease(myogenic hyperuricemia) and is help-ful from a diagnostic perspective.16

Myoadenylate deaminase does not ap-pear to be essential to muscle contrac-tion for the reasons noted previously.

The creatine-phosphocreatine sys-tem is important in anaerobic energymetabolism, where, during the rest-to-exercise transition, the increase in ADPis rephosphorylated by phosphocreatineback to ATP through the cytosolic CKreaction. This reaction results in theconsumption of a proton that is pro-duced during anaerobic glycolysis andglycogenolysis. Phosphocreatine storesare high in skeletal muscle, brain, andnerves, and phosphocreatine is presentin many other tissues. The phosphocre-atine stores in skeletalmuscle are depletedafter approximately 8 to 10 seconds ofhigh-intensity muscle contraction and arerephosphorylated during the rest periodby aerobically derived ATP. This initialcytosolic reaction is also important ininitiating mitochondrial respiration be-cause the increase in cytosolic ADP trans-locates through porin (voltage-dependantanion channel) to the intermembranespace where mitochondrial CK uses aer-obically derived ATP to convert creatineback to phosphocreatine. The resultantADP crosses through the adenine nucle-otide translocase to the mitochondrialmatrix to stimulate mitochondrial state3 respiration.17

Within the first few seconds of con-traction, the activation of glycogenolysisand glycolysis leads to the generationof lactate through the lactate dehydro-genase pathway. During the first fewminutes of muscle contraction, a progres-sive increase occurs in mitochondrialrespiration and in the delivery of blood-borne substrates to skeletal muscle. As

KEY POINT

h Anaerobic energy sourcesat the onset of exerciseinclude adenylatekinase/adenosinemonophosphatedeaminase,creatine/phosphocreatine,and anaerobicglycogenolysis/glycolysis.

1830 www.ContinuumJournal.com December 2016

Metabolic Myopathies


mitochondrial respiration increases, anexpansion of the tricarboxylic acid cycleintermediates occurs, which allows theglycolytic and glycogenolytically de-rived pyruvate to enter the tricarboxylicacid cycle via the pyruvate dehydroge-nase pathway.18

The specific selection of intermediarymetabolites to fuel aerobic muscle con-traction is a function of many factorsincluding exercise training status, mac-ronutrient intake (habitual and duringexercise), as well as exercise intensityand duration. Aerobic exercise intensityis usually measured as a percentage ofthe maximum oxygen consumption(VO2max). At exercise intensities below

50% VO2max, most individuals willoxidize predominantly free fatty acids.The proportion of carbohydrates con-tributing to energy supply increases athigher exercise intensities.19 Mostuntrained individuals will reach an an-aerobic threshold at about 70% ofVO2max, where the anaerobic systemwill be required and both minute ven-tilation and plasma lactate concen-tration will disproportionately increase.For well-trained athletes, the anaerobicthreshold can approach 85% VO2max,and the proportionate contribution offree fatty acids to energy production willalso increase at any given absoluteexercise intensity with endurance

KEY POINTS

h Aerobic energy ispredominantly derivedfrom muscle glycogenolysis(glucose) and lipolysis(free fatty acids) withminor contributions fromamino acids. The relativeproportion of free fattyacid oxidation increaseswith longer-durationendurance exerciseand fasting.

h The specific selection ofintermediary metabolitesto fuel aerobic musclecontraction is a functionof many factors includingexercise training status,macronutrient intake(habitual and duringexercise), as well asexercise intensityand duration.

h At exercise intensitiesbelow 50% VO2max,most individuals willoxidize predominantlyfree fatty acids. Theproportion ofcarbohydratescontributing to energysupply increases at higherexercise intensities.

TABLE 4-1 Metabolic Myopathies in Skeletal Muscle

b Glycogen-Storage Disease (GSD)

McArdle disease/GSD5 (myophosphorylase deficiency)

Tarui disease/GSD7 (phosphofructokinase deficiency)

GSD9 (phosphorylase b kinase deficiency)

GSD10 (phosphoglycerate mutase deficiency)

GSD11 (lactate dehydrogenase deficiency)

GSD12 (aldolase A deficiency)

GSD13 ("-enolase deficiency)

Phosphoglucomutase deficiency

Phosphoglycerate kinase 1 deficiency

b Fatty Acid Oxidation Defect

Carnitine palmitoyltransferase II deficiency

Trifunctional protein deficiency

VeryYlong-chain acyl-coenzyme A dehydrogenase deficiency

b Mitochondrial Myopathy

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)

Myoclonic epilepsy with ragged red fibers (MERRF)

Chronic progressive external ophthalmoplegia

Kearns-Sayre syndrome

Complex IV deficiency

Cytochrome b mutations

Cytochrome c oxidase mutations



exercise training.20,21 A small proportionof exercise fuel can come from thedecarboxylation of amino acids (pri-marily branched-chain amino acids);however, this is quantitatively less impor-tant (2% to 5% of total energy) thancarbohydrates and fats.22 In general,women oxidize proportionately morelipids at any relative exercise intensityas compared to men.22 This latterpoint is important in fatty acid oxida-tion defects where men tend to haveproportionately more symptoms thanwomen, especially in the case of carni-tine palmitoyltransferase II deficiency.

The source of carbohydrate for en-ergy provision during exercise is pre-dominantly intramuscular glycogen;however, with longer-duration activitywhen glycogen stores can become lim-ited (approximately 2 hours), the pro-portion of oxidized blood-borne glucoseincreases. The potential energy fromcarbohydrates is ultimately trapped asflavin adenine dinucleotide hydroge-nated (FADH2) and nicotinamide adeninedinucleotide hydrogenase (NADH + H+)in the tricarboxylic acid cycle, which thenprovides these reducing equivalents tocomplex I (NADH + H+) and complex II(FADH2), which is then used by themitochondria to shuttle electrons to com-plex IV, where oxygen is reduced to water.The potential energy from these reducingequivalents is used to pump a protonfrom the mitochondrial matrix to theintermembrane space at complex I, III,and IV, where the resultant proton motiveforce leads to generation of ATP synthaseat complex V. The source of lipid duringexercise comes from intramyocellularlipidYderived free fatty acids and blood-borneYderived free fatty acids from pe-ripheral lipolysis. The free fatty acids aretransported into muscle through threedifferent fatty acid transporters withCD36 being quantitatively the most im-portant.23 Once inside the cell, the freefatty acids are chaperoned through acyl-coenzyme A (acyl-CoA) synthetase tocarnitine palmitoyltransferase I, where

carnitine is added to the acyl group thatis then translocated via carnitineacylcarnitine translocase to the innermitochondrial membrane where carni-tine palmitoyltransferase II removes thecarnitine and adds CoA to the acyl group.The resultant acyl-CoA moiety enters themitochondrial matrix, which leads to theproduction of one molecule of FADH2

and one molecule of NADH + H+ forevery turn of "-oxidation. The reducingequivalents are then used by the mito-chondria as described in the previoussection. Branched-chain amino acids arefirst deaminated by branched-chainamino acyltransferase to a keto acid andare then decarboxylated by branchedketo acid dehydrogenase to generateacetoacetate (or propionyl-CoA) andacetyl-CoA that enters the tricarboxylicacid cycle.

METABOLIC MYOPATHIESThe first metabolic myopathy to bedescribed was a glycogen-storage dis-ease referred to as McArdle disease in ayoung man with exercise-induced crampsin 1951.24 This disorder was due to agene mutation in the myophosphorylasegene (PYGM), which leads to an inabilityto activate glycogenolysis and signifi-cant disruption of cellular energy chargewithin the first 10 to 20 seconds ofexercise. Many enzymes in the glycolyticand glycogenolytic pathway have beenassociated with metabolic myopathies(Table 4-1). In general, these presentwith higher-intensity exercise and atthe onset of exercise initiation. One ofthe glycogen-storage diseases calledPompe disease (glycogen-storage dis-ease type 2 [GSD2]) leads to a progres-sive myopathy but does not alter cellularmetabolism and will not be further con-sidered in this review.

