Metabolic Myopathies of Texas Health Science Center San Antonio, 8300 Floyd Curl Alejandro Tobon, MD Drive, San Antonio, TX, 78229, Tobon@Uthscsa.Edu

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Address correspondence to Dr Alejandro Tobon, University Metabolic Myopathies of Texas Health Science Center San Antonio, 8300 Floyd Curl Alejandro Tobon, MD Drive, San Antonio, TX, 78229, [email protected]. Relationship Disclosure: Dr Tobon reports no disclosure. ABSTRACT Unlabeled Use of Purpose of Review: The metabolic myopathies result from inborn errors of Products/Investigational metabolism affecting intracellular energy production due to defects in glycogen, Use Disclosure: Dr Tobon reports no disclosure. lipid, adenine nucleotides, and mitochondrial metabolism. This article provides an * 2013, American Academy overview of the most common metabolic myopathies. of Neurology. Recent Findings: Our knowledge of metabolic myopathies has expanded rapidly in recent years, providing us with major advances in the detection of genetic and biochemical defects. New and improved diagnostic tools are now available for some of these disorders, and targeted therapies for specific biochemical deficits have been developed (ie, enzyme replacement therapy for acid maltase deficiency). Summary: The diagnostic approach for patients with suspected metabolic myopathy should start with the recognition of a static or dynamic pattern (fixed versus exercise-induced weakness). Individual presentations vary according to age of onset and the severity of each particular biochemical dysfunction. Additional clinical clues include the presence of multisystem disease, family history, and laboratory characteristics. Appropriate investigations, timely treatment, and genetic counseling are discussed for the most common conditions.

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INTRODUCTION (cramps, myalgias, exercise intolerance, The metabolic myopathies represent a myoglobinuria). Metabolic myopathies heterogeneous group of disorders of should be considered in the differential cellular metabolism characterized by in- diagnosis of patients with exercise- sufficient energy production as a result induced muscle symptoms, static or of specific defects of glycogen, lipid, progressive myopathy, isolated neuro- or mitochondrial metabolism. Myo- muscular respiratory weakness, and adenylate deaminase deficiency, a dis- muscle disease associated with systemic order of nucleotide metabolism, has conditions. Common presentations vary traditionally been considered as a meta- with age of onset, with older children bolic myopathy; however, the high prev- and adults frequently having exercise alence of this disorder in the general intolerance, weakness, and myoglobinuria, population (2%) and the documentation whereas newborns and infants tend to of completely asymptomatic individuals present with hypotonia and severe render its pathogenicity into question.1 multisystem disorders. From a clinical standpoint, the meta- The diagnostic evaluation for a sus- bolic myopathies can be viewed as static pected metabolic myopathy varies or dynamic disorders.2 The first group according to age of onset, presentation includes patients with fixed symptoms, (dynamic versus static symptoms), and such as weakness, often associated with comorbid conditions, and may include systemic involvement (eg, cardiomyop- blood tests (serum creatine kinase athy, endocrinopathy, encephalopathy). [CK], lactate, acylcarnitine profile, and Patients with dynamic disorders exhibit amino acids), urine testing (organic symptoms and signs related to exercise acids and myoglobin), EMG, forearm

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KEY POINT h From a clinical exercise testing, muscle biopsy, bio- help to narrow the differential diagnosis standpoint, the chemical analysis, genetic testing, and (Figure 3-1). metabolic myopathies muscle magnetic resonance spectros- The forearm exercise test is a very can be viewed as static copy (MRS). It is important to remember helpful tool in the evaluation of patients or dynamic disorders. that patients with exercise intolerance with dynamic symptoms, particularly to may have normal laboratory and EMG differentiate those with defects of the testing during interictal periods. In these glycolytic pathway. Several studies have cases, a careful evaluation of the type of shown that it can be performed in a safe exercise that triggers symptoms (high and effective manner without need for intensity for less than 10 minutes versus ischemic conditions.3 Different protocols low intensity for more than 10 minutes) are available, but a common approach and associated precipitating factors can includes the insertion of a butterfly

FIGURE 3-1 Clinical algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK = creatine kinase; PYGM = muscle isoform of glycogen phosphorylase; PPL = myophosphorylase; GSD = glycogen storage disease; PFK = phosphofructokinase; PGK = phosphoglycerate kinase; PGAM = phosphoglycerate mutase; COX = cytochrome c oxidase; RRF = ragged red fibers; mtDNA = mitochondrial DNA; nDNA = nuclear DNA; CPT = carnitine palmitoyl transferase; VLCAD = very long chain acyl coenzyme A dehydrogenase.

