1829 . 2016 American Academy of triheptanoin, which is under license and investigation by Ultragenyx Pharmaceutical, Inc, to treat fattyoxidation acid defects. * of Neurology. Address correspondence to Dr Mark A. Tarnopolsky, Division of Neuromuscular and Neurometabolic Disorders, McMaster University, 1200 Main St W, HSC-2H26, Hamilton, ON L8N 3Z5, Canada, [email protected] Relationship Disclosure: Dr Tarnopolsky has received personal compensation as a speaker and consultant for Sanofi Genzyme and has received research funding from the Canadian Institutes of Health Research, Exerkine Corporation, and MitoCanada. Dr Tarnopolsky is alsoshareholder a and stockholder for Exerkine Corporation. Unlabeled Use of Products/Investigational Use Disclosure: Dr Tarnopolsky discusses the unlabeled/investigational use and RYR1 SGCA, SGCB, deficient pa- deficient indi- Y Y ), and DYSF Review Article , and mutations) can present with and Tarnopolsky and col- have shown that homozygous 5 6 Consequently, myoadenylate de- 6 Structural such as Becker aminase will notin be this further review. considered (),girdle limb- muscular dystrophy ( SGCD, ANO5 leagues blood flow appearsmyoadenylate to be deaminase enhancedtients in with nopower, significant lowering of myoadenylate deaminase viduals docellular not show chargehigh-intensity alterations in nor do in response anyproposed of pathophysiologic to the mechanisms of the supposedvalid. energy deficit appear symptoms triggeredthus by mimic exercise the and metabolic myopathies; malignant hyperthermiaCACNA1S ( it is muscle 2,3 4 the amino 1 Metabolic myopathies are genetic disorders that impair intermediary The metabolic myopathies can present in the neonatal and infant period Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is Accurate and early identification of metabolic myopathies can lead to ther- Mark A. Tarnopolsky, MD, PhD bouts of high-intensity exercise,myopathies whereas present during fatty a acid long-duration/low-intensity endurance-type activity oxidationfasting or or defects during another and metabolically stressful event mitochondrial (eg,is surgery, ). The often clinical examination normaltesting between ( acute kinase, events, acylcarnitine and(ketones, dicarboxylic profile, acids, evaluation 3-methylglutaconic lactate, acid), involves muscle amino exerciseture, biopsy (histology, acids), testing, ultrastruc- testing), MRI/spectroscopy, blood urine and targeted organic orSummary: untargeted acids genetic testing. apeutic interventions with lifestylerapid and treatment nutritional of modification, . cofactor treatment, and Continuum (Minneap Minn) 2016;22(6):1829–1851. Purpose of Review: metabolism in . Impairmentsdisease), in fatty / (-storage acid transportchondrial and respiratory oxidation chain (fatty (mitochondrial aciddefects. myopathies) The represent oxidation purpose the defects), of this and majority reviewthe of the is metabolic myopathies. to known mito- develop a diagnosticRecent and Findings: treatment algorithm for as part of more systemic involvementhowever, with most , hypoglycemia, cases and present ; in childhoodwith or rhabdomyolysis) in and adulthood with weakness. exercise The intolerance (often glycogen-storage diseases present during brief ABSTRACT Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com acids are partlism of and intermediary metabo- extent can by be skeletal oxidized muscle, to a small INTRODUCTION Metabolic myopathies are genetictal skele- musclezymes disorders and thatintermediary impact proteins metabolism en- involvedand of in free fatty acids. Although amino Metabolic Myopathies questioned. First,homozygous the mutations is approximately prevalence2% of in the general population, not directlymetabolism, involved and in itsmetabolic intermediary defect role in in muscle causing is a seriously acid oxidation defectsmyopathy do not but resultneurocognitive rather in delay present orinfancy with regression orexperts in childhood. have Although considereddeaminase some myoadenylate deficiency togroup be of part of metabolic the myopathies,

Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 Metabolic Myopathies

KEY POINT h these have been referred to as the monophosphate, which, through a se- Anaerobic energy sources 7Y9 at the onset of exercise pseudometabolic myopathies. The ries of reactions, culminates in the enzy- include adenylate aforementioned myopathies often ini- matic (xanthine oxidase) conversion of kinase/adenosine tially present with hyperCKemia and xanthine to uric acid under anaerobic monophosphate exercise-induced cramps, , or conditions. Although this pathway is deaminase, rhabdomyolysis, and may progress to a active in normal , it is creatine/, fixed after many accentuated in glycogen-storage disease and anaerobic years. A key to considering a pseudo- (myogenic hyperuricemia) and is help- glycogenolysis/glycolysis. metabolic is the persistence ful from a diagnostic perspective.16 of (CK) elevation beyond Myoadenylate deaminase does not ap- 10 days after a bout of rhabdomyolysis, pear to be essential to muscle contrac- although the CK often normalizes in tion for the reasons noted previously. malignant hyperthermia. Statins can The creatine-phosphocreatine sys- also present with a pseudometabolic tem is important in anaerobic energy pattern.10,11 For example, exercising metabolism, where, during the rest-to- while taking a statin leads to a greater exercise transition, the increase in ADP increase in CK (likely reflective of greater is rephosphorylated by phosphocreatine muscle damage) than the same exer- back to ATP through the cytosolic CK cise in those not taking a statin.10,11 reaction. This reaction results in the Statins can lead to myalgia in up to consumption of a proton that is pro- 10% of individuals, and rhabdomyolysis duced during anaerobic glycolysis and and autoimmune myopathies may oc- glycogenolysis. Phosphocreatine stores cur in a small fraction of patients are high in skeletal muscle, brain, and 12Y14 treated with statins. Statins are also nerves, and phosphocreatine is present contextually relevant in that they can in many other tissues. The phosphocre- unmask a metabolic myopathy as has atinestoresinskeletalmusclearedepleted been described in fatty acid oxidation after approximately 8 to 10 seconds of defects, glycogen-storage disease, and high-intensity muscle contraction and are 15 mitochondrial cytopathies. rephosphorylated during the rest period The current review focuses on the by aerobically derived ATP. This initial metabolic myopathies associated with cytosolic reaction is also important in glycogen-storage diseases, fatty acid ox- initiating mitochondrial respiration be- idation defects, and mitochondrial my- cause the increase in cytosolic ADP trans- opathies (Table 4-1). locates through porin (voltage-dependant For a true clinical understanding of anion channel) to the intermembrane the metabolic myopathies, it is first space where mitochondrial CK uses aer- necessary to review the metabolic path- obically derived ATP to convert creatine ways in the context of exercise and back to phosphocreatine. The resultant physiologic stress. ADP crosses through the adenine nucle- otide translocase to the mitochondrial SKELETAL MUSCLE METABOLISM matrix to stimulate mitochondrial state The rest-to-exercise transition initiates 3 respiration.17 an immediate mass action effect of Within the first few seconds of con- ADP + ADP 9 ATP + AMP through the traction, the activation of glycogenolysis adenylate kinase reaction, where ADP and glycolysis leads to the generation is , ATP is aden- of lactate through the lactate dehydro- osine triphosphate, and AMP is adeno- genase pathway. During the first few sine monophosphate. The flux is minutes of muscle contraction, a progres- maintained in the forward direction by sive increase occurs in mitochondrial myoadenylate deaminase, which cataly- respiration and in the delivery of blood- ses the deamination of AMP to inosine borne substrates to skeletal muscle. As

1830 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS h Aerobic energy is Metabolic Myopathies in Skeletal Muscle TABLE 4-1 predominantly derived from muscle glycogenolysis b Glycogen-Storage Disease (GSD) (glucose) and lipolysis McArdle disease/GSD5 (myophosphorylase deficiency) (free fatty acids) with minor contributions from Tarui disease/GSD7 (phosphofructokinase deficiency) amino acids. The relative GSD9 (phosphorylase b kinase deficiency) proportion of free fatty acid oxidation increases GSD10 (phosphoglycerate mutase deficiency) with longer-duration GSD11 (lactate dehydrogenase deficiency) endurance exercise and fasting. GSD12 ( deficiency) h The specific selection of GSD13 ("- deficiency) intermediary metabolites Phosphoglucomutase deficiency to fuel aerobic muscle contraction is a function Phosphoglycerate kinase 1 deficiency of many factors including b Fatty Acid Oxidation Defect exercise training status, Carnitine palmitoyltransferase II deficiency macronutrient intake (habitual and during Trifunctional protein deficiency exercise), as well as VeryYlong-chain acyl-coenzyme A dehydrogenase deficiency exercise intensity and duration. b h At exercise intensities Mitochondrial encephalomyopathy, , and strokelike episodes (MELAS) below 50% VO2max, Myoclonic epilepsy with ragged red fibers (MERRF) most individuals will oxidize predominantly Chronic progressive external ophthalmoplegia free fatty acids. The Kearns-Sayre syndrome proportion of carbohydrates Complex IV deficiency contributing to energy Cytochrome b mutations supply increases at higher Cytochrome c oxidase mutations exercise intensities.

mitochondrial respiration increases, an 50% VO2max, most individuals will expansion of the tricarboxylic acid cycle oxidize predominantly free fatty acids. intermediates occurs, which allows the The proportion of carbohydrates con- glycolytic and glycogenolytically de- tributing to energy supply increases at rived pyruvate to enter the tricarboxylic higher exercise intensities.19 Most acid cycle via the pyruvate dehydroge- untrained individuals will reach an an- nase pathway.18 aerobic threshold at about 70% of The specific selection of intermediary VO2max, where the anaerobic system metabolites to fuel aerobic muscle con- will be required and both minute ven- traction is a function of many factors tilation and plasma lactate concen- including exercise training status, mac- tration will disproportionately increase. ronutrient intake (habitual and during For well-trained athletes, the anaerobic exercise), as well as exercise intensity threshold can approach 85% VO2max, and duration. Aerobic exercise intensity and the proportionate contribution of is usually measured as a percentage of free fatty acids to energy production will the maximum oxygen consumption also increase at any given absolute (VO2max). At exercise intensities below exercise intensity with endurance