The fatty acid oxidation defects aregenetic disorders affecting free fatty acidtransport (eg, carnitine palmitoyltransferaseII) and "-oxidation (eg, veryYlong-chainacyl-CoA dehydrogenase or trifunctionalprotein) deficiency. Fatty acid oxidation

KEY POINTS

h In general, womenoxidize proportionatelymore lipids at any relativeexercise intensity ascompared to men. Thislatter point is important infatty acid oxidationdefects where men tendto have proportionatelymore symptoms thanwomen, especiallyin the case of carnitinepalmitoyltransferaseII deficiency.

h Many enzymes in theglycolytic andglycogenolytic pathwayhave been associatedwith metabolicmyopathies. In general,these present withhigher-intensity exerciseand at the onset ofexercise initiation.




defects such as medium-chain acyl-CoAdehydrogenase deficiency or glutaricaciduria type II predominantly presentwith central nervous system symptomsand will not be considered in this review.In general, the fatty acid oxidation defectspresent during longer-duration exercise,fasting, or during times of superimposedmetabolic stress such as fever or infection.

Themitochondrial ‘‘myopathies’’ referto metabolic genetic defects that affectthe electron transport chain and lead toexercise intolerance with or without rhab-domyolysis or fixed weakness. Like thefatty acid oxidation defects, mitochon-drial myopathies often manifest symp-toms during longer-duration activity orphysical activity performed during pe-riods of metabolic stress such as fasting,superimposed fever, flu, or other illness.

The next section of this article re-views the diagnosis and treatment of themetabolic myopathies with an emphasison the more common disorders andwith a clinical emphasis. The metabolicmyopathies are classified as disordersof glycolysis/glycogenolysis (glycogen-storage diseases), fatty acid oxidationdefects, and mitochondrial myopathies.

Disorders of Glycolysis/GlycogenolysisAll of the glycogen-storage diseases areautosomal recessive with the exceptionof phosphorylase b kinase deficiency(GSD9) and phosphoglycerate kinase 1deficiency, which are X-linked recessivedisorders. McArdle disease (GSD5) is themost common metabolic myopathy (ap-proximately 1 in 100,000 individuals), andis due to heterozygous mutations in thePYGM gene. Myophosphorylase initiatesglycogen breakdown in the rest-to-exercise transition, and as a consequencethere is a huge reliance on the adenylatekinase/myoadenylate deaminase pathwayand phosphocreatine hydrolysis to pro-vide energy during the first 10 secondsof muscle contraction. Symptoms usuallybegin shortly after exercise initiation withmuscle pain and eventually a muscle con-

tracture (muscle contraction in the ab-sence of electrical activity). Usually,significant muscle discomfort occurs afterexercise (delayed-onset muscle soreness)and often pigmenturia.

The most common glycolytic disorderis Tarui disease, which affects the rate-limiting enzyme in the glycolytic pathwaycalled phosphofructokinase. These pa-tients present with symptoms very similarto patients with McArdle disease as do theother rarer forms of glycolytic disorders,which include phosphoglycerate kinase 1deficiency, phosphoglucomutase defi-ciency (also known as congenital disorderof glycosylation type IA), GSD10 (phos-phoglycerate mutase deficiency), GSD11(lactate dehydrogenase deficiency),GSD12 (aldolase A deficiency), andGSD13 ("-enolase deficiency). Phosphory-lase b kinase deficiency (GSD9) is aglycogenolytic defect that reportedly pre-sents similarly to McArdle disease; how-ever, evidence suggests that the phenotypemay be mild or nonexistent.25,26

Clinical presentation. Most patientswith disorders of glycolysis/glycogenolysiswill present with muscle cramps inducedduring the first seconds to minutes ofexercise (Case 4-1). The presentationoften does not occur until the second orthird decade of life but can be even latersince most patients adapt to their disor-der by avoiding exercise or starting off at avery low intensity of exercise and gradu-ally increasing the intensity as aerobicmetabolism becomes predominant andblood-borne substrates are delivered tomuscle. Patients with McArdle diseaseoften report a significant reduction inthe perception of effort after a fewminutes of activity co-temporal with thedelivery of blood-borne substrates, whichis referred to as the second wind phe-nomenon.27 In contrast, patients withglycolytic defects do not experience thesecond wind phenomenon.28,29

Often, patients have a history ofpigmenturia (myoglobin in the urine)due to rhabdomyolysis induced by thesevere deficit in energy charge with

KEY POINTS

h In general, the fatty acidoxidation defects presentduring longer-durationexercise, fasting, orduring times ofsuperimposed metabolicstress such as feveror infection.

h The mitochondrial‘‘myopathies’’ refer tometabolic genetic defectsthat affect the electrontransport chain and leadto exercise intolerancewith or withoutrhabdomyolysis or fixedweakness. Like the fattyacid oxidation defects,mitochondrial myopathiesoften manifest symptomsduring longer-durationactivity or physical activityperformed during periodsof metabolic stress such asfasting, superimposedfever, flu, or other illness.

h Glycogenolytic andglycolytic disordersusually present withmuscle cramps duringhigh-intensity activityand usually in thefirst few minutes ofmuscle contraction.

h Patients with McArdledisease often report asignificant reduction inthe perception of effortafter a few minutes ofactivity co-temporalwith the delivery ofblood-borne substrates,which is referred to asthe second windphenomenon. Incontrast, patients withglycolytic defects do notexperience the secondwind phenomenon.



resultant calcium dysregulation, activa-tion of proteolysis, and muscle fibernecrosis. Patients usually describe theurine as dark, tea colored, red, and cola-colored due to the presence of muscle-derived proteins imparting pigment(usually myoglobin). The presence ofpigmenturia is an important clinicalfeature for it can lead to acute renalfailure. Some patients experience exces-sive shortness of breath upon exertion,and occasionally patients can developfixed muscle weakness, but this is usu-

ally a later manifestation of untreateddisease. Patients with McArdle diseasemay report that they are less symptom-atic following a high-carbohydrate meal,whereas patients with glycolytic defectsoften feel that their symptoms are worseafter a high-carbohydrate meal and feelbetter after a prolonged period of fast-ing. The family history is usually nega-tive for this condition given that theseare autosomal recessive disorders.

The neurologic examination is usuallycompletely normal between episodes

KEY POINTS

h Most patients withMcArdle disease willhave a chronicelevation in serumcreatine kinase.

h The presence ofpigmenturia is animportant clinical featurefor it can lead to acuterenal failure.

h Patients with McArdledisease may reportthat they are lesssymptomatic following ahigh-carbohydrate meal,whereas patients withglycolytic defects oftenfeel that their symptomsare worse after ahigh-carbohydrate mealand feel better after aprolonged periodof fasting.

Case 4-1A 24-year-old woman presented to the emergency department 24 hours afterstarting a new fitness class involving boot campYlike exercises. She hadexperienced painful muscle cramps starting in the first 3 minutes of the class.She had lessened the intensity of her exercise, and the cramps had eased up a bit.However, the cramps had intensified again after 20 minutes, and she had toleave the class. The patient’smuscles were tight, swollen, and very sore that night,and the next morning her urine was reddish brown.

Other than pain-inhibited proximal muscle weakness, the neurologicexamination was normal. Her serum creatine kinase (CK) level was 300,000 IU/L(normal being less than 220 IU/L) in the emergency department, and herurine was positive for hemoglobin but negative for red blood cells.