Modified from Berardo A, et al. Curr Neurol Neurosci Rep.2 B 2010, with permission from Springer Science + Business Media. link.springer.com/article/10.1007/s11910-010-0096-4.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS needle in the antecubital fossa. Base- recessive disorder caused by a deficiency h Metabolic myopathies line blood is drawn for ammonia, of lysosomal !-glucosidase (Table 3-2). should be considered lactate, and pyruvate. The patient then This enzyme cleaves 1,4 and 1,6 link- in the differential opens and closes the hand rapidly and ages in glycogen, and its deficiency diagnosis of patients strenuously for 1 minute. Immediately results in glycogen accumulation with exercise-induced after this and at 1, 2, 4, 6, and 10 (Figure 3-2). The threshold amount muscle symptoms, static minutes post exercise, further blood is seems to vary depending on the organ, or progressive drawn and levels of ammonia, lactate, and the process by which skeletal myopathy, isolated and pyruvate are documented. The muscle is eventually impaired is still neuromuscular respiratory normal physiologic response is a three- not fully understood. Both atrophy and weakness, and muscle fold to fivefold rise above baseline in reduced performance by unit of muscle disease associated with systemic conditions. ammonia, lactate, and pyruvate. Com- mass seem to have a role.4 mon patterns seen in different meta- Clinical features. The disease has h The forearm exercise bolic disorders are shown in Table 3-1. three phenotypical presentations: severe test is a very helpful tool Our knowledge of metabolic myop- infantile form (Pompe disease), juvenile- in the evaluation of patients with dynamic athies has expanded dramatically over onset type, and an adult-onset variant. symptoms, particularly the past decade, especially in the The infantile form presents with cardiac to differentiate those detection of specific genetic and bio- symptoms, hypotonia, hepatomegaly, with defects of the chemical defects of these disorders. macroglossia, and failure to thrive. Re- glycolytic pathway. New treatment options are now avail- spiratory muscle weakness and feeding h Glycogen storage able for some of these conditions, difficulties are common. The disease is disease (GSD) type II has making early recognition of para- generally fatal by 2 years of age due to three phenotypical mount importance in order to reduce cardiorespiratory failure. The juvenile- presentations: severe morbidity and mortality. onset form of GSD-II usually manifests infantile form (Pompe during the first decade of life. Affected disease), juvenile-onset DISORDERS OF GLYCOGEN children have delayed gross motor de- type, and an adult-onset METABOLISM velopment with proximal greater than variant. Type II Glycogenosis distal limb-girdle weakness. Calf hyper- Glycogen storage disease (GSD) type II trophy, waddling gait, and a positive (acid maltase deficiency) is an autosomal Gower sign are commonly present.

TABLE 3-1 Forearm Exercise Test

Diagnosis Ammonia Lactate Pyruvate Normal 3Y4 times increase 3Y4 times increase 3Y5 times increase Glycolysis/glycogenolysis defectsa 3Y4 times increase No rise No rise Phosphorylase b kinase 3Y4 times increase 3Y4 times increase 3Y4 times increase deficiency (sometimes less) (sometimes less) Acid maltase deficiency 3Y4 times increase 3Y4 times increase 3Y5 times increase Lactate dehydrogenase 3Y4 times increase No rise 3Y4 times increase deficiency Fatty oxidation defects 3Y4 times increase 3Y4 times increase 3Y5 times increase Myoadenylate deficiency No rise 3Y4 times increase 3Y5 times increase Mitochondrial 3Y4 times increase 3Y4 times increase 3Y5 times increase Insufficient effort No rise No rise No rise a Except for phosphorylase b kinase deficiency, acid maltase deficiency, and lactate dehydrogenase deficiency, which represent glycolysis/glycogenolysis defects that do not follow the same pattern as other glycogen disorders.