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1831

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

KEY POINTS exercise training.20,21 A small proportion carnitine is added to the acyl group that h In general, women oxidize proportionately of exercise fuel can come from the is then translocated via carnitine more lipids at any relative decarboxylation of amino acids (pri- acylcarnitine translocase to the inner exercise intensity as marily branched-chain amino acids); mitochondrial membrane where carni- compared to men. This however, this is quantitatively less impor- tine palmitoyltransferase II removes the latter point is important in tant (2% to 5% of total energy) than carnitine and adds CoA to the acyl group. fatty acid oxidation carbohydrates and fats.22 In general, The resultant acyl-CoA moiety enters the defects where men tend women oxidize proportionately more mitochondrial matrix, which leads to the to have proportionately lipids at any relative exercise intensity production of one molecule of FADH2 more symptoms than as compared to men.22 This latter and one molecule of NADH + H+ for women, especially point is important in fatty acid oxida- every turn of "-oxidation. The reducing in the case of carnitine tion defects where men tend to have equivalents are then used by the mito- palmitoyltransferase chondria as described in the previous II deficiency. proportionately more symptoms than section. Branched-chain amino acids are h women, especially in the case of carni- Many in the tine palmitoyltransferase II deficiency. first deaminated by branched-chain glycolytic and amino acyltransferase to a keto acid and glycogenolytic pathway The source of carbohydrate for en- are then decarboxylated by branched have been associated ergy provision during exercise is pre- with metabolic dominantly intramuscular glycogen; keto acid dehydrogenase to generate myopathies. In general, however, with longer-duration activity acetoacetate (or propionyl-CoA) and these present with when glycogen stores can become lim- acetyl-CoA that enters the tricarboxylic higher-intensity exercise ited (approximately 2 hours), the pro- acid cycle. and at the onset of portion of oxidized blood-borne glucose exercise initiation. increases. The potential energy from METABOLIC MYOPATHIES carbohydrates is ultimately trapped as The first metabolic myopathy to be flavin adenine dinucleotide hydroge- described was a glycogen-storage dis- nated (FADH2) and adenine ease referred to as McArdle disease in a dinucleotide hydrogenase (NADH + H+) young man with exercise-induced cramps in the tricarboxylic acid cycle, which then in 1951.24 This disorder was due to a provides these reducing equivalents to gene in the myophosphorylase complex I (NADH + H+) and complex II gene (PYGM), which leads to an inability (FADH2), which is then used by the to activate glycogenolysis and signifi- mitochondria to shuttle electrons to com- cant disruption of cellular energy charge plex IV, where oxygen is reduced to water. within the first 10 to 20 seconds of The potential energy from these reducing exercise. Many enzymes in the glycolytic equivalents is used to pump a proton and glycogenolytic pathway have been from the mitochondrial matrix to the associated with metabolic myopathies intermembrane space at complex I, III, (Table 4-1). In general, these present and IV, where the resultant proton motive with higher-intensity exercise and at leads to generation of ATP synthase the onset of exercise initiation. One of at complex V. The source of lipid during the glycogen-storage diseases called exercise comes from intramyocellular Pompe disease (glycogen-storage dis- lipidYderived free fatty acids and blood- ease type 2 [GSD2]) leads to a progres- borneYderived free fatty acids from pe- sive myopathy but does not alter cellular ripheral lipolysis. The free fatty acids are metabolism and will not be further con- transported into muscle through three sidered in this review. different fatty acid transporters with The fatty acid oxidation defects are CD36 being quantitatively the most im- genetic disorders affecting free fatty acid portant.23 Onceinsidethecell,thefree transport (eg, carnitine palmitoyltransferase fatty acids are chaperoned through acyl- II) and "-oxidation (eg, veryYlong-chain coenzyme A (acyl-CoA) synthetase to acyl-CoA dehydrogenase or trifunctional carnitine palmitoyltransferase I, where protein) deficiency. Fatty acid oxidation

1832 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS defects such as medium-chain acyl-CoA tracture (muscle contraction in the ab- h In general, the fatty acid dehydrogenase deficiency or glutaric sence of electrical activity). Usually, oxidation defects present aciduria type II predominantly present significant muscle discomfort occurs after during longer-duration with central symptoms exercise (delayed-onset muscle soreness) exercise, fasting, or and will not be considered in this review. and often pigmenturia. during times of In general, the fatty acid oxidation defects The most common glycolytic disorder superimposed metabolic present during longer-duration exercise, is Tarui disease, which affects the rate- stress such as fever fasting, or during times of superimposed limiting enzyme in the glycolytic pathway or . metabolic stress such as fever or infection. called phosphofructokinase. These pa- h The mitochondrial The mitochondrial ‘‘myopathies’’ refer tients present with symptoms very similar ‘‘myopathies’’ refer to to metabolic genetic defects that affect to patients with McArdle disease as do the metabolic genetic defects the electron transport chain and lead to other rarer forms of glycolytic disorders, that affect the electron exercise intolerance with or without rhab- which include phosphoglycerate kinase 1 transport chain and lead domyolysis or fixed weakness. Like the deficiency, phosphoglucomutase defi- to exercise intolerance fatty acid oxidation defects, mitochon- ciency (also known as congenital disorder with or without rhabdomyolysis or fixed drial myopathies often manifest symp- of glycosylation type IA), GSD10 (phos- weakness. Like the fatty toms during longer-duration activity or phoglycerate mutase deficiency), GSD11 acid oxidation defects, physical activity performed during pe- (lactate dehydrogenase deficiency), mitochondrial myopathies riods of metabolic stress such as fasting, GSD12 (), and often manifest symptoms superimposed fever, flu, or other illness. GSD13 ("-). Phosphory- during longer-duration The next section of this article re- lase b kinase deficiency (GSD9) is a activity or physical activity views the diagnosis and treatment of the glycogenolytic defect that reportedly pre- performed during periods metabolic myopathies with an emphasis sents similarly to McArdle disease; how- of metabolic stress such as on the more common disorders and ever, evidence suggests that the phenotype fasting, superimposed with a clinical emphasis. The metabolic may be mild or nonexistent.25,26 fever, flu, or other illness. myopathies are classified as disorders Clinical presentation. Most patients h Glycogenolytic and of glycolysis/glycogenolysis (glycogen- with disorders of glycolysis/glycogenolysis glycolytic disorders storage diseases), fatty acid oxidation will present with muscle cramps induced usually present with defects, and mitochondrial myopathies. during the first seconds to minutes of muscle cramps during exercise (Case 4-1). The presentation high-intensity activity Disorders of Glycolysis/ often does not occur until the second or and usually in the first few minutes of Glycogenolysis third decade of life but can be even later muscle contraction. All of the glycogen-storage diseases are since most patients adapt to their disor- h autosomal recessive with the exception der by avoiding exercise or starting off at a Patients with McArdle of phosphorylase b kinase deficiency very low intensity of exercise and gradu- disease often report a significant reduction in (GSD9) and phosphoglycerate kinase 1 ally increasing the intensity as aerobic the perception of effort deficiency, which are X-linked recessive metabolism becomes predominant and after a few minutes of disorders. McArdle disease (GSD5) is the blood-borne substrates are delivered to activity co-temporal most common metabolic myopathy (ap- muscle. Patients with McArdle disease with the delivery of proximately 1 in 100,000 individuals), and often report a significant reduction in blood-borne substrates, is due to heterozygous mutations in the the perception of effort after a few which is referred to as PYGM gene. Myophosphorylase initiates minutes of activity co-temporal with the the second wind glycogenbreakdownintherest-to- delivery of blood-borne substrates, which phenomenon. In exercise transition, and as a consequence is referred to as the second wind phe- contrast, patients with there is a huge reliance on the adenylate nomenon.27 In contrast, patients with glycolytic defects do not kinase/myoadenylate deaminase pathway glycolytic defects do not experience the experience the second and phosphocreatine hydrolysis to pro- second wind phenomenon.28,29 wind phenomenon. vide energy during the first 10 seconds Often, patients have a history of of muscle contraction. Symptoms usually pigmenturia (myoglobin in the urine) begin shortly after exercise initiation with due to rhabdomyolysis induced by the muscle pain and eventually a muscle con- severe deficit in energy charge with

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1833

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

KEY POINTS h Most patients with McArdle disease will Case 4-1 have a chronic A 24-year-old woman presented to the emergency department 24 hours after elevation in serum starting a new fitness class involving boot campYlike . She had creatine kinase. experienced painful muscle cramps starting in the first 3 minutes of the class. h The presence of She had lessened the intensity of her exercise, and the cramps had eased up a bit. pigmenturia is an However, the cramps had intensified again after 20 minutes, and she had to important clinical feature leave the class. The patient’s muscles were tight, swollen, and very sore that night, for it can lead to acute and the next morning her urine was reddish brown. renal failure. Other than pain-inhibited proximal muscle weakness, the neurologic h examination was normal. Her serum creatine kinase (CK) level was 300,000 IU/L Patients with McArdle (normal being less than 220 IU/L) in the emergency department, and her disease may report urine was positive for hemoglobin but negative for red blood cells. that they are less She was admitted to the hospital for 4 days and treated with normal saline symptomatic following a and small amounts of added potassium on days 3 and 4. Twenty-four hours after high-carbohydrate meal, admission, the patient’s urine was clear in color, and at discharge, the CK was whereas patients with 40,000 IU/L and her muscle pain was markedly diminished. glycolytic defects often During follow-up at the neuromuscular and neurometabolic clinic 2 weeks feel that their symptoms later, the patient’s neurologic examination was normal, and the CK was down are worse after a to 800 IU/L; however, she did recall that this was elevated in several previous high-carbohydrate meal routine blood tests but no further investigations had been initiated at that time. and feel better after a In retrospect, she had experienced muscle cramps in the first few minutes of prolonged period initiating exercise for most of her life but had ‘‘learned to live with it.’’ Her of fasting. symptoms had improved when she had attended college and had frequently done endurance exercise, but she had not exercised for 2 years prior to the recent 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 in lactate, implying a defect in glycolysis or glycogenolysis. Given the history, a molecular test for five common McArdle disease genes was performed and revealed a homozygous p.Arg49X mutation. Comment. This patient’s history of rhabdomyolysis and a history of similar events in the past with a likely second wind phenomenon is very suspicious for McArdle disease. Furthermore, the chronic CK elevation is a common feature in McArdle disease. Many patients adapt their lifestyle and activities to accommodate the symptoms and often do not seek out medical attention until in their twenties or even later. Her history of being less active and then going back to a gym to rapidly get back into shape is a common scenario that initiates significant rhabdomyolysis and subsequently prompts investigations.

resultant calcium dysregulation, activa- ally a later manifestation of untreated tion of proteolysis, and muscle fiber disease. Patients with McArdle disease necrosis. Patients usually describe the may report that they are less symptom- urine as dark, tea colored, red, and cola- atic following a high-carbohydrate meal, colored due to the presence of muscle- whereas patients with glycolytic defects derived proteins imparting pigment often feel that their symptoms are worse (usually myoglobin). The presence of after a high-carbohydrate meal and feel pigmenturia is an important clinical better after a prolonged period of fast- feature for it can lead to acute renal ing. The family history is usually nega- failure. Some patients experience exces- tive for this condition given that these sive shortness of breath upon exertion, are autosomal recessive disorders. and occasionally patients can develop The neurologic examination is usually fixed muscle weakness, but this is usu- completely normal between episodes