She was admitted to the hospital for 4 days and treated with normal salineand small amounts of added potassium on days 3 and 4. Twenty-four hours afteradmission, the patient’s urine was clear in color, and at discharge, the CK was40,000 IU/L and her muscle pain was markedly diminished.

During follow-up at the neuromuscular and neurometabolic clinic 2 weekslater, the patient’s neurologic examination was normal, and the CK was downto 800 IU/L; however, she did recall that this was elevated in several previousroutine blood tests but no further investigations had been initiated at that time.In retrospect, she had experienced muscle cramps in the first few minutes ofinitiating exercise for most of her life but had ‘‘learned to live with it.’’ Hersymptoms had improved when she had attended college and had frequentlydone endurance exercise, but she had not exercised for 2 years prior to therecent event. Her family history was negative for anyone with similar symptoms.The forearm exercise test showed a 10-fold increase in ammonia and no rise inlactate, implying a defect in glycolysis or glycogenolysis. Given the history,a molecular test for five common McArdle disease genes was performed andrevealed a homozygous p.Arg49X mutation.

Comment. This patient’s history of rhabdomyolysis and a history of similarevents in the past with a likely second wind phenomenon is very suspiciousfor McArdle disease. Furthermore, the chronic CK elevation is a commonfeature in McArdle disease. Many patients adapt their lifestyle and activitiesto accommodate the symptoms and often do not seek out medical attentionuntil in their twenties or even later. Her history of being less active and thengoing back to a gym to rapidly get back into shape is a common scenario thatinitiates significant rhabdomyolysis and subsequently prompts investigations.




with the exception of fixed muscle weak-ness in GSD12, which can also occurrarely in GSD5 and others. Routine bloodchemistries between events are oftennormal; however, CK is chronically ele-vated in nearly all cases of McArdle dis-ease. Some disorders can be associatedwith hemolysis/hemolytic anemia (eg,GSD7, phosphoglycerate kinase 1 defi-ciency, GSD12). Many of the glycogeno-lytic and glycolytic defects are alsoassociated with myogenic hyperuricemia,which can lead to gout.30 A summary ofsome key features in the history sug-gesting a diagnosis of a glycogen-storagedisease is found in Table 4-2.

Diagnostic testing. The classic diag-nostic test is the forearm exercise test.With an impairment of glycolysis or gly-cogenolysis, no pyruvate is producedunder anaerobic conditions and conse-

quently no lactate is produced throughthe lactate dehydrogenase reaction.16 Usu-ally, a sphygmomanometer cuff is inflatedbeyond arterial pressure and isometricrhythmic exercises are performed for1 minute, followed by release of thesphygmomanometer cuff. Lactate andammonia values are determined prior toinflating the cuff and immediately post-inflation. Normally, lactate and ammoniarise approximately threefold; however,lactate rise is markedly attenuated in theglycolytic and glycogenolytic defects. Fail-ure of both lactate and ammonia to riseusually indicates a suboptimal perfor-mance (decreased effort); however, thecoexistence of a glycolytic/glycogenolyticdefect with the common polymorphismin AMPD1 has been reported and canlead to false-negative testing by mimick-ing a suboptimal effort. The author of this

KEY POINT

h Routine blood chemistriesbetween events are oftennormal; however, creatinekinase is chronicallyelevated in nearly all casesof McArdle disease.

TABLE 4-2 Clinical Features Suggesting Specific Metabolic Myopathies

History Disorder (Descending Likelihood)

Rhabdomyolysis/pigmenturia Glycogen-storage disease (GSD), fatty acidoxidation defects, mitochondrial myopathies

Myalgia 9 cramps withendurance sports

Fatty acid oxidation defects, mitochondrialmyopathies

Shortness of breath withendurance sports

Mitochondrial myopathies

Myalgia/cramps with power/sprint sports

Glycogen-storage disease

Symptoms triggered by fastingor superimposed illness

Fatty acid oxidation defects, mitochondrialmyopathies

Gout Glycogen-storage disease

Nausea/vomiting with exercise Mitochondrial myopathies, GSD7

Multiple system involvement Mitochondrial myopathies

Family history

X-linked Phosphorylase b kinase deficiency, phosphoglyceratekinase 1 deficiency

Maternal Mitochondrial myopathies (mitochondrial DNA only)

Autosomal recessive/consanguineous

Carnitine palmitoyltransferase II deficiency, mostglycogen-storage diseases, nuclear-encodedmitochondrial myopathies

DNA = deoxyribonucleic acid.



article in addition to other investigatorshave found that the blood pressure cuff isnot necessary and that rhythmic contrac-tion in itself is sufficient to yield optimalsensitivity and specificity.31,32 Conse-quently, the author recommends thenon-ischemic forearm exercise test toavoid the possibility of rhabdomyolysisand acute compartment syndrome, whichis somewhat more likely if a sphygmoma-nometer cuff is used. Given the very highsensitivity and specificity of the forearmischemic test and nonischemic forearmexercise test, a normal test rules outevery glycolytic and glycogenolytic de-fect with the possible exception ofphosphorylase b kinase deficiency,25

which can be further evaluated with theaerobic cycling exercise test. There aremany examples of aerobic cycling tests;however, a standard Bruce protocol testused for cardiac evaluation where theintensity/speed of either a cycle ergometeror treadmill is progressively increaseduntil voluntary exhaustion with mea-surement of lactate and ammonia pre/post is sufficient.

Nerve conduction studies and EMGare normal in all of the glycogen-storage disease disorders except forthe electrical silence during a contrac-ture; however, an EMG is rarely neces-sary in the workup of glycogen-storagediseases. An extensive body of litera-ture exists that uses exercise magneticresonance spectroscopy (MRS) to showaccentuated phosphocreatine hydroly-sis and the lack of acidosis in muscle inMcArdle disease as well as the increasein phosphomonoesters in distal glyco-lytic defects.33 An issue with MRS isthat the test is expensive and requireshigh technical expertise and optimiza-tion and, in the author’s opinion, doesn’tadd much to the clinical approachdescribed herein.

If the patient’s history is highlysuspicious for a glycolytic/glycogenolyticdefect and the forearm exercise test isnormal, the remote possibility of phos-phorylase b kinase deficiency can be

further ruled out with the aerobic exer-cise test previously described. If a normallactate rise occurs with the aerobic exer-cise test, all of the glycolytic and glyco-genolytic defects are ruled out, furthergenetic investigations for glycogen-storagediseases are not warranted, and cliniciansshould consider one of the other meta-bolic myopathies or a pseudometabolicmyopathy. If the exercise test is positive, atargeted or untargeted genetic approachwould be prudent. A variety of laborato-ries offer full sequencing of the codingregions and the intronic boundaries ofthe genes for all known glycolytic andglycogenolytic defects. With the advent ofnext-generation sequencing, this ap-proach is often less expensive than doinga single targeted gene (eg, PYGM) usingSanger sequencing methods. However, ifa laboratory does have PYGM sequencingavailable, this would be a prudent firststep given that McArdle disease is themost common of the glycogen-storagediseases causing a metabolic myopathy. Amuscle biopsy is not necessary in a classiccase of glycolytic/glycogenolytic defectwith a positive genetic result; however, amuscle biopsy would be recommended ifsuch testing is negative with the diagnos-tic algorithm described previously. Anadvantage of the muscle biopsy is that apattern may be seen that would targetfurther genetic analysis such as centralcores (RYR1, CACNA1S mutations), ab-normal dystrophin staining (dystro-phinopathy) , ragged red f ibers(mitochondrial cytopathy), or membrane-bound glycogen (Pompe disease). Theother potential need for a muscle biopsywould be the finding of a genetic variantof uncertain significance in a gene of in-terest (eg, PYGM). In such cases, enzymeanalysis of muscle revealing the absenceof phosphorylase activity would confirmthe mutation. In other rare cases, an un-known splicing variant could be furtherevaluated with messenger RNA (mRNA)analysis frommuscle. A summary of someof the tests for the glycogen-storage dis-eases is presented in Table 4-3.