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TABLE 3-2 Glycogen Storage Disorders Associated With Myopathies

Name of Enzyme, Gene, Static or Type Disease Chromosome Clinical Features Dynamic II Pompe disease Acid maltase, GAA, Infantile: Hypotonia, Static 17q21-23 hepatomegaly, macroglossia Juvenile: Proximal limb girdle weakness Adult: Proximal or distal weakness, respiratory muscle weakness III Cori disease Debrancher, AGL, 1p21 Infantile: Hypotonia, hypoglycemia Static Adult: Predominantly distal weakness (calves/peroneal), associated polyneuropathy IV Andersen disease Branching, GBE1, 3p12 Infantile: Hypotonia and Static generalized weakness Adult: Isolated myopathy or upper/lower motor neuron combination, ataxia, neurogenic bladder, dementia V McArdle disease Myophosphorylase, Infantile: Form is rare and presents Dynamic PYGM, 11q13 with generalized weakness Adult: Exercise intolerance VII Tarui disease Phosphofructokinase, Infantile: Hypotonia and Dynamic PFKM, 12q13 generalized weakness Adults: Exercise intolerance VIII Unnamed Phosphorylase b kinase, Exercise intolerance Dynamic PHBK, 16q12-q13 IX Unnamed Phosphoglycerate Exercise intolerance; some cases Dynamic kinase, PGK, Xq13 reported with progressive weakness X Unnamed Phosphoglycerate Exercise intolerance Dynamic mutase, PGAM-M, 7p13-p12.3 XI Unnamed Lactate dehydrogenase, Exercise intolerance Dynamic LDHA, 11p15.4 XII Unnamed Aldolase A, ALDOA, Exercise intolerance Dynamic 16q22-q24 XIII Unnamed "-Enolase, ENO3, 17 Exercise intolerance Dynamic XIV Unnamed Phosphoglucomutase 1, Exercise intolerance Dynamic PGM1, 1p31.3 Unnamed Triosephosphate Childhood: Progressive Static isomerase, TIM, 12p13 weakness, facial involvement, polyneuropathy and tremor

Cardiac and liver involvement is less Adult-onset acid maltase deficiency common. Respiratory muscle weakness typically begins in the third or fourth eventually develops, leading to death in decade of life (age range 18 to 65 the second or third decade of life. years). Predominant proximal more

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-2 Glycolytic pathways. Glycogen storage diseases (GSDs) are designated with Roman numerals. GSD I and VI are not included since they do not cause muscle disease. The numerals denote defects in the following enzymes: II, acid maltase; III, debrancher; IV, brancher; V, myophosphorylase; VII, phosphofructokinase; VIII, phosphorylase b kinase; IX, phosphoglycerate kinase; X, phosphoglycerate mutase; XI, lactate dehydrogenase; XII, aldolase A; XIII, beta enolase, XIV, phosphoglucomutase 1.

cAMP = cyclic adenosine monophosphate; UDPG = uridine diphosphoglucose; PLD = phosphorylase-limit dextrin; TPI = triose phosphate isomerase. than distal weakness is the main from the forearm exercise test are manifestation of the disease, similar normal. Motor and sensory nerve to cases of polymyositis or limb-girdle conduction study results are normal, muscular dystrophy (Case 3-1). Other and EMG often reveals increased in- presentations include scapuloperoneal sertional activity with fibrillations, pos- weakness and rarely macroglossia. itive sharp waves, complex repetitive Hepatomegaly and cardiomegaly are discharges, and, not infrequently, usually not present; however, cardiac myotonic discharges, especially in the arrhythmias can develop. Involvement paraspinal muscles. Motor unit poten- of the respiratory muscles is common tials often display myopathic features and in some patients may represent with early recruitment. !-Glucosidase the initial manifestation of the disease. activity may be assayed in muscle Laboratory. Moderate elevations of fibers, fibroblasts, lymphocytes, and the serum CK are common in all types urine. A dried blood spot that mea- of GSD-II, but occasionally adult pa- sures !-glucosidase activity is the tients can have normal levels. Findings recommended screening test, followed