1834 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT with the exception of fixed muscle weak- quently no lactate is produced through h 16 Routine blood chemistries ness in GSD12, which can also occur the lactate dehydrogenase reaction. Usu- between events are often rarely in GSD5 and others. Routine blood ally, a sphygmomanometer cuff is inflated normal; however, creatine chemistries between events are often beyond arterial pressure and isometric kinase is chronically normal; however, CK is chronically ele- rhythmic exercises are performed for elevated in nearly all cases vated in nearly all cases of McArdle dis- 1 minute, followed by release of the of McArdle disease. ease. Some disorders can be associated sphygmomanometer cuff. Lactate and with hemolysis/ (eg, ammonia values are determined prior to GSD7, phosphoglycerate kinase 1 defi- inflating the cuff and immediately post- ciency, GSD12). Many of the glycogeno- inflation. Normally, lactate and ammonia lytic and glycolytic defects are also rise approximately threefold; however, associated with myogenic hyperuricemia, lactate rise is markedly attenuated in the which can lead to gout.30 A summary of glycolytic and glycogenolytic defects. Fail- some key features in the history sug- ure of both lactate and ammonia to rise gesting a diagnosis of a glycogen-storage usually indicates a suboptimal perfor- disease is found in Table 4-2. mance (decreased effort); however, the Diagnostic testing. The classic diag- coexistence of a glycolytic/glycogenolytic nostic test is the forearm exercise test. defect with the common polymorphism With an impairment of glycolysis or gly- in AMPD1 has been reported and can cogenolysis, no pyruvate is produced lead to false-negative testing by mimick- under anaerobic conditions and conse- ing a suboptimal effort. The author of this

TABLE 4-2 Clinical Features Suggesting Specific Metabolic Myopathies

History Disorder (Descending Likelihood) Rhabdomyolysis/pigmenturia Glycogen-storage disease (GSD), fatty acid oxidation defects, mitochondrial myopathies Myalgia 9 cramps with Fatty acid oxidation defects, mitochondrial endurance sports myopathies Shortness of breath with Mitochondrial myopathies endurance sports Myalgia/cramps with power/ Glycogen-storage disease sprint sports Symptoms triggered by fasting Fatty acid oxidation defects, mitochondrial or superimposed illness myopathies Gout Glycogen-storage disease Nausea/vomiting with exercise Mitochondrial myopathies, GSD7 Multiple system involvement Mitochondrial myopathies Family history X-linked Phosphorylase b kinase deficiency, phosphoglycerate kinase 1 deficiency Maternal Mitochondrial myopathies (mitochondrial DNA only) Autosomal recessive/ Carnitine palmitoyltransferase II deficiency, most consanguineous glycogen-storage diseases, nuclear-encoded mitochondrial myopathies

DNA = deoxyribonucleic acid.

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1835

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

KEY POINT article in addition to other investigators further ruled out with the aerobic exer- h A forearm exercise test or aerobic cycle test have found that the blood pressure cuff is cise test previously described. If a normal showing a normal rise in not necessary and that rhythmic contrac- lactate rise occurs with the aerobic exer- serum lactate (greater tion in itself is sufficient to yield optimal cise test, all of the glycolytic and glyco- 31,32 than three times that of sensitivity and specificity. Conse- genolytic defects are ruled out, further baseline) is good for quently, the author recommends the genetic investigations for glycogen-storage ruling out nearly every non-ischemic forearm exercise test to diseases are not warranted, and clinicians genetic defect in the avoid the possibility of rhabdomyolysis should consider one of the other meta- glycogenolytic and and acute compartment syndrome, which bolic myopathies or a pseudometabolic glycolytic pathways. is somewhat more likely if a sphygmoma- myopathy. If the exercise test is positive, a nometer cuff is used. Given the very high targeted or untargeted genetic approach sensitivity and specificity of the forearm would be prudent. A variety of laborato- ischemic test and nonischemic forearm ries offer full sequencing of the coding exercise test, a normal test rules out regions and the intronic boundaries of every glycolytic and glycogenolytic de- the genes for all known glycolytic and fect with the possible exception of glycogenolytic defects. With the advent of phosphorylase b kinase deficiency,25 next-generation sequencing, this ap- which can be further evaluated with the proach is often less expensive than doing aerobic cycling exercise test. There are a single targeted gene (eg, PYGM)using many examples of aerobic cycling tests; Sanger sequencing methods. However, if however, a standard Bruce protocol test alaboratorydoeshavePYGM sequencing used for cardiac evaluation where the available, this would be a prudent first intensity/speed of either a cycle ergometer step given that McArdle disease is the or treadmill is progressively increased most common of the glycogen-storage until voluntary exhaustion with mea- diseases causing a metabolic myopathy. A surement of lactate and ammonia pre/ muscle biopsy is not necessary in a classic post is sufficient. case of glycolytic/glycogenolytic defect Nerve conduction studies and EMG with a positive genetic result; however, a are normal in all of the glycogen- muscle biopsy would be recommended if storage disease disorders except for such testing is negative with the diagnos- the electrical silence during a contrac- tic algorithm described previously. An ture; however, an EMG is rarely neces- advantage of the muscle biopsy is that a sary in the workup of glycogen-storage pattern may be seen that would target diseases. An extensive body of litera- further genetic analysis such as central ture exists that uses exercise magnetic cores (RYR1, CACNA1S mutations), ab- resonance spectroscopy (MRS) to show normal dystrophin staining (dystro- accentuated phosphocreatine hydroly- phinopathy), ragged red fibers sis and the lack of acidosis in muscle in (mitochondrial cytopathy), or membrane- McArdle disease as well as the increase bound glycogen (Pompe disease). The in phosphomonoesters in distal glyco- other potential need for a muscle biopsy lytic defects.33 An issue with MRS is would be the finding of a genetic variant that the test is expensive and requires of uncertain significance in a gene of in- high technical expertise and optimiza- terest (eg, PYGM). In such cases, enzyme tion and, in the author’s opinion, doesn’t analysis of muscle revealing the absence add much to the clinical approach of phosphorylase activity would confirm described herein. the mutation. In other rare cases, an un- If the patient’s history is highly known splicing variant could be further suspicious for a glycolytic/glycogenolytic evaluated with messenger RNA (mRNA) defect and the forearm exercise test is analysis from muscle. A summary of some normal, the remote possibility of phos- of the tests for the glycogen-storage dis- phorylase b kinase deficiency can be eases is presented in Table 4-3.

1836 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Treatment. Many patients adjust intensity and duration while self- their lifestyle activities to mitigate symp- monitoring for symptoms and reducing toms long before a diagnosis is made. the intensity as needed. As expected For example, patients often avoid high- from the well-known physiologic adap- intensity activity and start off activity at a tations that occur with exercise training, low intensity to wait for their second regular exercise has been shown to Y wind. The greatest risk for rhabdomyol- lessen symptoms in McArdle disease.34 36 ysis comes with unaccustomed exercise The consumption of simple sugars or large increases in exercise intensity. containing glucose (glucose, ) Consequently, it is important for pa- shortly before exercise can bypass the tients to start exercise at a lower glycogenolytic metabolic defects.37,38 intensity and to gradually increase the One study found that oral sucrose (37 g)

TABLE 4-3 Testing for Metabolic Myopathies

Disease Testing Glycogen- Serum creatine kinase (CK) is chronically elevated in McArdle storage disease disease; otherwise it is usually normal in the other glycogen-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, absent phosphorylase, or absent phosphofructokinase Genetic testing options Specific mutation analysis: (R49X in È70% of white individuals with McArdle disease) Next-generation sequencing panels for glycogen-storage diseases or myopathy panels with glycogen-storage disease genes or whole-exome sequencing Fatty acid Serum CK usually normal oxidation defects Serum total carnitine often normal Serum acylcarnitine profile often abnormal (fasted or following 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 usually nonspecific findings Continued on page 1838

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1837

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

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

Disease Testing Mitochondrial Serum CK may be chronically elevated myopathy Serum lactate is elevated in È65% Serum 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, high respiratory exchange ratio EMG is often normal Muscle biopsy may show ragged red fibers, cytochrome oxidaseYnegative fibers, or paracrystalline inclusions (electron microscopy) Enzyme analysis on muscle and skin fibroblasts can show mixed or single electron transport chain defects Genetic testing options (usually on muscle tissue) Specific mutation analysis for classic features of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) (m.3243A9G); Leber hereditary optic neuropathy (m.11778G9A, m.14484T9C, m.3460G9A); chronic progressive external ophthalmoplegia (mitochondrial DNA deletion); or myoclonic epilepsy with ragged red fibers (MERRF) (m.8363G9A) Mitochondrial DNA sequencing (if mitochondrial DNA mutation is suspected) Next-generation sequencing targeted mitochondrial panels or whole-exome sequencing (both for nuclear mutations)

DNA = deoxyribonucleic acid; EMG = .

taken 5 to 10 minutes before exercise sequently, they have a secondary de- improved exercise capacity and lessened ficiency of pyridoxine ( B6) symptoms.37 In contrast, patients with because these two have a protein- phosphofructokinase glycolytic defects protein interaction. Consequently, some generally perform better in the fasted have advocated the use of pyridoxine state and are worse off following carbo- supplementation (approximately 50 mg/d) hydrate ingestion because they cannot in patients with null PYGM mutations40,41; use the blood-borne glucose and because however, efficacy has not yet been con- the glucose raises insulin levels that at- firmed in a randomized clinical trial. High- tenuates lipolysis and proteolysis that are protein diets have also been advocated used as alternative fuel sources.39 in an attempt to increase alternative fuel Patients with the most common availability (amino acids); however, this McArdle disease mutation (R49X) have has not been tested in a randomized no protein expressed because of controlled trial. Furthermore, branched- nonsense-mediated mRNA decay; con- chain supplements did not