KEY POINT

h A forearm exercise testor aerobic cycle testshowing a normal rise inserum lactate (greaterthan three times that ofbaseline) is good forruling out nearly everygenetic defect in theglycogenolytic andglycolytic pathways.




Treatment. Many patients adjusttheir lifestyle activities to mitigate symp-toms long before a diagnosis is made.For example, patients often avoid high-intensity activity and start off activity at alow intensity to wait for their secondwind. The greatest risk for rhabdomyol-ysis comes with unaccustomed exerciseor large increases in exercise intensity.Consequently, it is important for pa-tients to start exercise at a lowerintensity and to gradually increase the

intensity and duration while self-monitoring for symptoms and reducingthe intensity as needed. As expectedfrom the well-known physiologic adap-tations that occur with exercise training,regular exercise has been shown tolessen symptoms in McArdle disease.34Y36

The consumption of simple sugarscontaining glucose (glucose, sucrose)shortly before exercise can bypass theglycogenolytic metabolic defects.37,38

One study found that oral sucrose (37 g)

TABLE 4-3 Testing for Metabolic Myopathies

Disease Testing

Glycogen-storage disease

Serum creatine kinase (CK) is chronically elevated in McArdledisease; otherwise it is usually normal in the otherglycogen-storage diseases

Serum uric acid is elevated in È50%

Forearm exercise test shows no lactate with high ammonia rise

Graded exercise stress test:

Second wind phenomenon is seen in McArdle disease

No second wind phenomenon suggests the glycolytic defects

EMG is often normal in cases of glycogen-storage disease

Muscle biopsy may show high glycogen, absentphosphorylase, or absent phosphofructokinase

Genetic testing options

Specific mutation analysis: (R49X in È70% of whiteindividuals with McArdle disease)

Next-generation sequencing panels for glycogen-storagediseases or myopathy panels with glycogen-storage diseasegenes or whole-exome sequencing

Fatty acidoxidation defects

Serum CK usually normal

Serum total carnitine often normal

Serum acylcarnitine profile often abnormal (fasted orfollowing a graded exercise stress test)

Urine organic acids (dicarboxylic acids) may be elevated

Hypoketotic hypoglycemia during an event

Skin biopsy for enzyme analysis and acylcarnitine in fibroblasts

Specific mutation analysis (S113L in È70%) in blood

EMG is often normal

Muscle biopsy may show increased lipids, but usuallynonspecific findings

Continued on page 1838



taken 5 to 10 minutes before exerciseimproved exercise capacity and lessenedsymptoms.37 In contrast, patients withphosphofructokinase glycolytic defectsgenerally perform better in the fastedstate and are worse off following carbo-hydrate ingestion because they cannotuse the blood-borne glucose and becausethe glucose raises insulin levels that at-tenuates lipolysis and proteolysis that areused as alternative fuel sources.39

Patients with the most commonMcArdle disease mutation (R49X) haveno protein expressed because ofnonsense-mediated mRNA decay; con-

sequently, they have a secondary de-ficiency of pyridoxine (vitamin B6)because these two have a protein-protein interaction. Consequently, somehave advocated the use of pyridoxinesupplementation (approximately 50mg/d)in patients with null PYGMmutations40,41;however, efficacy has not yet been con-firmed in a randomized clinical trial. High-protein diets have also been advocatedin an attempt to increase alternative fuelavailability (amino acids); however, thishas not been tested in a randomizedcontrolled trial. Furthermore, branched-chain amino acid supplements did not

TABLE 4-3 Testing for Metabolic Myopathies Continued from page 1837

Disease Testing

Mitochondrialmyopathy

Serum CK may be chronically elevated

Serum lactate is elevated in È65%

Serum alanine is occasionally elevated

Urine organic acids (tricarboxylic acid intermediates,3-methylglutaconic aciduria) may be elevated

Forearm exercise test does not lead to deoxygenation

Graded exercise stress test is associated with low VO2max, highrespiratory exchange ratio

EMG is often normal

Muscle biopsy may show ragged red fibers, cytochromeoxidaseYnegative fibers, or paracrystalline inclusions (electronmicroscopy)

Enzyme analysis on muscle and skin fibroblasts can show mixedor single electron transport chain defects

Genetic testing options (usually on muscle tissue)

Specific mutation analysis for classic features of mitochondrialencephalomyopathy, lactic acidosis, and strokelike episodes(MELAS) (m.3243A9G); Leber hereditary optic neuropathy(m.11778G9A, m.14484T9C, m.3460G9A); chronic progressiveexternal ophthalmoplegia (mitochondrial DNA deletion);or myoclonic epilepsy with raggedred fibers (MERRF) (m.8363G9A)

Mitochondrial DNA sequencing (if mitochondrial DNAmutation is suspected)

Next-generation sequencing targeted mitochondrial panelsor whole-exome sequencing (both for nuclear mutations)

DNA = deoxyribonucleic acid; EMG = electromyography.




show a benefit.42 Creatine monohydratein low to moderate doses (approximately0.1 g/kg/d) did show bioenergetic im-provements during exercise in patientswith McArdle disease43; however, higherdoses of creatine monohydrate led toexercise impairment.43 Although GSD3(debranching enzyme) is considered tobe a glycogen-storage disease associatedwith fixed weakness, a recent studyshowed improvements in exercise capac-ity with pre-exercise fructose ingestion.44

Finally, D-ribose, verapamil, anddantrolene were not effective in treatingMcArdle disease.45 In fact, adverse eventsor worsening of symptoms were ob-served with oral D-ribose (diarrhea andhypoglycemia symptoms) and dantrolene(fatigue, vertigo, andmuscle weakness).45

One study found mild improvements inexercise capacity and improved symp-toms in patients with a deletion-deletionhaplotype for angiotensin-convertingenzyme following treatment with 2.5 mgof ramipril.46 In summary, studies pro-vide some support for the use of low-dose creatine monohydrate, pre-exercisesucrose/glucose, ramipril (only in the caseof the deletion-deletion polymorphism),and possibly a high-carbohydrate diet.45

Although vitamin B6 (pyridoxine) is notuniversally beneficial, a low dose maynot be imprudent in patients who havenull phosphorylase mutations and haverelative pyridoxine deficiency (Table 4-4).

Fatty Acid Oxidation DefectsFatty acids are generally categorizedaccording to the number of carbons intoshort-chain (two to four), medium-chain(six to 12), long-chain (14 to 18), andveryYlong-chain (20 or more) fatty acids.The oxidation of long-chain and veryYlong-chain free fatty acids requires the carni-tine palmitoyltransferase system, whereasshort- and medium-chain free fatty acidscan directly enter the mitochondrialmatrix for "-oxidation. All of the currentlyknown clinically relevant fatty acid oxida-tion defects are autosomal recessive dis-orders with the three most common

being carnitine palmitoyltransferase IIdeficiency (approximately 1 in 250,000individuals), trifunctional protein defi-ciency, and veryYlong-chain acyl-CoAdehydrogenase deficiency.