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KEY POINT h A dried blood spot that Case 3-1 measures -glucosidase ! A 50-year-old man presented to the clinic with progressive weakness activity is the affecting his legs more than his arms. He had always had difficulty going recommended screening up and down the stairs and was never able to perform push-ups or pull-ups. test for glycogen storage He described a Gower sign when getting off the floor as a child. Weakness disease type II, followed became more noticeable in his twenties, and by 40 years of age, he noticed by genetic testing if difficulty breathing. He had no relevant personal or family medical history results are abnormal. and was not taking any medications. On examination, he displayed bilateral scapular winging with mild biceps and quadriceps atrophy. Mild calf hypertrophy was noted, and no clinical myotonia was seen on examination. He had proximal weakness (3/5) in the arms and legs as well as a mild waddling gait. Deep tendon reflexes were 1+ throughout, including biceps, triceps, patellar, and Achilles jerks. Plantar responses were flexor, and sensory examination was normal. The serum creatine kinase was 750 U/L. Electrodiagnostic testing revealed normal nerve conduction studies with small-amplitude, brief-duration, polyphasic motor unit potentials and occasional myotonic discharges. !-Glucosidase activity (measured by the dried blood spot test) was 1.2 pmol/punch/hour (with normal being more than 10 pmol/punch/ hour), and sequencing of the gene encoding !-glucosidase activity (GAA) confirmed a C.-32-13T9G mutation on chromosome 17. Comment. This case illustrates that acid maltase deficiency can present with gradually progressive muscle weakness, often resembling a limb-girdle muscular dystrophy. The presence of myotonic discharges is not uncommon, especially over the paraspinal muscles. A dried blood spot measuring !-glucosidase activity can be obtained easily as a screening test, in some cases helping to reach a final diagnosis before more invasive procedures like muscle biopsy are performed. Acid maltase deficiency is one of the few metabolic myopathies with specific medical treatment and should not be missed.

by genetic testing if findings from the The vacuoles also stain intensely to dried blood spot test are abnormal. acid phosphatase, confirming that the ECG abnormalities can include left axis vacuoles are secondary lysosomes deviation, short PR interval, large QRS (Figure 3-3). These vacuoles are very complexes, inverted T waves, and prominent in the infantile form, but in persistent sinus tachycardia. Wolff- the childhood and adult forms they Parkinson-White syndrome and hyper- may be present in only 25% to 75% of trophic cardiomyopathy have been fibers and could be absent in unaffected reported. Pulmonary function tests muscles. Free glycogen can be seen in frequently show reductions in forced the cytoplasm by electron microscopy; vital capacity and maximal inspiratory however, some of it may be lost during and expiratory pressures. processing and the excessive amount is Muscle biopsies have a pronounced not always apparent. vacuolar appearance, and periodic Molecular genetics. GSD-II is inher- acid-Schiff (PAS) staining shows large ited in an autosomal recessive manner. deposits of glycogen in most fibers. The gene encoding acid !-glucosidase The glycogen is digested by diastase, (GAA)islocalizedtochromosome but some resistant material remains. 17q25.2-q25.3 and contains 19 coding

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT h Prevention of further loss of muscle function is the target treatment goal for enzyme replacement therapy in patients with acid maltase deficiency.

FIGURE 3-3 Acid maltase deficiency. Nonrimmed vacuoles in muscle fibers due to glycogen deposition. A, Hematoxylin and eosin stain; B, Acid phosphatase stain.