1838 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. show a benefit.42 Creatine monohydrate being carnitine palmitoyltransferase II in low to moderate doses (approximately deficiency (approximately 1 in 250,000 0.1 g/kg/d) did show bioenergetic im- individuals), trifunctional protein defi- provements during exercise in patients ciency, and veryYlong-chain acyl-CoA with McArdle disease43; however, higher dehydrogenase deficiency. doses of creatine monohydrate led to Clinical presentation. Unlike the exercise impairment.43 Although GSD3 true cramping symptoms experienced (debranching enzyme) is considered to by the glycolytic/glycogenolytic defects, be a glycogen-storage disease associated the fatty acid oxidation defects usually with fixed weakness, a recent study present with exercise-induced myalgia. showed improvements in exercise capac- The patients may experience pig- ity with pre-exercise ingestion.44 menturia later on in the same day or Finally, D-ribose, verapamil, and within 24 hours of exercise due to dantrolene were not effective in treating rhabdomyolysis. Most patients do have McArdle disease.45 In fact, adverse events delayed-onset muscle soreness for several or worsening of symptoms were ob- days following a bout of rhabdomyolysis. served with oral D-ribose (diarrhea and The symptoms are often precipitated by hypoglycemia symptoms) and dantrolene prolonged fasting, prolonged exercise, (fatigue, vertigo, and muscle weakness).45 or superimposed illness (Case 4-2). One study found mild improvements in Often, children have myalgia and occa- exercise capacity and improved symp- sionally pigmenturia during fever or toms in patients with a deletion-deletion vomiting (fasting) and will only notice haplotype for angiotensin-converting the exercise-induced symptoms in their enzyme following treatment with 2.5 mg teenage years when they do longer- of ramipril.46 In summary, studies pro- duration activities (Table 4-2). vide some support for the use of low- Diagnostic testing. Blood testing is dose creatine monohydrate, pre-exercise usually completely normal for CK, lac- sucrose/glucose, ramipril (only in the case tate, and glucose between episodes of of the deletion-deletion polymorphism), rhabdomyolysis. During an acute bout and possibly a high-carbohydrate diet.45 of rhabdomyolysis, an increase in CK Although vitamin B6 (pyridoxine) is not starts within a few hours, during which universally beneficial, a low dose may and hypoketotic hypogly- not be imprudent in patients who have cemia can occur. Following a bout of null phosphorylase mutations and have rhabdomyolysis, acute renal failure can relative pyridoxine deficiency (Table 4-4). occur with elevations of potassium, , and urea. The most sensitive Fatty Acid Oxidation Defects and specific test for a fatty acid oxida- Fatty acids are generally categorized tion defect is the acylcarnitine profile according to the number of carbons into performed by liquid chromatographyY short-chain (two to four), medium-chain tandem mass spectrometry. This test (six to 12), long-chain (14 to 18), and may be abnormal between acute events; veryYlong-chain (20 or more) fatty acids. however, a false-negative test can occur in The oxidation of long-chain and veryYlong- a nonstressed situation. The author of chain free fatty acids requires the carni- this article usually prefers that patients tine palmitoyltransferase system, whereas come in in the fasted state in the short- and medium-chain free fatty acids morning, which tends to increase the can directly enter the mitochondrial diagnostic yield. Additionally, this test matrix for "-oxidation. All of the currently should be sent if a fatty acid oxidation known clinically relevant fatty acid oxida- defect is suspected during an acute tion defects are autosomal recessive dis- metabolic crisis. Often, the specific acyl- orders with the three most common carnitine signature can target a specific

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1839

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

KEY POINT h Unlike the true cramping Metabolic Myopathy Treatments symptoms experienced by TABLE 4-4 the glycolytic/glycogenolytic a defects, the fatty acid Disease Treatment oxidation defects Glycogen-storage Careful and progressive exercise training usually present with disease Pre-exercise sucrose/glucose in glycogenolytic defects exercise-induced myalgia. (eg, McArdle disease) The patients may experience pigmenturia Overnight fasting for glycolytic defects later on in the same day or (eg, phosphofructokinase deficiency or Tarui disease) within 24 hours of exercise Creatine monohydrate (0.1 g/kg/d), NOT higher dose due to rhabdomyolysis. Consider pyridoxine 50 mg/d in patients with null phosphorylase mutations (eg, R49X mutations) Fatty acid oxidation Careful and progressive exercise training; no exercise defects during illness Avoid fasting L-carnitine (only if low or in SLC22A5 mutation transporter defect); start at 330 mg 2 times per day High-carbohydrate diet Carbohydrate before and during exercise Consider triheptanoin Mitochondrial Careful and progressive exercise training; no exercise myopathy during illness Avoid fasting

Cocktail treatment consists of or (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 times per day and retest

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

genetic mutation for subsequent gene acid oxidation defect is suspected and if analysis. Total and free carnitine levels plasma acylcarnitine profiling in the fasted may be secondarily abnormal; however, state is nonrevealing. If the acylcarnitine very low levels of these are usually seen in profile or history are strongly suspicious systemic carnitine deficiency due to mu- for a fatty acid oxidation defect, specific tations in OCTN2/SLC22A5 genes.47 genetic testing for the defect can be Urine testing during rhabdomyolysis carried out using Sanger sequencing of will often show a positive hemoglobin exons and intron-exon boundaries. More test with negative red blood cells on recently, next-generation sequencing has microscopy that reflects the myoglobin allowed the use of panels that cover the in the urine. Urine organic acid analysis more common fatty acid oxidation de- may also show an elevation of specific fects leading to rhabdomyolysis (carnitine dicarboxylic acids in "-oxidation defects. palmitoyltransferase II, trifunctional pro- The acylcarnitine profile can also be tein, veryYlong-chain acyl-CoA dehydro- assessed in fibroblast culture if a fatty genase) and some of the less common

1840 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Case 4-2 h A normal serum acylcarnitine level during A 56-year-old man presented to the neuromuscular and neurometabolic clinic fasting or following an with a history of Tarui disease. The patient requested exercise advice as he acute bout of wanted to join a cycling club. He and his sister had been given a diagnosis of rhabdomyolysis is a good Tarui disease in South Africa decades before after each had experienced a bout test for ruling out a fatty of rhabdomyolysis. The diagnosis had not been confirmed genetically and acid oxidation defect, and appeared to be based upon the fact that they both had rhabdomyolysis with an abnormal test pattern exercise and were of Ashkenazi Jewish descent. In retrospect, he did recall that can often suggest a as a child he could not walk to the synagogue during Yom Kippur (which specific genetic diagnosis. includes a 25-hour fast) due to myalgia. He also noted that he could not lift weights or do chores if he was ill or fasting. He also found that if he rode his bike h Most patients with a fatty after eating, especially if he had eaten some honey, he felt much better. acid oxidation defect will His neurologic examination was normal. With this history, a fasting have symptoms during acylcarnitine profile was sent and blood was banked for DNA. The acylcarnitine fasting, illness or fever, or profile showed a pattern of long-chain acyl-coenzyme A moieties characteristic during longer-duration for carnitine palmitoyltransferase II deficiency. The DNA was then sent for a physical activity. 5-gene common carnitine palmitoyltransferase mutation panel, which returned positive for a homozygous p.Ser113Leu common carnitine palmitoyltransferase II mutation. After this visit, the patient continued another 15 years without any bouts of rhabdomyolysis by avoiding activity during illness and fasting and by consuming a high-carbohydrate diet. He was able to cycle with a local club up to 80 km on the weekends with a preride meal and the consumption of glucose-based gels and other carbohydrate sources during the ride. Comment. The history of symptoms during fasting and improvements in exercise capacity with feeding and carbohydrate supplements is characteristic of a fatty acid oxidation defect and the opposite of what would be expected in a patient with Tarui disease (phosphofructokinase deficiency). Furthermore, the patient had symptoms with longer-duration exercise that would also be more characteristic of a fatty acid oxidation defect as opposed to a glycolytic or glycogenolytic disorder. Homozygosity for mutations is common in restricted populations where the possibility of remote consanguinity is higher. fatty acid oxidation defects associated lactate rise would be suspicious for a with exercise-induced rhabdomyolysis glycolytic/glycogenolytic defect and the (medium-chain acyl-CoA dehydrogenase postexercise acylcarnitine profiling can deficiency, carnitine acylcarnitine tran- sometimes reveal the specific fatty acid slocase deficiency). Recurrent rhabdo- oxidation defect. Furthermore, high rest- myolysis in the face of fever and ing lactate and a low VO2max with a high superimposed illness can also be seen in respiratory exchange ratio during cycle cases of LPIN1 deficiency (a magnesium- ergometry can indicate a mitochondrial dependent phosphatidic acid phos- myopathy. Muscle biopsy is usually not phohydrolase). To date, LPIN1 mutations required for the workup of a suspected have not been associated with exercise- fatty acid oxidation defect; however, induced rhabdomyolysis. muscle tissue may show a nonspecific In cases where the fasting acylcar- increase in neutral lipid, and this is felt nitine profile is normal, the author to be quite a nonspecific and subjec- usually carries out an aerobic exercise tive impression. Nerve conduction veloc- test on a cycle ergometer in the fasted ity and EMG testing is often normal in state with pre- and postexercise lactate fatty acid oxidation defects; however, a and postexercise acylcarnitine profiling. myopathic picture (small brief early This is helpful in that an attenuated recruiting potentials) can be seen for up