Clinical presentation. Unlike thetrue cramping symptoms experiencedby the glycolytic/glycogenolytic defects,the fatty acid oxidation defects usuallypresent with exercise-induced myalgia.The patients may experience pig-menturia later on in the same day orwithin 24 hours of exercise due torhabdomyolysis. Most patients do havedelayed-onsetmuscle soreness for severaldays following a bout of rhabdomyolysis.The symptoms are often precipitated byprolonged fasting, prolonged exercise,or superimposed illness (Case 4-2).Often, children have myalgia and occa-sionally pigmenturia during fever orvomiting (fasting) and will only noticethe exercise-induced symptoms in theirteenage years when they do longer-duration activities (Table 4-2).

Diagnostic testing. Blood testing isusually completely normal for CK, lac-tate, and glucose between episodes ofrhabdomyolysis. During an acute boutof rhabdomyolysis, an increase in CKstarts within a few hours, during whichhyperkalemia and hypoketotic hypogly-cemia can occur. Following a bout ofrhabdomyolysis, acute renal failure canoccur with elevations of potassium,creatinine, and urea. The most sensitiveand specific test for a fatty acid oxida-tion defect is the acylcarnitine profileperformed by liquid chromatographyYtandem mass spectrometry. This testmay be abnormal between acute events;however, a false-negative test can occur ina nonstressed situation. The author ofthis article usually prefers that patientscome in in the fasted state in themorning, which tends to increase thediagnostic yield. Additionally, this testshould be sent if a fatty acid oxidationdefect is suspected during an acutemetabolic crisis. Often, the specific acyl-carnitine signature can target a specific



genetic mutation for subsequent geneanalysis. Total and free carnitine levelsmay be secondarily abnormal; however,very low levels of these are usually seen insystemic carnitine deficiency due to mu-tations in OCTN2/SLC22A5 genes.47

Urine testing during rhabdomyolysiswill often show a positive hemoglobintest with negative red blood cells onmicroscopy that reflects the myoglobinin the urine. Urine organic acid analysismay also show an elevation of specificdicarboxylic acids in "-oxidation defects.The acylcarnitine profile can also beassessed in fibroblast culture if a fatty

acid oxidation defect is suspected and ifplasma acylcarnitine profiling in the fastedstate is nonrevealing. If the acylcarnitineprofile or history are strongly suspiciousfor a fatty acid oxidation defect, specificgenetic testing for the defect can becarried out using Sanger sequencing ofexons and intron-exon boundaries. Morerecently, next-generation sequencing hasallowed the use of panels that cover themore common fatty acid oxidation de-fects leading to rhabdomyolysis (carnitinepalmitoyltransferase II, trifunctional pro-tein, veryYlong-chain acyl-CoA dehydro-genase) and some of the less common

KEY POINT

h Unlike the true crampingsymptoms experienced bythe glycolytic/glycogenolyticdefects, the fatty acidoxidation defectsusually present withexercise-induced myalgia.The patients mayexperience pigmenturialater on in the same day orwithin 24 hours of exercisedue to rhabdomyolysis.

TABLE 4-4 Metabolic Myopathy Treatments

Disease Treatmenta

Glycogen-storagedisease

Careful and progressive exercise training

Pre-exercise sucrose/glucose in glycogenolytic defects(eg, McArdle disease)

Overnight fasting for glycolytic defects(eg, phosphofructokinase deficiency or Tarui disease)

Creatine monohydrate (0.1 g/kg/d), NOT higher dose

Consider pyridoxine 50 mg/d in patients with nullphosphorylase mutations (eg, R49X mutations)

Fatty acid oxidationdefects

Careful and progressive exercise training; no exerciseduring illness

Avoid fasting

L-carnitine (only if low or in SLC22A5 mutationtransporter defect); start at 330 mg 2 times per day

High-carbohydrate diet

Carbohydrate before and during exercise

Consider triheptanoin

Mitochondrialmyopathy

Careful and progressive exercise training; no exerciseduring illness

Avoid fasting

Cocktail treatment consists of coenzyme Q10 or idebenone(5Y15 mg/kg/d) plus "-lipoic acid (5Y15 mg/kg/d) plus vitamin E(5Y15 IU/kg/d) plus creatine monohydrate (0.1 g/kg/d)

L-carnitine, only if levels are low; start at 330 mg 2 timesper day and retest

a Start medications at the lower dose range and titrate to tolerance/clinical effect using twice daily dosingand taken with meals.




fatty acid oxidation defects associatedwith exercise-induced rhabdomyolysis(medium-chain acyl-CoA dehydrogenasedeficiency, carnitine acylcarnitine tran-slocase deficiency). Recurrent rhabdo-myolysis in the face of fever andsuperimposed illness can also be seen incases of LPIN1 deficiency (a magnesium-dependent phosphatidic acid phos-phohydrolase). To date, LPIN1 mutationshave not been associated with exercise-induced rhabdomyolysis.

In cases where the fasting acylcar-nitine profile is normal, the authorusually carries out an aerobic exercisetest on a cycle ergometer in the fastedstate with pre- and postexercise lactateand postexercise acylcarnitine profiling.This is helpful in that an attenuated

lactate rise would be suspicious for aglycolytic/glycogenolytic defect and thepostexercise acylcarnitine profiling cansometimes reveal the specific fatty acidoxidation defect. Furthermore, high rest-ing lactate and a low VO2max with a highrespiratory exchange ratio during cycleergometry can indicate a mitochondrialmyopathy. Muscle biopsy is usually notrequired for the workup of a suspectedfatty acid oxidation defect; however,muscle tissue may show a nonspecificincrease in neutral lipid, and this is feltto be quite a nonspecific and subjec-tive impression. Nerve conduction veloc-ity and EMG testing is often normal infatty acid oxidation defects; however, amyopathic picture (small brief earlyrecruiting potentials) can be seen for up

KEY POINTS

h A normal serumacylcarnitine level duringfasting or following anacute bout ofrhabdomyolysis is a goodtest for ruling out a fattyacid oxidation defect, andan abnormal test patterncan often suggest aspecific genetic diagnosis.

h Most patients with a fattyacid oxidation defect willhave symptoms duringfasting, illness or fever, orduring longer-durationphysical activity.

Case 4-2A 56-year-old man presented to the neuromuscular and neurometabolic clinicwith a history of Tarui disease. The patient requested exercise advice as hewanted to join a cycling club. He and his sister had been given a diagnosis ofTarui disease in South Africa decades before after each had experienced a boutof rhabdomyolysis. The diagnosis had not been confirmed genetically andappeared to be based upon the fact that they both had rhabdomyolysis withexercise and were of Ashkenazi Jewish descent. In retrospect, he did recall thatas a child he could not walk to the synagogue during Yom Kippur (whichincludes a 25-hour fast) due to myalgia. He also noted that he could not liftweights or do chores if he was ill or fasting. He also found that if he rode his bikeafter eating, especially if he had eaten some honey, he felt much better.

His neurologic examination was normal. With this history, a fastingacylcarnitine profile was sent and blood was banked for DNA. The acylcarnitineprofile showed a pattern of long-chain acyl-coenzyme A moieties characteristicfor carnitine palmitoyltransferase II deficiency. The DNA was then sent for a5-gene common carnitine palmitoyltransferase mutation panel, which returnedpositive for a homozygous p.Ser113Leu common carnitine palmitoyltransferaseII mutation. After this visit, the patient continued another 15 years without anybouts of rhabdomyolysis by avoiding activity during illness and fasting and byconsuming a high-carbohydrate diet. He was able to cycle with a local club upto 80 km on the weekends with a preride meal and the consumption ofglucose-based gels and other carbohydrate sources during the ride.