Courtesy of Derek A. Mathis, MD. exons. The locus is very heteroge- but statistically significant improvement neous. More than 250 different mis- in favor of alglucosidase alfa was no- sense, nonsense, and frame-shift ticed in both parameters. Patients in mutations have been reported,5 and the treatment and placebo group had about 75% of these are considered similar adverse effects except for ana- pathogenic. C.-32-13T-9G is the most phylactic reactions that occurred only common mutation in children and in patients treated with the medication. adults with a slowly progressive All alglucosidase alfa recipients tested course of disease,6 while c.2560C9T negative for IgG antiYGAA antibodies at is the most common mutation in the baseline and seroconverted by week 12. African American population. In gen- Patients treated with alglucosidase alfa eral, !-glucosidase activity and clinical who have persistently elevated titers severity have an inverse correlation, should be closely monitored until the but it is not considered 100% accurate. effect of the antibodies is more fully Treatment. Alglucosidase alfa was understood. approved in 2006 by the US Food and Consensus treatment recommenda- Drug Administration and the European tions based on stage and severity of Medicines Agency and became the Pompe disease have been recently first disease-specific treatment for published (Table 3-3).8 Overall, the childhood-onset Pompe disease. The clinical response observed in this trial Late-Onset Treatment Study in 20107 and in subsequent studies9 suggests led to the approval of alglucosidase alfa that prevention of further loss of for the treatment of late-onset Pompe muscle function is the target treatment disease in the United States. In this goal for enzyme replacement therapy. study, 90 patients ranging from 10 to 70 Management of GSD-II patients should years old were randomized to receive not only focus on enzyme replacement biweekly infusions of alglucosidase alfa therapy but also include a multi- (20 mg/kg, based on body weight) disciplinary approach with emphasis or placebo. The two primary end points on rehabilitation services, prevention were distance traveled during a 6- and management of contractures and minute walk test and the forced vital osteoporosis, and early recognition capacity percentage predicted in the and treatment of cardiac, pulmonary, upright position. At week 78, a modest and gastrointestinal disease.

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TABLE 3-3 Treatment Recommendations Based on the Stage and Severity of Pompe Disease

Condition Recommendations Presymptomatic patients Patients should be examined every 6 months for without objective signs proximal muscle weakness and pulmonary function Enzyme replacement therapy (ERT) should be started at: & Onset of symptoms & Onset of detectable proximal muscle weakness or reduced forced vital capacity in either upright or supine position Presymptomatic patients ERT should be started if presymptomatic patients with objective signs have proximal muscle weakness detectable on the Medical Research Council scale or reduced forced vital capacity in either upright or supine position Symptomatic patients ERT should be started if: & Either a reduction in forced vital capacity in either upright or supine position or increased limb weakness occurs & The patient has difficulties completing activities of daily living & The patient is or is not using noninvasive ventilation Severe symptoms If the patient is confined to a wheelchair and is using invasive ventilation during the day and at night: & ERT is recommended for 1 year, followed by evaluation of the effectiveness of therapy & After 1 year, ERT is recommended on a case-by- case basis for patients who require continuous invasive ventilation, using the collective information acquired by the multispecialty team & Continue ERT if severe signs and symptoms are stabilized or improved Patients receiving ERT One year followed by reassessment to consider monitoring whether treatment should be continued Patients receiving ERT should be monitored for IgG antibodies every 3 months for 2 years, then annually thereafter Modified from Cupler EJ, et al. Muscle Nerve.8 B 2011 Wiley Periodicals, Inc. onlinelibrary. wiley.com/doi/10.1002/mus.22329/abstract.

Type III Glycogenosis enzymes, which degrade glycogen Debranching enzyme deficiency, also branches, releasing glucose in a two- known as Cori disease or GSD-III, step reaction catalyzed by its two dis- represents approximately 25% of all tinct activities. GSD. It is an autosomal recessive dis- Clinical features. GSD-III has four order due to a deficiency of amylo-1,6- clinical forms: GSD-IIIa, with lack of glucosidase and 4-!-glucanotransferase both glucosidase and transferase in