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1841

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

KEY POINTS to 10 days following an acute bout of oxidation; however, the production of h A high-carbohydrate diet and possibly rhabdomyolysis, occasionally with fibrilla- reactive oxygen species may play a path- carbohydrate consumption tions, positive sharp waves, and complex ogenic role. As the final common pathway during exercise may repetitive discharges. A mixed axonal for fat and carbohydrate oxidation, the attenuate symptoms of a neuropathy can be seen in rare cases of symptoms of mitochondrial myopathies fatty acid oxidation defect. long-chain 3-hydroxyacyl-CoA dehydro- often manifest themselves during periods h Mitochondrial disorders genase deficiency (Table 4-3). of high metabolic demand such as fasting, often affect more than Treatment. Most patients avoid trig- superimposed illness, or longer-duration one tissue or organ gers of their disease such as exercising exercise. Given that mitochondria are system due to the in the fasted state, exercising with a present in all tissues with the exception ubiquitous distribution of superimposed illness, and long-duration of red blood cells, multisystemic manifes- the mitochondria. exercise. Most patients generally tend to tations of the disease often occur from choose higher-carbohydrate foods espe- tissues with a high metabolic demand cially immediately before and during such as heart, brain, skeletal muscle, and long-term endurance exercise, and a nerves (especially cranial nerves II and relatively low-fat (less than 30%) higher- VIII). The term mitochondrial cytopathy carbohydrate diet is recommended. A is the preferred term for patients with carbohydrate-enriched diet improved multisystemic clinical manifestations, and exercise tolerance in patients with carni- the term mitochondrial myopathy is tine palmitoyltransferase II deficiency,48 used when skeletal muscle is the pre- whereas oral glucose did not.49 The dominant tissue involved. Although fixed administration of vitamin B2 (), weakness can be a manifestation of a medium-chain triglyceride oil, and mitochondrial myopathy, the current L-carnitine has been advocated50,51 but review will focus on the metabolic none have been proven in a clinical trial; function of skeletal muscle and the however, replacement of L-carnitine resultant exercise intolerance with or Y would be prudent if patients are found without rhabdomyolysis.57 59 to be deficient. The use of bezafibrate Mitochondria are cellular organelles (not available in the United States) has that likely evolved from photosynthetic been suggested52; however, Class I evi- bacteria that took on a symbiotic rela- dence now suggests this is not effective tionship with a proto-eukaryotic cell in carnitine palmitoyltransferase II defi- nearly 1.5 billion years ago. Through ciency.53 The use of triheptanoin (odd evolution, the DNA encoding for most chain free fatty acid) has been shown to of the approximately 1200 proteins re- improve energy production in cells from quired by a are part of patients with fatty acid oxidation de- the nuclear DNA and imported into the fects.54,55 Triheptanoin has been shown mitochondria through a transport sys- to reduce hospitalizations in a retrospec- tem. The mitochondrial DNA (mtDNA) tive study56 and was also shown to is a maternally inherited small (16,569 improve exercise capacity.55 Asummary base pairs) circular, double-stranded of some of the treatment options is molecule that resembles bacterial DNA. present in Table 4-4. The mtDNA composition is highly con- served across species and encodes for Mitochondrial Myopathies two ribosomal RNAs, 22 transfer RNAs, Mitochondrial myopathies are a diverse and 13 protein encoding mRNAs. Mito- group of genetic disorders with a pri- chondrial replication is dependent mary defect in electron transport chain upon many nuclear encoded proteins function. The metabolic consequences such as polymerase-+ (POLG1) and is of mitochondrial dysfunction result pri- not dependent upon the cell cycle. marily from a decrease in aerobic energy Consequently, mitochondrial biogenesis production from fat and carbohydrate can occur in postmitotic cells such as

1842 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. skeletal muscle in response to stimuli In general, a higher level of mutant het- such as exercise. eroplasmy is associated with more severe Each mitochondrion contains several and earlier-onset symptoms and tissue mtDNA copies, and hundreds to thou- biochemical pathology. sands of mitochondria are present in Clinical presentation. Mitochondrial every cell, roughly in proportion to the myopathies are notorious for the ex- aerobic needs of the cell. The mtDNA is treme phenotypic and genotypic het- maternally inherited whilst all nuclear erogeneity. A classic example is MELAS mitochondrial genes follow mendelian syndrome, where people within the inheritance rules. The first mutations same family may present with adult- that were found in mtDNA in 1988 and onset deafness and diabetes, while 1989 were point mutations at posi- others may present with any combina- tion 3243 (m.3243A9G) and 11,778 tion of , seizures, cardiomyopa- (m.11778G9A) responsible for mito- thy, short stature, dementia, and severe chondrial encephalomyopathy, lactic exercise intolerance. In contrast, pa- acidosis, and strokelike episodes (MELAS) tients with the same phenotype (eg, and Leber hereditary optic neuropathy as chronic progressive external ophthal- well as a large-scale deletion seen in moplegia) may have a sporadic mtDNA Y Kearns-Sayre syndrome.60 62 mtDNA deletion, a nuclear encoded mtDNA contains many benign polymorphisms maintenance gene mutation, or a specific that may contribute to evolutionary bio- mtDNA point mutation. logical fitness,63 and some define the Many patients with mitochondrial mitochondrial haplotypes, but these can cytopathies and myopathies will have be a challenge when a variant of uncer- limitations in exercise capacity because tain significance is found with mtDNA of a low VO2max. The protean manifes- sequencing. The number of pathogenic tations of the disorder (eg, seizures, mtDNA mutations described in the past encephalopathy, cardiomyopathy) may 2 decades has been substantial. In ad- overshadow exercise intolerance. For dition, the number of nuclear encoded example, we found a severely reduced genes linked to mitochondrial cytopathies/ VO2max (9.2 mL/kg/min, normal being myopathies has dramatically increased 32 mL/kg/min) in seven patients with because of the advent of next-generation MELAS and yet none of them presented sequencing (see the MITOMAP human with exercise intolerance as the pres- mitochondrial database at www. enting symptom.64 In retrospect, the mitomap.org/MITOMAP). aforementioned patients often reported Some diseases such as Leber hered- that they were ‘‘last in sports’’ or ‘‘the itary optic neuropathy affect all copies worst athlete in the class.’’ Most pa- of mtDNA and are termed homoplasmic; tients with mitochondrial myopathies however, having a variable proportion of report shortness of breath and pre- mutant to wild-type mtDNA copies within mature fatigue during exertion that is a tissue is more common, which is often exacerbated with superimposed referred to as . Because of infection or fasting; however, some replicative segregation that occurs within patients may also have exertional nausea and between tissues during embryogene- and vomiting. A few cases of temporary/ sis, the heteroplasmy can be very differ- partial visual loss and/or hearing loss ent between tissues. Furthermore, the during exertion have also been ob- mutant heteroplasmy does tend to be served by the author in patients with lower in tissues with rapid turnover, such MELAS (Case 4-3). In contrast to the lay as blood cells, while maintaining a con- perception and biological plausibility, stant level in more terminally differenti- most patients do not report symp- ated tissues, such as muscle and brain. toms of fatigue and tiredness at rest

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1843

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

KEY POINTS h A normal serum lactate level does not rule out Case 4-3 in A 46-year-old woman presented to the neuromuscular and neurometabolic clinic adults or children. with a history of exercise-induced deafness and stomach discomfort that she h A high serum lactate in had experienced for several years. The referral was also prompted by the fact that adults is suggestive of her eldest daughter underwent a heart transplant for severe hypertrophic cardiomyopathy and experienced severe postoperative lactic acidemia (up to mitochondrial disease, 20 mmol/L, with the normal range being 2.2 mmol/L) with no identified cause whereas a high lactate 1 month prior to the evaluation. Her mother and her maternal grandmother had level in children can be a died of ‘‘encephalitis’’ in their midforties based on a history of rapid-onset false positive due to seizures and strokelike episodes for which no cause had been identified. She had struggling or difficulties short stature (less than the third percentile) and her neurologic examination taking the blood. showed mild proximal weakness (4 out of 5) for hip flexors and shoulder abductors. Serum lactate was mildly elevated at 3.1 mmol/L (normal range being less than 2.2 mmol/L). Muscle biopsy showed a few ragged red fibers (approximately 2%), and mitochondrial DNA (mtDNA) testing from the muscle biopsy sample using polymerase chain reaction (PCR)Yrestriction fragment length polymorphism for three common mutations (m.3243A9G, m.3260A9G, and m.3271T9C) revealed 86% heteroplasmy for the m.3260A9G mutation. The patient’s blood heteroplasmy for m.3260A9G was 22%. Subsequent testing in her three daughters showed that blood mtDNA mutant heteroplasmy for the m.3260A9G mutation was 55%, 48%, and 60%, respectively. The patient went on to have a severe temporooccipital strokelike episode with complete homonymous hemianopsia, severe dysphasia, and acalculia 1 year after the initial diagnosis that completely resolved after 3 months. Comment. This patient’s family history was suggestive of maternal inheritance of neurologic symptoms that prompted mtDNA analysis. The exercise intolerance and exercise-induced deafness had been attributed by the patient to ‘‘just being out of shape,’’ and she did not seek medical attention for it until her daughter’s postoperative course. A higher mutational heteroplasmy level in muscle-derived mtDNA versus blood-derived mtDNA is a common feature of mitochondrial disease that can lead to a missed diagnosis if mtDNA testing is only done on blood samples.

with any greater frequency than com- episodes, head and neck lipomas, periph- monly seen in the general population. eral neuropathy, , cardiomyopathy, Unlike fatty acid oxidation defects or cardiac conduction block, and intestinal glycogen-storage diseases where rhab- pseudoobstruction. Fixed weakness may domyolysis and pigmenturia are com- also be seen with or without an elevated mon, most patients with mitochondrial CK that can mimic muscular dystrophy myopathy do not experience such or . A positive ma- events. Rhabdomyolysis has, however, ternal family history with any number been seen in cases of cytochrome b, of the previously described signs and cytochrome c oxidase, and MELAS symptoms is helpful to rule in an mtDNA- m.3260A9Gmutations.65Y67 based mitochondrial myopathy, but a Other signs and symptoms often negative family history cannot be used occur that suggest a mitochondrial dis- to rule out a mitochondrial myopathy ease diagnosis such as hypoacusis, short given that many are autosomal recessive stature, ptosis, ophthalmoparesis, type 2 (Table 4-2). diabetes mellitus, migraine variant head- Diagnostic testing. Testing for mito- aches, seizures, strokes and strokelike chondrial myopathy is complex and