Comment. The history of symptoms during fasting and improvements inexercise capacity with feeding and carbohydrate supplements is characteristicof a fatty acid oxidation defect and the opposite of what would be expectedin a patient with Tarui disease (phosphofructokinase deficiency). Furthermore,the patient had symptoms with longer-duration exercise that would also bemore characteristic of a fatty acid oxidation defect as opposed to a glycolytic orglycogenolytic disorder. Homozygosity for mutations is common in restrictedpopulations where the possibility of remote consanguinity is higher.



to 10 days following an acute bout ofrhabdomyolysis, occasionally with fibrilla-tions, positive sharp waves, and complexrepetitive discharges. A mixed axonalneuropathy can be seen in rare cases oflong-chain 3-hydroxyacyl-CoA dehydro-genase deficiency (Table 4-3).

Treatment. Most patients avoid trig-gers of their disease such as exercisingin the fasted state, exercising with asuperimposed illness, and long-durationexercise. Most patients generally tend tochoose higher-carbohydrate foods espe-cially immediately before and duringlong-term endurance exercise, and arelatively low-fat (less than 30%) higher-carbohydrate diet is recommended. Acarbohydrate-enriched diet improvedexercise tolerance in patients with carni-tine palmitoyltransferase II deficiency,48

whereas oral glucose did not.49 Theadministration of vitamin B2 (riboflavin),medium-chain triglyceride oil, andL-carnitine has been advocated50,51 butnone have been proven in a clinical trial;however, replacement of L-carnitinewould be prudent if patients are foundto be deficient. The use of bezafibrate(not available in the United States) hasbeen suggested52; however, Class I evi-dence now suggests this is not effectivein carnitine palmitoyltransferase II defi-ciency.53 The use of triheptanoin (oddchain free fatty acid) has been shown toimprove energy production in cells frompatients with fatty acid oxidation de-fects.54,55 Triheptanoin has been shownto reduce hospitalizations in a retrospec-tive study56 and was also shown toimprove exercise capacity.55 A summaryof some of the treatment options ispresent in Table 4-4.

Mitochondrial MyopathiesMitochondrial myopathies are a diversegroup of genetic disorders with a pri-mary defect in electron transport chainfunction. The metabolic consequencesof mitochondrial dysfunction result pri-marily from a decrease in aerobic energyproduction from fat and carbohydrate

oxidation; however, the production ofreactive oxygen species may play a path-ogenic role. As the final common pathwayfor fat and carbohydrate oxidation, thesymptoms of mitochondrial myopathiesoften manifest themselves during periodsof highmetabolic demand such as fasting,superimposed illness, or longer-durationexercise. Given that mitochondria arepresent in all tissues with the exceptionof red blood cells, multisystemic manifes-tations of the disease often occur fromtissues with a high metabolic demandsuch as heart, brain, skeletal muscle, andnerves (especially cranial nerves II andVIII). The term mitochondrial cytopathyis the preferred term for patients withmultisystemic clinical manifestations, andthe term mitochondrial myopathy isused when skeletal muscle is the pre-dominant tissue involved. Although fixedweakness can be a manifestation of amitochondrial myopathy, the currentreview will focus on the metabolicfunction of skeletal muscle and theresultant exercise intolerance with orwithout rhabdomyolysis.57Y59

Mitochondria are cellular organellesthat likely evolved from photosyntheticbacteria that took on a symbiotic rela-tionship with a proto-eukaryotic cellnearly 1.5 billion years ago. Throughevolution, the DNA encoding for mostof the approximately 1200 proteins re-quired by a mitochondrion are part ofthe nuclear DNA and imported into themitochondria through a transport sys-tem. The mitochondrial DNA (mtDNA)is a maternally inherited small (16,569base pairs) circular, double-strandedmolecule that resembles bacterial DNA.The mtDNA composition is highly con-served across species and encodes fortwo ribosomal RNAs, 22 transfer RNAs,and 13 protein encoding mRNAs. Mito-chondrial replication is dependentupon many nuclear encoded proteinssuch as polymerase-+ (POLG1) and isnot dependent upon the cell cycle.Consequently, mitochondrial biogenesiscan occur in postmitotic cells such as

KEY POINTS

h A high-carbohydratediet and possiblycarbohydrate consumptionduring exercise mayattenuate symptoms of afatty acid oxidation defect.

h Mitochondrial disordersoften affect more thanone tissue or organsystem due to theubiquitous distribution ofthe mitochondria.




skeletal muscle in response to stimulisuch as exercise.

Each mitochondrion contains severalmtDNA copies, and hundreds to thou-sands of mitochondria are present inevery cell, roughly in proportion to theaerobic needs of the cell. The mtDNA ismaternally inherited whilst all nuclearmitochondrial genes follow mendelianinheritance rules. The first mutationsthat were found in mtDNA in 1988 and1989 were point mutations at posi-tion 3243 (m.3243A9G) and 11,778(m.11778G9A) responsible for mito-chondrial encephalomyopathy, lacticacidosis, and strokelike episodes (MELAS)and Leber hereditary optic neuropathy aswell as a large-scale deletion seen inKearns-Sayre syndrome.60Y62 mtDNAcontains many benign polymorphismsthat may contribute to evolutionary bio-logical fitness,63 and some define themitochondrial haplotypes, but these canbe a challenge when a variant of uncer-tain significance is found with mtDNAsequencing. The number of pathogenicmtDNA mutations described in the past2 decades has been substantial. In ad-dition, the number of nuclear encodedgenes linked tomitochondrial cytopathies/myopathies has dramatically increasedbecause of the advent of next-generationsequencing (see the MITOMAP humanmitochondrial genome database at www.mitomap.org/MITOMAP).

Some diseases such as Leber hered-itary optic neuropathy affect all copiesof mtDNA and are termed homoplasmic;however, having a variable proportion ofmutant to wild-type mtDNA copies withina tissue is more common, which isreferred to as heteroplasmy. Because ofreplicative segregation that occurs withinand between tissues during embryogene-sis, the heteroplasmy can be very differ-ent between tissues. Furthermore, themutant heteroplasmy does tend to belower in tissues with rapid turnover, suchas blood cells, while maintaining a con-stant level in more terminally differenti-ated tissues, such as muscle and brain.

In general, a higher level of mutant het-eroplasmy is associated with more severeand earlier-onset symptoms and tissuebiochemical pathology.

Clinical presentation. Mitochondrialmyopathies are notorious for the ex-treme phenotypic and genotypic het-erogeneity. A classic example is MELASsyndrome, where people within thesame family may present with adult-onset deafness and diabetes, whileothers may present with any combina-tion of strokes, seizures, cardiomyopa-thy, short stature, dementia, and severeexercise intolerance. In contrast, pa-tients with the same phenotype (eg,chronic progressive external ophthal-moplegia) may have a sporadic mtDNAdeletion, a nuclear encoded mtDNAmaintenance gene mutation, or a specificmtDNA point mutation.