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT liver and muscle; GSD-IIIb, with lack biochemical assay of muscle, fibro- h Deficiency of debranching of both activities in liver only; GSD- blasts, or lymphocytes. enzyme can be IIIc, with selective loss of glucosidase Molecular genetics. The gene for demonstrated with activity; and GSD-IIId, with selective debranching enzyme (AGL) is local- biochemical assay of loss of transferase activity. Children ized to chromosome 1p21, and six muscle, fibroblasts, or with GSD-IIIa present with recurrent transcript isoforms have been isolated. lymphocytes. fasting hypoglycemia, seizures, hepa- Most GSD-IIIb patients have muta- tomegaly, decreased muscle tone, and tions in exon 3,11 whereas GSD-IIIa growth retardation. Episodic hypogly- arises from downstream mutations. cemia seems to resolve after puberty, Treatment. Specific therapy is not and most patients have only minimal available for debranching enzyme defi- signs of liver disease afterward except ciency. For management of hypoglyce- for a small subgroup that may develop mic episodes during childhood, dietary cirrhosis and hepatocellular carcinoma measures have been recommended, later in life. Adult-onset GSD-IIIa usually with frequent daytime high-protein starts in the third or fourth decade with feedings and supplementation of un- distal weakness, affecting calves and cooked cornstarch before sleep. Anec- peroneal muscles predominantly, and dotal cases of improved cardiac function variable proximal weakness with slow after initiation of diet changes have disease progression. A superimposed been reported. Improvement of muscle neuropathy can occur due to glycogen symptoms with dietary changes has not deposition in Schwann cells and axons. been consistently proven. Rare cases of exercise intolerance have been reported, associated with cardio- Type IV Glycogenosis myopathy.10 Respiratory weakness has GSD-IV, also known as Andersen dis- been described, which sometimes can ease, is an autosomal recessive disorder be very rapidly progressive. caused by branching enzyme deficiency. Laboratory. CK elevations 2 to 20 This enzyme catalyzes the last step in times above normal levels are com- glycogen biosynthesis by transferring mon. The forearm exercise test shows short glucosyl chains in !,1-6 glycosidic a normal increase in serum ammonia links to naked peripheral chains of but no rise in lactate levels. ECG may nascent glycogen. reveal conduction defects, and echo- Clinical features. GSD-IV most com- cardiogram may show findings sugges- monly presents in children with failure tive of hypertrophic cardiomyopathy. to thrive, hepatosplenomegaly, and liver Nerve conduction studies can be cirrhosis, leading to death at a young normal or show changes consistent age. Neuromuscular symptoms vary with a mild sensorimotor poly- according to the age of presentation neuropathy. Concentric needle EMG with the following patterns: congenital, can demonstrate similar findings juvenile, and adult. The congenital form to those seen in acid maltase defi- presents as fetal akinesia deformation ciency. Muscle biopsy reveals glycogen sequence with multiple contractures particles, which are PAS positive and (FADS) or as a severe congenital myop- digestible by diastase. Nonetheless, athy inconsistently associated with vacuoles do not stain with acid phos- cardiomyopathy, often resembling phatase, suggesting that glycogen does Werdnig-Hoffman disease.12 The juve- not primarily accumulate in the lyso- nile phenotype is dominated by myop- some. Deficiency of debranching en- athy or cardiomyopathy. The adult zyme can be demonstrated with form can present as isolated myopathy