1844 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT somewhat controversial; however, most drome, fibromyalgia). Forearm non- h The muscle biopsy is more experts agree that a systematic and ischemic testing linked with near helpful in the analysis of multiple testing approach is required. infrared spectroscopy or venous blood mitochondrial myopathies Serum/plasma lactate is an important gas measurements has been used to as compared to fatty acid blood test for the evaluation of a sus- demonstrate the failure of deoxygenation oxidation defects and pected mitochondrial myopathy. The secondary to a mitochondrial defect.70,71 glycogen-storage diseases. lactate concentration is elevated in For example, the venous blood oxy- approximately 65% of adult patients gen content at rest is usually 28 mm Hg with mitochondrial myopathy (sensiti- to 48 mm Hg, and this drops after ex- vity) and normal in over 90% of people ercise because of deoxygenation, which without mitochondrial myopathy (speci- imparts a dark purple/black color to the ficity).16 It is important to take the blood blood in healthy people; in contrast, no to the laboratory while it is on ice and drop or even a slight increase in oxygen- analyze promptly to avoid false-positive ation (arterialization) of the venous results. Other causes of false-positive blood occurs after exercise in patients results include diabetes mellitus, difficult with a mitochondrial myopathy. Phos- blood draws (eg, struggling, prolonged phorus (31P) MRS has also been used to tourniquet use), and if the patient has show rapid phosphocreatine hydrolysis, recently (within less than 1 hour) con- an increase in lactate during exercise, or sumed a high-carbohydrate meal. Serum a delayed ATP recovery following exer- CK activity is often normal but will be cise33,72; however, exercise MRS is best elevated after rhabdomyolysis and in a used by specialized centers. fraction of patients in whom the eleva- EMG is often normal in the mito- tion is usually less than three times the chondrial myopathies but may show a upper limit of normal. CK levels higher nonspecific myopathic pattern with than this should prompt consideration small, brief, early recruiting action po- of a muscular dystrophy. About 50% tentials. EMG is perhaps best used as a of patients with MELAS will have type tool to rule out myotonic disorders and 2 diabetes mellitus or impaired oral glu- muscular dystrophies if the diagnosis is cose tolerance. Plasma amino acid testing not clear. Similarly, nerve conduction can reveal an elevated alanine, especially if studies are often normal in mitochon- taken after an aerobic exercise test. Urine drial myopathies but may show an organic acid analysis may reveal elevations axonal sensory (eg, POLG1 mutations) of 3-methylglutaconic acid or the tricar- or sensorimotor neuropathy (eg, myo- boxylic acid intermediates (fumarate, clonic epilepsy with ragged red fibers malate, citrate). [MERRF]; mitochondrial neurogastro- Cycle ergometry exercise testing in intestinal encephalomyopathy [MNGIE]; mitochondrial myopathies may demon- and neuropathy, ataxia, retinitis pig- strate a low VO2max, or a high respiratory mentosa [NARP] syndrome). exchange ratio (indicative of early lactate The muscle biopsy is more helpful in production), or both.68 The author of the analysis of mitochondrial myopa- this article has tended to do far fewer thies as compared to fatty acid oxidation exercise tests recently because of the defects and glycogen-storage diseases large number of false-positive tests that for several reasons. First, the histologic are due to physical inactivity associated changes may give a clue to the genetic loss of mitochondrial enzyme activity.69 defect. For example, the presence of Hypodynamia is a secondary manifesta- ragged red fibers (subsarcolemmal ac- tion of nearly every myopathy seen in cumulation of mitochondria on modi- the clinic but is also a very common fied Gomori trichrome staining) or consequence of many common disorders cytochrome c oxidaseYnegative fibers (eg, immobilization, chronic fatigue syn- can suggest an mtDNA mutation. The

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1845

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

presence of ragged blue fibers (succi- a defect. Muscle is the ideal tissue to use nate dehydrogenase plus cytochrome c for mtDNA testing; a moderate to high oxidase staining combined) is also level of mutant heteroplasmy in a known suggestive of an mtDNA mutation. The gene can establish the diagnosis. Blood finding of strongly positive succinate is not ideal for mtDNA analysis because dehydrogenaseYstained blood vessels is of lower or nondetectable mutational suggestive of MELAS syndrome. Second, heteroplasmy or mtDNA deletions. Var- skeletal muscle is the ideal choice for iants of uncertain significance do re- DNA extraction for mtDNA analysis in a quire more sophisticated evaluation in a suspected mitochondrial myopathy as research-based laboratory. Long-range mtDNA deletions are notoriously absent PCR has been used to screen muscle in blood and mtDNA heteroplasmy is for mtDNA deletions given that a nega- often very low to nondetectable in blood. tive test rules out disease (high sensitiv- Finally, the muscle biopsy is a good ity) and a positive test can be followed source for electron transport chain en- up with more definitive testing such as zyme analysis given that some mito- next-generation sequencing or ND1/ chondrial myopathies do not manifest ND4 ratios (specific regions within the enzymatic defects in fibroblasts or white mtDNA) with PCR. Next-generation se- blood cells. The author of this article quencing panels are rather popular, recommends electron microscopy in and are currently able to screen dozens every case of suspected mitochondrial to hundreds of nuclear encoded genes disease for it can reveal mitochondrial at once; however, with the lower cost alterations (eg, pleomorphic mitochon- of next-generation sequencing and the dria, paracrystalline inclusions, abnor- discovery of many new genes associated mal cristae) before the light microscopic with mitochondrial cytopathies (eg, changes are evident.73 combined oxidative Many ways exist to evaluate electron defects are now up to 26 recently dis- transport chain enzyme activity/protein covered genes), many experts are using content; however, most centers use whole-exome sequencing with next- spectrophotometric methods in skeletal generation sequencing methodology muscle homogenates or isolated mito- (Table 4-3). chondria.58,74 Single enzyme defects Treatment. Mitochondrial myopa- are often seen in complex assembly genes thies lead to a reduction in aerobic (eg, SCO2) or with mutations in specific energy transduction, increased free rad- electron transport chain subunits, while ical production, and a greater reliance multiple defects can be seen in transfer on alternative energy stores (eg, phos- RNA mutations or mutations in genes phocreatine). Therefore, interventions involved in mtDNA maintenance (eg, have usually focused on ameliorating POLG1) or any of the many recently dis- one or several of these consequences. covered genes under the umbrella of com- Attempts to bypass specific electron bined oxidative phosphorylation defects. transport chain complex impairments A large number of genetic testing have included succinate and riboflavin to methods are available for diagnosis of bypass complex I and coenzyme Q10 to mitochondrial myopathy; however, most bypass complex I and II. are being replaced by next-generation have been heavily studied, including sequencing because of cost and through- vitamin E, vitamin C, "-lipoic acid, 58,75 76 put reasons. mtDNA sequencing idebenone, and coenzyme Q10. Crea- (next-generation sequencing or Sanger tine monohydrate has been used to pro- sequencing) of the entire mtDNA is a fast vide an alternative energy source with and easy way to screen for mtDNA mu- variable success.64,77 The most common tations if the testing is suggestive of such approach is the use of a combination of

1846 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT compounds that target multiple final the glycogen-storage diseases present h 59,78,79 Exercise and resistance common pathways of mitochondria. early on during high-intensity exercise exercises are effective There have been very few randomized, whereas the fatty acid oxidation defects therapies for some double-blind, controlled clinical trials and mitochondrial myopathies usually pre- patients with metabolic in mitochondrial myopathies but we sent during longer-duration/endurance myopathies but must be have shown some objective benefits type activities or during fasting or other individualized and titrated to exercise capacity with creatine acute illness. Clinical examination is usu- to tolerance. 64 76 monohydrate, coenzyme Q10, and ally normal in the glycogen-storage dis- combined coenzyme Q10 plus vitamin E, eases or fatty acid oxidation defects but "-lipoic acid, and creatine mono- can show other neurologic features in hydrate.78 Some visual improvement patients with mitochondrial myopathies was noted in patients with Leber he- (ptosis, external ophthalmoplegia, hypo- reditary optic neuropathy using acusis, visual loss, ataxia, neuropathy). idebenone80,81; however, no exercise The clinical examination can be sup- outcomes were reported, and most plemented by blood (CK, lactate, uric patients with Leber hereditary optic acid, amino acids, acylcarnitine) and urine neuropathy do not have myopathic tests (organic acids). symptoms. Some evidence exists that a A relatively simple nonischemic coenzyme Q10 analogue called EPI-743 forearm exercise test can be readily done may have therapeutic potential82;how- in most clinics and is helpful to rule in or ever, randomized double-blind studies rule out several of the metabolic myo- are needed.83 Studies have found lower pathies. The author of this article uses a lactate and some exercise improve- 22 Ga plastic catheter in the antecubital ments in patients with mitochondrial vein and a three-way stop cock and myopathy using a drug called dichlo- takes resting samples (on ice) for CK, roacetate that activates pyruvate dehy- lactate, ammonia, acylcarnitines, and drogenase84; however, safety concerns blood gas (the latter only if mitochon- have raised serious questions about drial disease is suspected). Following 83,85 long-term clinical utility. this, the author instructs the subjects to As expected, significant improve- perform 30 contractions in 60 seconds ments in exercise capacity and quality of (1 second on:1 second off or 9 seconds life have occurred with endurance exer- on:1 sec off repeated six times) and takes cise training in patients with mitochon- 86Y89 apostexercisesampleafter1minutefor drial myopathy. One study found lactate, ammonia, acylcarnitines, and significant improvements in strength blood gas (optional). A normal test rules following a resistance exercise program out essentially all glycogen-storage dis- in patients with predominantly chronic eases, and a normal resting lactate and progressive external ophthalmoplegia.90 normal deoxygenation lowers the post- Studies in both endurance and resistance exercise appear to be safe86,87,90 and also test probability of mitochondrial disease. appear to improve both mitochondrial A normal acylcarnitine level before and enzyme capacity86,88 as well as reduce after exercise in the fasted state lowers the mutational burden in sporadic mito- the posttest probability of a fatty acid oxi- chondrial myopathies.91 Asummaryof dation defect. If these tests do not provide some of the possible treatments is present a high likelihood of a specific disorder for in Table 4-4. genetic testing, clinicians can then consid- er a graded exercise stress test with VO2max CONCLUSION and respiratory exchange ratio measure- A detailed history of the triggering mentsaswellasthebloodtestsmen- symptoms often points to a specific type tioned previously (except blood gases). A of metabolic myopathy. For example, muscle biopsy should be considered in