Many patients with mitochondrialcytopathies and myopathies will havelimitations in exercise capacity becauseof a low VO2max. The protean manifes-tations of the disorder (eg, seizures,encephalopathy, cardiomyopathy) mayovershadow exercise intolerance. Forexample, we found a severely reducedVO2max (9.2 mL/kg/min, normal being32 mL/kg/min) in seven patients withMELAS and yet none of them presentedwith exercise intolerance as the pres-enting symptom.64 In retrospect, theaforementioned patients often reportedthat they were ‘‘last in sports’’ or ‘‘theworst athlete in the class.’’ Most pa-tients with mitochondrial myopathiesreport shortness of breath and pre-mature fatigue during exertion that isoften exacerbated with superimposedinfection or fasting; however, somepatients may also have exertional nauseaand vomiting. A few cases of temporary/partial visual loss and/or hearing lossduring exertion have also been ob-served by the author in patients withMELAS (Case 4-3). In contrast to the layperception and biological plausibility,most patients do not report symp-toms of fatigue and tiredness at rest



http://www.mitomap.org/MITOMAP

http://www.mitomap.org/MITOMAP

with any greater frequency than com-monly seen in the general population.Unlike fatty acid oxidation defects orglycogen-storage diseases where rhab-domyolysis and pigmenturia are com-mon, most patients with mitochondrialmyopathy do not experience suchevents. Rhabdomyolysis has, however,been seen in cases of cytochrome b,cytochrome c oxidase, and MELASm.3260A9G mutations.65Y67

Other signs and symptoms oftenoccur that suggest a mitochondrial dis-ease diagnosis such as hypoacusis, shortstature, ptosis, ophthalmoparesis, type 2diabetes mellitus, migraine variant head-aches, seizures, strokes and strokelike

episodes, head and neck lipomas, periph-eral neuropathy, ataxia, cardiomyopathy,cardiac conduction block, and intestinalpseudoobstruction. Fixed weakness mayalso be seen with or without an elevatedCK that can mimic muscular dystrophyor congenital myopathy. A positive ma-ternal family history with any numberof the previously described signs andsymptoms is helpful to rule in anmtDNA-based mitochondrial myopathy, but anegative family history cannot be usedto rule out a mitochondrial myopathygiven that many are autosomal recessive(Table 4-2).

Diagnostic testing. Testing for mito-chondrial myopathy is complex and

KEY POINTS

h A normal serum lactatelevel does not rule outmitochondrial disease inadults or children.

h A high serum lactate inadults is suggestive ofmitochondrial disease,whereas a high lactatelevel in children can be afalse positive due tostruggling or difficultiestaking the blood.

Case 4-3A 46-year-old woman presented to the neuromuscular and neurometabolic clinicwith a history of exercise-induced deafness and stomach discomfort that shehad experienced for several years. The referral was also prompted by the fact thather eldest daughter underwent a heart transplant for severe hypertrophiccardiomyopathy and experienced severe postoperative lactic acidemia (up to20 mmol/L, with the normal range being 2.2 mmol/L) with no identified cause1 month prior to the evaluation. Her mother and her maternal grandmother haddied of ‘‘encephalitis’’ in their midforties based on a history of rapid-onsetseizures and strokelike episodes for which no cause had been identified. She hadshort stature (less than the third percentile) and her neurologic examinationshowed mild proximal weakness (4 out of 5) for hip flexors and shoulderabductors. Serum lactate was mildly elevated at 3.1 mmol/L (normal range beingless than 2.2 mmol/L).

Muscle biopsy showed a few ragged red fibers (approximately 2%), andmitochondrial DNA (mtDNA) testing from the muscle biopsy sample usingpolymerase chain reaction (PCR)Yrestriction fragment length polymorphism forthree common mutations (m.3243A9G, m.3260A9G, and m.3271T9C) revealed86% heteroplasmy for the m.3260A9G mutation. The patient’s bloodheteroplasmy for m.3260A9G was 22%. Subsequent testing in her threedaughters showed that blood mtDNA mutant heteroplasmy for the m.3260A9Gmutation was 55%, 48%, and 60%, respectively. The patient went on to havea severe temporooccipital strokelike episode with complete homonymoushemianopsia, severe dysphasia, and acalculia 1 year after the initial diagnosis thatcompletely resolved after 3 months.

Comment. This patient’s family history was suggestive of maternalinheritance of neurologic symptoms that prompted mtDNA analysis. Theexercise intolerance and exercise-induced deafness had been attributed bythe patient to ‘‘just being out of shape,’’ and she did not seek medicalattention for it until her daughter’s postoperative course. A higher mutationalheteroplasmy level in muscle-derived mtDNA versus blood-derived mtDNAis a common feature of mitochondrial disease that can lead to a misseddiagnosis if mtDNA testing is only done on blood samples.




somewhat controversial; however, mostexperts agree that a systematic andmultiple testing approach is required.Serum/plasma lactate is an importantblood test for the evaluation of a sus-pected mitochondrial myopathy. Thelactate concentration is elevated inapproximately 65% of adult patientswith mitochondrial myopathy (sensiti-vity) and normal in over 90% of peoplewithout mitochondrial myopathy (speci-ficity).16 It is important to take the bloodto the laboratory while it is on ice andanalyze promptly to avoid false-positiveresults. Other causes of false-positiveresults include diabetes mellitus, difficultblood draws (eg, struggling, prolongedtourniquet use), and if the patient hasrecently (within less than 1 hour) con-sumed a high-carbohydrate meal. SerumCK activity is often normal but will beelevated after rhabdomyolysis and in afraction of patients in whom the eleva-tion is usually less than three times theupper limit of normal. CK levels higherthan this should prompt considerationof a muscular dystrophy. About 50%of patients with MELAS will have type2 diabetes mellitus or impaired oral glu-cose tolerance. Plasma amino acid testingcan reveal an elevated alanine, especially iftaken after an aerobic exercise test. Urineorganic acid analysis may reveal elevationsof 3-methylglutaconic acid or the tricar-boxylic acid intermediates (fumarate,malate, citrate).

Cycle ergometry exercise testing inmitochondrial myopathies may demon-strate a low VO2max, or a high respiratoryexchange ratio (indicative of early lactateproduction), or both.68 The author ofthis article has tended to do far fewerexercise tests recently because of thelarge number of false-positive tests thatare due to physical inactivity associatedloss of mitochondrial enzyme activity.69

Hypodynamia is a secondary manifesta-tion of nearly every myopathy seen inthe clinic but is also a very commonconsequence of many common disorders(eg, immobilization, chronic fatigue syn-

drome, fibromyalgia). Forearm non-ischemic testing linked with nearinfrared spectroscopy or venous bloodgas measurements has been used todemonstrate the failure of deoxygenationsecondary to a mitochondrial defect.70,71

For example, the venous blood oxy-gen content at rest is usually 28 mm Hgto 48 mm Hg, and this drops after ex-ercise because of deoxygenation, whichimparts a dark purple/black color to theblood in healthy people; in contrast, nodrop or even a slight increase in oxygen-ation (arterialization) of the venousblood occurs after exercise in patientswith a mitochondrial myopathy. Phos-phorus (31P) MRS has also been used toshow rapid phosphocreatine hydrolysis,an increase in lactate during exercise, ora delayed ATP recovery following exer-cise33,72; however, exercise MRS is bestused by specialized centers.

EMG is often normal in the mito-chondrial myopathies but may show anonspecific myopathic pattern withsmall, brief, early recruiting action po-tentials. EMG is perhaps best used as atool to rule out myotonic disorders andmuscular dystrophies if the diagnosis isnot clear. Similarly, nerve conductionstudies are often normal in mitochon-drial myopathies but may show anaxonal sensory (eg, POLG1 mutations)or sensorimotor neuropathy (eg, myo-clonic epilepsy with ragged red fibers[MERRF]; mitochondrial neurogastro-intestinal encephalomyopathy [MNGIE];and neuropathy, ataxia, retinitis pig-mentosa [NARP] syndrome).