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1847

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

cases without a definitive diagnosis in Neurol 2007;64(8):1176Y1182. doi:10.1001/ archneur.64.8.1176. whom weakness and a high CK are found or if there is a high index of suspicion for 10. Parker BA, Augeri AL, Capizzi JA, et al. Effect of statins on creatine kinase levels before a mitochondria myopathy. and after a marathon run. Am J Cardiol Prompt and accurate identification of 2012;109(2):282Y287. doi:10.1016/ the specific metabolic myopathy can lead j.amjcard.2011.08.045. to effective therapies such as lifestyle 11. Thompson PD, Gadaleta PA, Yurgalevitch S, et al. modification, nutritional intervention, co- Effects of exercise and lovastatin on serum creatine kinase activity. Metabolism 1991;40(12): factor treatment, and proper exercise 1333Y1336. doi:10.1016/0026-0495(91)90039-Y. prescription in order to prevent or delay 12. Stolcpart RS, Olson KL, Delate T, et al. The risk rhabdomyolysis and eventual muscle weak- for significant creatine kinase elevation with ness. An accurate diagnosis is also impor- statins. Am J Cardiovasc Drugs 2010;10(3): tant from a genetic counseling perspective. 187Y192. doi:10.2165/11536130-000000000-00000. 13. Thompson PD, Clarkson P, Karas RH. REFERENCES Statin-associated myopathy. JAMA 2003;289(13): Y 1. Phillips SM, Atkinson SA, Tarnopolsky MA, 1681 1690. doi:10.1001/jama.289.13.1681. MacDougall JD. Gender differences in 14. Wu Y, Lach B, Provias JP, et al. Statin-associated kinetics and nitrogen balance in endurance athletes. autoimmune myopathies: a pathophysiologic Y J Appl Physiol (1985) 1993;75(5):2134 2141. spectrum. Can J Neurol Sci 2014;41(5):638Y647. 2. Fishbein WN, Armbrustmacher VW, Griffin JL. doi:10.1017/cjn.2014.22. Myoadenylate deaminase deficiency: a new 15. Vladutiu GD, Simmons Z, Isackson PJ, et al. Genetic disease of muscle. Science 1978;200(4341): risk factors associated with lipid-lowering Y 545 548. doi:10.1126/science.644316. drug-induced myopathies. Muscle Nerve Y 3. Landau ME, Kenney K, Deuster P, Campbell W. 2006;34(2):153 162. doi:10.1002/mus.20567. Exertional rhabdomyolysis: a clinical review 16. Tarnopolsky M, Stevens L, MacDonald JR, et al. with a focus on genetic influences. Diagnostic utility of a modified forearm J Clin Neuromuscul Dis 2012;13(3):122Y136. ischemic exercise test and technical issues doi:10.1097/CND.0b013e31822721ca. relevant to exercise testing. Muscle Nerve Y 4. Gross M, Ro¨ tzer E, Ko¨ lle P, et al. A G468-T 2003;27(3):359 366. doi:10.1002/mus.10330. AMPD1 mutant allele contributes to the high 17. Terjung RL, Clarkson P, Eichner ER, et al. incidence of myoadenylate deaminase American College of Sports Medicine deficiency in the Caucasian population. roundtable. The physiological and health Neuromuscul Disord 2002;12(6):558Y565. effects of oral creatine supplementation. Med doi:10.1016/S0960-8966(02)00008-1. Sci Sports Exerc 2000;32(3):706Y717. 5. Norman B, Nygren AT, Nowak J, Sabina RL. doi:10.1097/00005768-200003000-00024. The effect of AMPD1 genotype on blood flow 18. Gibala MJ, MacLean DA, Graham TE, Saltin B. response to sprint exercise. Eur J Appl Anaplerotic processes in human skeletal muscle Physiol 2008;103(2):173Y180. doi:10.1007/ during brief dynamic exercise. J Physiol 1997; s00421-008-0683-0. 502(pt 3):703Y713. doi:10.1111/j.1469-7793. 1997.703bj.x. 6. Tarnopolsky MA, Parise G, Gibala MJ, et al. Myoadenylate deaminase deficiency does not 19. Romijn JA, Coyle EF, Sidossis LS, et al. Substrate affect muscle anaplerosis during exhaustive metabolism during different exercise intensities exercise in humans. J Physiol 2001;533(pt 3): in endurance-trained women. J Appl Physiol 881Y889. doi:10.1111/j.1469-7793.2001. (1985) 2000;88(5):1707Y1714. t01-1-00881.x. 20. Phillips SM, Green HJ, Tarnopolsky MA, et al. 7. Lahoria R, Winder TL, Lui J, et al. Novel ANO5 Effects of training duration on substrate homozygous microdeletion causing myalgia turnover and oxidation during exercise. and unprovoked rhabdomyolysis in an Arabic J Appl Physiol (1985) 1996;81(5):2182Y2191. man. Muscle Nerve 2014;50(4):610Y613. 21. Phillips SM, Green HJ, Tarnopolsky MA, et al. doi:10.1002/mus.24302. Progressive effect of endurance training on 8. Veerapandiyan A, Shashi V, Jiang YH, et al. metabolic adaptations in working skeletal Pseudometabolic presentation of dystrophinopathy muscle. Am J Physiol 1996;270(2 pt 1):E265YE272. due to a missense mutation. Muscle Nerve 22. McKenzie S, Phillips SM, Carter SL, et al. Endurance 2010;42(6):975Y979. doi:10.1002/mus.21823. exercise training attenuates leucine oxidation 9. Nguyen K, Bassez G, Krahn M, et al. Phenotypic and BCOAD activation during exercise in humans. study in 40 patients with dysferlin gene mutations: Am J Physiol Endocrinol Metab 2000; high frequency of atypical phenotypes. Arch 278(4):E580YE587.

1848 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 23. Monaco C, Whitfield J, Jain SS, et al. Activation 37. Andersen ST, Haller RG, Vissing J. Effect of oral of AMPK"2 is not required for mitochondrial sucrose shortly before exercise on capacity FAT/CD36 accumulation during exercise. PLoS in McArdle disease. Arch Neurol 2008;65(6): One 2015;10(5):e0126122. doi:10.1371/ 786Y789. doi:10.1001/archneur.65.6.786. journal.pone.0126122. 38. Vissing J, Haller RG. The effect of oral sucrose 24. McArdle B. Myopathy due to a defect in muscle on exercise tolerance in patients with McArdle’s glycogen breakdown. Clin Sci 1951;10(1):13Y35. disease. N Engl J Med 2003;349(26):2503Y2509. doi:10.1056/NEJMoa031836. 25. Ørngreen MC, Schelhaas HJ, Jeppesen TD, et al. Is muscle glycogenolysis impaired in X-linked 39. Haller RG, Lewis SF. Glucose-induced exertional phosphorylase b kinase deficiency? Neurology fatigue in muscle phosphofructokinase Y 2008;70(20):1876Y1882. doi:10.1212/ deficiency. N Engl J Med 1991;324(6):364 369. 01.wnl.0000289190.66955.67. doi:10.1056/NEJM199102073240603. 26. Preisler N, Orngreen MC, Echaniz-Laguna A, 40. Sato S, Ohi T, Nishino I, Sugie H. Confirmation of et al. Muscle phosphorylase kinase deficiency: the efficacy of vitamin B6 supplementation for a neutral metabolic variant or a disease? McArdle disease by follow-up muscle biopsy. Y Neurology 2012;78(4):265Y268. doi:10.1212/ Muscle Nerve 2012;45(3):436 440. WNL.0b013e31824365f9. doi:10.1002/mus.22290. 27. Haller RG, Vissing J. Spontaneous ‘‘second wind’’ 41.IzumiR,SuzukiN,KatoK,etal.Acaseof and glucose-induced second ‘‘second wind’’ in McArdle disease: efficacy of vitamin B6 on McArdle disease: oxidative mechanisms. Arch fatigability and impaired glycogenolysis. Intern Y Neurol 2002;59(9):1395Y1402. doi:10.1001/ Med 2010;49(15):1623 1625. doi:10.2169/ internalmedicine.49.3525. archneur.59.9.1395. 28. Vissing J, Quistorff B, Haller RG. Effect of fuels 42. MacLean D, Vissing J, Vissing SF, Haller RG. Oral on exercise capacity in muscle phosphoglycerate branched-chain amino acids do not improve mutase deficiency. Arch Neurol 2005;62(9): exercise capacity in McArdle disease. Neurology Y 1440Y1443. doi:10.1001/archneur.62.9.1440. 1998;51(5):1456 1459. doi:10.1212/ WNL.51.5.1456. 29. Haller RG, Vissing J. No spontaneous second wind in muscle phosphofructokinase 43. Vorgerd M, Grehl T, Jager M, et al. Creatine deficiency. Neurology 2004;62(1):82Y86. therapy in myophosphorylase deficiency doi:10.1212/WNL.62.1.82. (McArdle disease): a placebo-controlled crossover trial. Arch Neurol 2000;57(7):956Y963. 30. Mineo I, Tarui S. Myogenic hyperuricemia: what doi:10.1001/archneur.57.7.956. can we learn from metabolic myopathies? Muscle Nerve Suppl 1995;3:S75YS81. doi:10.1002/ 44. Preisler N, Laforeˆ t P, Madsen KL, et al. Skeletal mus.880181416. muscle metabolism is impaired during exercise in type III. 31. Hanisch F, Eger K, Bork S, et al. Lactate Neurology 2015;84(17):1767Y1771. doi:10.1212/ production upon short-term non-ischemic WNL.0000000000001518. forearm exercise in mitochondrial disorders and other myopathies. J Neurol 2006;253(6): 45. Quinlivan R, Martinuzzi A, Schoser B. 735Y740. doi:10.1007/s00415-006-0101-7. Pharmacological and nutritional treatment 32. Kazemi-Esfarjani P, Skomorowska E, Jensen TD, for McArdle disease (glycogen storage disease et al. A nonischemic forearm exercise test for type V). Cochrane Database Syst Rev 2014;11: McArdle disease. Ann Neurol 2002;52(2): CD003458. doi:10.1002/14651858. 153Y159. doi:10.1002/ana.10263. CD003458.pub5. 33. Argov Z, Lo¨ fberg M, Arnold DL. Insights into 46. Martinuzzi A, Liava A, Trevisi E, et al. Chronic muscle diseases gained by phosphorus magnetic therapy for McArdle disease: the randomized trial resonance spectroscopy. Muscle Nerve 2000;23(9): with ACE inhibitor. Acta Myol 2007;26(1):64Y66. Y 1316 1334. doi:10.1002/1097-4598(200009)23: 47. Tamai I. Pharmacological and pathophysiological G 9 9 1316::AID-MUS2 3.0.CO;2-I. roles of carnitine/organic cation transporters 34. Mate´ -Mun˜ oz JL, Moran M, Pe´ rez M, et al. (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Favorable responses to acute and chronic exercise Biopharm Drug Dispos 2013;34(1):29Y44. in McArdle patients. Clin J Sport Med 2007;17(4): doi:10.1002/bdd.1816. 297Y303. doi:10.1097/JSM.0b013e3180f6168c. 48. Ørngreen MC, Ejstrup R, Vissing J. Effect of 35. Quinlivan R, Vissing J, Hilton-Jones D, Buckley J. diet on exercise tolerance in carnitine Physical training for McArdle disease. Cochrane palmitoyltransferase II deficiency. Neurology Database Syst Rev 2011;(12):CD007931. 2003;61(4):559Y561. doi:10.1212/ doi:10.1002/14651858.CD007931.pub2. 01.WNL.0000078195.05396.20. 36. Haller RG, Wyrick P, Taivassalo T, Vissing J. 49. Ørngreen MC, Olsen DB, Vissing J. Exercise Aerobic conditioning: an effective therapy in tolerance in carnitine palmitoyltransferase II McArdle’s disease. Ann Neurol 2006; deficiency with IV and oral glucose. Neurology 59(6):922Y928. doi:10.1002/ana.20881. 2002;59(7):1046Y1051. doi:10.1212/WNL.59.7.1046.

Continuum (Minneap Minn) 2016;22(6):1829–1851 www.ContinuumJournal.com 1849

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

50. Bonnefont JP, Demaugre F, Prip-Buus C, et al. 62. Holt IJ, Harding AE, Morgan-Hughes JA. Carnitine palmitoyltransferase deficiencies. Mol Deletions of muscle mitochondrial DNA in patients Genet Metab 1999;68(4):424Y440. doi:10.1006/ with mitochondrial myopathies. Nature mgme.1999.2938. 1988;331(6158):717Y719. doi:10.1038/331717a0. 51. Longo N, Amat di San Filippo C, Pasquali M. 63. Ruiz-Pesini E, Mishmar D, Brandon M, et al. Disorders of carnitine transport and the carnitine Effects of purifying and adaptive selection on cycle. Am J Med Genet C Semin Med Genet regional variation in human mtDNA. Science 2006;142C(2):77Y85. doi:10.1002/ajmg.c.30087. 2004;303(5655):223Y226. doi:10.1126/ science.1088434. 52. Bonnefont JP, Bastin J, Laforeˆ t P, et al. Long-term follow-up of bezafibrate treatment in 64. Tarnopolsky MA, Roy BD, MacDonald JR. patients with the myopathic form of carnitine A randomized, controlled trial of creatine palmitoyltransferase 2 deficiency. Clin Pharmacol monohydrate in patients with mitochondrial Ther 2010;88(1):101Y108. doi:10.1038/ cytopathies. Muscle Nerve 1997;20(12): clpt.2010.55. 1502Y1509. doi:10.1002/(SICI)1097-4598 (199712)20:12G1502::AID-MUS493.0.CO;2-C. 53. Ørngreen MC, Madsen KL, Preisler N, et al. 65. Connolly BS, Feigenbaum AS, Robinson BH, Bezafibrate in skeletal muscle fatty acid oxidation et al. MELAS syndrome, cardiomyopathy, disorders: a randomized clinical trial. Neurology rhabdomyolysis, and autism associated with the 2014;82(7):607Y613. doi:10.1212/ A3260G mitochondrial DNA mutation. Biochem WNL.0000000000000118. Biophys Res Commun 2010;402(2):443Y447. 54. Roe CR, Mochel F. Anaplerotic diet therapy in doi:10.1016/j.bbrc.2010.10.060. inherited metabolic disease: therapeutic 66. Andreu AL, Hanna MG, Reichmann H, et al. Y potential. J Inherit Metab Dis 2006;29(2 3): Exercise intolerance due to mutations in the Y 332 340. doi:10.1007/s10545-006-0290-3. cytochrome b gene of mitochondrial DNA. Y 55. Roe CR, Yang BZ, Brunengraber H, et al. N Engl J Med 1999;341(14):1037 1044. Carnitine palmitoyltransferase II deficiency: doi:10.1056/NEJM199909303411404. successful anaplerotic diet therapy. Neurology 67. Vissing CR, Duno M, Olesen JH, et al. Recurrent 2008;71(4):260Y264. doi:10.1212/ myoglobinuria and deranged acylcarnitines 01.wnl.0000318283.42961.e9. due to a mutation in the mtDNA MT-CO2 gene. Neurology 2013;80(20):1908Y1910. doi:10.1212/ 56. Vockley J, Marsden D, McCracken E, et al. WNL.0b013e3182929fb2. Long-term major clinical outcomes in patients with long chain fatty acid oxidation 68. Tarnopolsky M. Exercise testing in metabolic disorders before and after transition to myopathies. Phys Med Rehabil Clin N Am Y triheptanoin treatmentVa retrospective chart 2012;23(1):173 186, xii. doi:10.1016/ j.pmr.2011.11.011. review. Mol Genet Metab 2015;116(1Y2):53Y60. doi:10.1016/j.ymgme.2015.06.006. 69. Abadi A, Glover EI, Isfort RJ, et al. Limb immobilization induces a coordinate 57. Parikh S, Goldstein A, Koenig MK, et al. Practice down-regulation of mitochondrial and other patterns of mitochondrial disease physicians in metabolic pathways in men and women. PLoS NorthAmerica.Part2:treatment,careand One 2009;4(8):e6518. doi:10.1371/ management. Mitochondrion 2013;13(6): journal.pone.0006518. 681Y687. doi:10.1016/j.mito.2013.09.003. 70. Jensen TD, Kazemi-Esfarjani P, Skomorowska E, 58. Parikh S, Goldstein A, Koenig MK, et al. Vissing J. A forearm exercise screening Diagnosis and management of mitochondrial test for mitochondrial myopathy. Neurology disease: a consensus statement from the 2002;58(10):1533Y1538. doi:10.1212/ Mitochondrial Medicine Society. Genet Med WNL.58.10.1533. 2015;17(9):689Y701. doi:10.1038/gim.2014.177. 71. Grassi B, Marzorati M, Lanfranconi F, et al. 59. Tarnopolsky MA. The mitochondrial cocktail: Impaired oxygen extraction in metabolic rationale for combined nutraceutical therapy in myopathies: detection and quantification by mitochondrial cytopathies. Adv Drug Deliv Rev near-infrared spectroscopy. Muscle Nerve 2008;60(13Y14):1561Y1567. doi:10.1016/ 2007;35(4):510Y520. doi:10.1002/mus.20708. j.addr.2008.05.001. 60. Singh G, Lott MT, Wallace DC. A mitochondrial 72. Arnold DL, Matthews PM, Radda GK. DNA mutation as a cause of Leber’s Metabolic recovery after exercise and the hereditary optic neuropathy. N Engl J Med assessment of mitochondrial function in vivo in 1989;320(20):1300Y1305. doi:10.1056/ human skeletal muscle by means of 31P NMR. Y NEJM198905183202002. Magn Reson Med 1984;1(3):307 315. doi:10.1002/mrm.1910010303. 61. Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and 73. Bourgeois JM, Tarnopolsky MA. Pathology of epileptic features and maternal transmission. skeletal muscle in mitochondrial disorders. Y Y Neurology 1988;38(5):751Y754. doi:10.1212/ Mitochondrion 2004;4(5 6):441 452. WNL.38.5.751. doi:10.1016/j.mito.2004.07.036.

1850 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 74. Frazier AE, Thorburn DR. Biochemical analyses of 83. Avula S, Parikh S, Demarest S, et al. Treatment the electron transport chain complexes of mitochondrial disorders. Curr Treat Options by spectrophotometry. Methods Mol Biol 2012; Neurol 2014;16(6):292. doi:10.1007/ 837:49Y62. doi:10.1007/978-1-61779-504-6_4. s11940-014-0292-7. 75. Falk MJ, Shen L, Gonzalez M, et al. 84. Stacpoole PW, Kerr DS, Barnes C, et al. Mitochondrial Disease Sequence Data Resource Controlled clinical trial of dichloroacetate for (MSeqDR): a global grass-roots consortium to treatment of congenital lactic acidosis in facilitate deposition, curation, annotation, and children. Pediatrics 2006;117(5):1519Y1531. integrated analysis of genomic data for the doi:10.1542/peds.2005-1226. mitochondrial disease clinical and research 85. Stacpoole PW, Gilbert LR, Neiberger RE, et al. communities. Mol Genet Metab 2015;114(3): Evaluation of long-term treatment of Y 388 396. doi:10.1016/j.ymgme.2014.11.016. children with congenital lactic acidosis with 76. Glover EI, Martin J, Maher A, et al. dichloroacetate. Pediatrics 2008;121(5): A randomized trial of coenzyme Q10 in e1223Ye1228. doi:10.1542/peds.2007-2062. mitochondrial disorders. Muscle Nerve 86. Taivassalo T, Gardner JL, Taylor RW, et al. 2010;42(5):739Y748. doi:10.1002/mus.21758. Endurance training and detraining in 77. Klopstock T, Querner V, Schmidt F, et al. A mitochondrial myopathies due to single placebo-controlled crossover trial of creatine in large-scale mtDNA deletions. Brain Y mitochondrial diseases. Neurology 2000;55(11): 2006;129(pt 12):3391 3401. doi:10.1093/ 1748Y1751. doi:10.1212/WNL.55.11.1748. brain/awl282. 78. Rodriguez MC, MacDonald JR, Mahoney DJ, 87. Taivassalo T, Haller RG. Exercise and training in et al. Beneficial effects of creatine, CoQ10, and mitochondrial myopathies. Med Sci Sports Exerc Y lipoic acid in mitochondrial disorders. Muscle Nerve 2005;37(12):2094 2101. doi:10.1249/01.mss. 2007;35(2):235Y242. doi:10.1002/mus.20688. 0000177446.97671.2a.

79. Tarnopolsky MA, Beal MF. Potential for creatine 88. Taivassalo T, Shoubridge EA, Chen J, and other therapies targeting cellular energy et al. Aerobic conditioning in patients dysfunction in neurological disorders. Ann Neurol with mitochondrial myopathies: physiological, 2001;49(5):561Y574. doi:10.1002/ana.1028. biochemical, and genetic effects. Ann Neurol 2001;50(2):133Y141. doi:10. 80. Rudolph G, Dimitriadis K, Bu¨ chner B, et al. 1002/ana.1050. Effects of idebenone on color vision in patients with leber hereditary optic neuropathy. 89. Tarnopolsky MA. Exercise as a therapeutic J Neuroophthalmol 2013;33(1):30Y36. strategy for primary mitochondrial cytopathies. Y doi:10.1097/WNO.0b013e318272c643. J Child Neurol 2014;29(9):1225 1234. doi:10.1177/0883073814538512. 81. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of 90. Murphy JL, Blakely EL, Schaefer AM, et al. idebenone in Leber’s hereditary optic neuropathy. Resistance training in patients with single, Brain 2011;134(pt 9):2677Y2686. doi:10.1093/ large-scale deletions of mitochondrial DNA. brain/awr170. Brain 2008;131(pt 11):2832Y2840. doi:10.1093/ brain/awn252. 82. Enns GM, Kinsman SL, Perlman SL, et al. Initial experience in the treatment of inherited 91. Taivassalo T, Fu K, Johns T, et al. Gene shifting: mitochondrial disease with EPI-743. Mol Genet a novel therapy for mitochondrial myopathy. Metab 2012;105(1):91Y102. doi:10.1016/ Hum Mol Genet 1999;8(6):1047Y1052. j.ymgme.2011.10.009. doi:10.1093/hmg/8.6.1047.

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

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