The muscle biopsy is more helpful inthe analysis of mitochondrial myopa-thies as compared to fatty acid oxidationdefects and glycogen-storage diseasesfor several reasons. First, the histologicchanges may give a clue to the geneticdefect. For example, the presence ofragged red fibers (subsarcolemmal ac-cumulation of mitochondria on modi-fied Gomori trichrome staining) orcytochrome c oxidaseYnegative fiberscan suggest an mtDNA mutation. The

KEY POINT

h The muscle biopsy is morehelpful in the analysis ofmitochondrial myopathiesas compared to fatty acidoxidation defects andglycogen-storage diseases.



presence of ragged blue fibers (succi-nate dehydrogenase plus cytochrome coxidase staining combined) is alsosuggestive of an mtDNA mutation. Thefinding of strongly positive succinatedehydrogenaseYstained blood vessels issuggestive of MELAS syndrome. Second,skeletal muscle is the ideal choice forDNA extraction for mtDNA analysis in asuspected mitochondrial myopathy asmtDNA deletions are notoriously absentin blood and mtDNA heteroplasmy isoften very low to nondetectable in blood.Finally, the muscle biopsy is a goodsource for electron transport chain en-zyme analysis given that some mito-chondrial myopathies do not manifestenzymatic defects in fibroblasts or whiteblood cells. The author of this articlerecommends electron microscopy inevery case of suspected mitochondrialdisease for it can reveal mitochondrialalterations (eg, pleomorphic mitochon-dria, paracrystalline inclusions, abnor-mal cristae) before the light microscopicchanges are evident.73

Many ways exist to evaluate electrontransport chain enzyme activity/proteincontent; however, most centers usespectrophotometric methods in skeletalmuscle homogenates or isolated mito-chondria.58,74 Single enzyme defectsare often seen in complex assembly genes(eg, SCO2) or with mutations in specificelectron transport chain subunits, whilemultiple defects can be seen in transferRNA mutations or mutations in genesinvolved in mtDNA maintenance (eg,POLG1) or any of the many recently dis-covered genes under the umbrella of com-bined oxidative phosphorylation defects.

A large number of genetic testingmethods are available for diagnosis ofmitochondrial myopathy; however, mostare being replaced by next-generationsequencing because of cost and through-put reasons.58,75 mtDNA sequencing(next-generation sequencing or Sangersequencing) of the entire mtDNA is a fastand easy way to screen for mtDNA mu-tations if the testing is suggestive of such

a defect. Muscle is the ideal tissue to usefor mtDNA testing; a moderate to highlevel of mutant heteroplasmy in a knowngene can establish the diagnosis. Bloodis not ideal for mtDNA analysis becauseof lower or nondetectable mutationalheteroplasmy or mtDNA deletions. Var-iants of uncertain significance do re-quire more sophisticated evaluation in aresearch-based laboratory. Long-rangePCR has been used to screen musclefor mtDNA deletions given that a nega-tive test rules out disease (high sensitiv-ity) and a positive test can be followedup with more definitive testing such asnext-generation sequencing or ND1/ND4 ratios (specific regions within themtDNA) with PCR. Next-generation se-quencing panels are rather popular,and are currently able to screen dozensto hundreds of nuclear encoded genesat once; however, with the lower costof next-generation sequencing and thediscovery of many new genes associatedwith mitochondrial cytopathies (eg,combined oxidative phosphorylationdefects are now up to 26 recently dis-covered genes), many experts are usingwhole-exome sequencing with next-generation sequencing methodology(Table 4-3).

Treatment. Mitochondrial myopa-thies lead to a reduction in aerobicenergy transduction, increased free rad-ical production, and a greater relianceon alternative energy stores (eg, phos-phocreatine). Therefore, interventionshave usually focused on amelioratingone or several of these consequences.Attempts to bypass specific electrontransport chain complex impairmentshave included succinate and riboflavin tobypass complex I and coenzyme Q10 tobypass complex I and II. Antioxidantshave been heavily studied, includingvitamin E, vitamin C, "-lipoic acid,idebenone, and coenzyme Q10.

76 Crea-tine monohydrate has been used to pro-vide an alternative energy source withvariable success.64,77 The most commonapproach is the use of a combination of




compounds that target multiple finalcommon pathways of mitochondria.59,78,79

There have been very few randomized,double-blind, controlled clinical trialsin mitochondrial myopathies but wehave shown some objective benefitsto exercise capacity with creatinemonohydrate,64 coenzyme Q10,

76 andcombined coenzyme Q10 plus vitamin E,"-lipoic acid, and creatine mono-hydrate.78 Some visual improvementwas noted in patients with Leber he-reditary optic neuropathy usingidebenone80,81; however, no exerciseoutcomes were reported, and mostpatients with Leber hereditary opticneuropathy do not have myopathicsymptoms. Some evidence exists that acoenzyme Q10 analogue called EPI-743may have therapeutic potential82; how-ever, randomized double-blind studiesare needed.83 Studies have found lowerlactate and some exercise improve-ments in patients with mitochondrialmyopathy using a drug called dichlo-roacetate that activates pyruvate dehy-drogenase84; however, safety concernshave raised serious questions aboutlong-term clinical utility.83,85

As expected, significant improve-ments in exercise capacity and quality oflife have occurred with endurance exer-cise training in patients with mitochon-drial myopathy.86Y89 One study foundsignificant improvements in strengthfollowing a resistance exercise programin patients with predominantly chronicprogressive external ophthalmoplegia.90

Studies in both endurance and resistanceexercise appear to be safe86,87,90 and alsoappear to improve both mitochondrialenzyme capacity86,88 as well as reducethe mutational burden in sporadic mito-chondrial myopathies.91 A summary ofsome of the possible treatments is presentin Table 4-4.

CONCLUSIONA detailed history of the triggeringsymptoms often points to a specific typeof metabolic myopathy. For example,

the glycogen-storage diseases presentearly on during high-intensity exercisewhereas the fatty acid oxidation defectsand mitochondrial myopathies usually pre-sent during longer-duration/endurancetype activities or during fasting or otheracute illness. Clinical examination is usu-ally normal in the glycogen-storage dis-eases or fatty acid oxidation defects butcan show other neurologic features inpatients with mitochondrial myopathies(ptosis, external ophthalmoplegia, hypo-acusis, visual loss, ataxia, neuropathy).The clinical examination can be sup-plemented by blood (CK, lactate, uricacid, amino acids, acylcarnitine) and urinetests (organic acids).

A relatively simple nonischemicforearm exercise test can be readily donein most clinics and is helpful to rule in orrule out several of the metabolic myo-pathies. The author of this article uses a22 Ga plastic catheter in the antecubitalvein and a three-way stop cock andtakes resting samples (on ice) for CK,lactate, ammonia, acylcarnitines, andblood gas (the latter only if mitochon-drial disease is suspected). Followingthis, the author instructs the subjects toperform 30 contractions in 60 seconds(1 second on:1 second off or 9 secondson:1 sec off repeated six times) and takesa postexercise sample after 1 minute forlactate, ammonia, acylcarnitines, andblood gas (optional). A normal test rulesout essentially all glycogen-storage dis-eases, and a normal resting lactate andnormal deoxygenation lowers the post-test probability of mitochondrial disease.A normal acylcarnitine level before andafter exercise in the fasted state lowersthe posttest probability of a fatty acid oxi-dation defect. If these tests do not providea high likelihood of a specific disorder forgenetic testing, clinicians can then consid-er a graded exercise stress test with VO2max

and respiratory exchange ratio measure-ments as well as the blood tests men-tioned previously (except blood gases). Amuscle biopsy should be considered in

KEY POINT

h Exercise and resistanceexercises are effectivetherapies for somepatients with metabolicmyopathies but must beindividualized and titratedto tolerance.



cases without a definitive diagnosis inwhomweakness and a high CK are foundor if there is a high index of suspicion fora mitochondria myopathy.

Prompt and accurate identification ofthe specific metabolic myopathy can leadto effective therapies such as lifestylemodification, nutritional intervention, co-factor treatment, and proper exerciseprescription in order to prevent or delayrhabdomyolysis and eventualmuscleweak-ness. An accurate diagnosis is also impor-tant from a genetic counseling perspective.

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