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KEY POINTS h The adult form of or adult polyglucosan body disease Type V Glycogenosis glycogen storage characterized by a combination GSD-V, also known as McArdle dis- disease type IV can of upper and lower motor neuron ease, is the most common disorder of present as isolated syndromes, sensory nerve involve- carbohydrate metabolism. It is an auto- myopathy or adult ment, cerebellar ataxia, neurogenic somal recessive disorder caused by 13 polyglucosan body bladder, and dementia. defects in the gene (PYGM) encoding disease characterized by Laboratory. Serum CK can be nor- for myophosphorylase enzyme. This a combination of upper mal or mildly elevated. ECG may show enzyme is involved in the breakdown and lower motor neuron conduction defects, and echocardio- of glycogen to glucose for use in muscle. syndromes, sensory gram may reveal a dilated cardiomy- Myophosphorylase removes 1,4 glycosyl nerve involvement, opathy. Nerve conduction studies are cerebellar ataxia, residues from outer branches of glyco- usually normal. Needle EMG demon- neurogenic bladder, gen and adds inorganic phosphate to and dementia. strates myopathic motor unit action form glucose-1 phosphate. potentials, occasionally with abnormal Clinical features. GSD-V affects h A second-wind insertional activity. In adult polyglucosan phenomenon is very only skeletal muscle, and symptoms body disease, an associated sensorimo- characteristic of usually start during childhood with glycogen storage tor axonal polyneuropathy can be pres- exercise intolerance, fatigue, myalgias, disease type V, in which ent, and EMG may reveal active cramps, poor endurance, muscle the muscle pain may denervation and reinnervation. Diagno- swelling, and later fixed weakness. dissipate after a brief sis is usually confirmed by determina- Symptoms are triggered by brief, in- rest period and allow tion of the branching enzyme activity in tense activity but can also occur after the patient to resume affected tissues. Muscle biopsy reveals prolonged low-intensity exercise. If exercise at the previous deposition of PAS-positive, diastase- patients continue to exercise, painful or slightly reduced level. resistant filamentous polysaccharides muscle cramping and contractures h In glycogen storage (polyglucosan bodies). They are also followed by myoglobinuria occurs disease type V, serum found in the CNS, axons, Schwann cells, (rare in children, more common after creatine kinase is usually skin, liver, and cardiac muscle. the second or third decade of life). A elevated even between Molecular genetics. GSD-IV is an second-wind phenomenon is very episodes of autosomal recessive disorder associated characteristic of the disease, in which myoglobinuria (in with mutations (deletion, nonsense, the muscle pain may dissipate after a contrast to another and missense) within the GBE1 gene brief rest period and allow the patient common cause of localized to chromosome 3p12. More to resume exercise at the previous or episodic myoglobinuria, carnitine than 21 mutations have been identified, a slightly reduced level (Case 3-2). It palmitoyltransferase II at least a quarter of which are localized occurs due to a switch to alternative 14 deficiency, where to exon 12. There is significant phe- fuel substrates required for aerobic 16 interictal creatine kinase notypic variability with differential ex- metabolism. Some patients with is usually normal). pression of enzyme activity. The exact McArdle disease do not present with mechanism by which the abnormal classic symptoms and may develop accumulation of polysaccharides results progressive muscle weakness.17 in muscle damage remains unclear. Laboratory. Serum CK is usually Treatment. Liver transplantation elevated even between episodes of has been performed in children with myoglobinuria (in contrast to another both the classic and progressive he- common cause of episodicmyoglobinuria, patic form, with good results.15 Pre- carnitine palmitoyltransferase II [CPT II] vention of nutritional deficiencies and deficiency, where interictal CK is usually early recognition and management of normal). Forearm exercise test reveals a cardiomyopathy are very important. normal rise in ammonia but no signifi- Heart transplantation can be an option cant lactate elevation. Results of routine for severe cases of cardiomyopathy. nerve conduction studies are usually

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 3-2 A 17-year-old boy presented to the clinic 6 weeks after an episode of rhabdomyolysis. He had recently joined a soccer team and, during his first practice, noticed moderate to severe myalgia, cramping, and dark urine. He was seen at a local hospital, where his creatine kinase (CK) was found to be 8560 U/L. He denied any toxic exposure, and his personal and family history were unremarkable apart from two previous episodes of myalgia induced by brief exercise during his last summer camp. In the hospital, he was treated with aggressive IV hydration and a repeat CK 2 weeks later was 750 U/L. Findings from the general physical and neurologic examinations were completely normal. EMG and nerve conduction studies performed during the visit were normal. Forearm exercise test showed a normal increase in ammonia with no rise in lactate. Muscle biopsy showed abnormal glycogen accumulation in the subsarcolemmal and intermyofibrillar areas. Immunohistochemical staining for myophosphorylase was absent (Figure 3-4).

FIGURE 3-4 Myophosphorylase deficiency. Hematoxylin eosin stain demonstrates subsarcolemmal vacuoles (A), immunohistochemical analysis for myophosphorylase confirms its absence (B), compared with normal control (C).

Courtesy of Derek A. Mathis, MD.

Comment. This is a classic presentation of myophosphorylase deficiency. A negative family history is not uncommon for autosomal recessive disorders. Physical and electrophysiologic examinations frequently have normal results. A forearm exercise test with normal elevation of ammonia but no rise in lactate is consistent with a glycolysis/glycogenolysis disorder. Muscle biopsy shows abnormal glycogen accumulation, and immunohistochemical staining confirms the diagnosis. normal. Repetitive nerve stimulation the presence of fetal isozyme that is after a short period of maximal exercise immunohistochemically indistinct may show a decremental response. from the adult form. For this reason, Needle EMG is usually normal but may some experts advocate waiting at least reveal occasional myotonic discharges, 1 month after a severe episode before fibrillations, and positive sharp waves in performing a muscle biopsy. Biochem- some patients. Early recruitment and ical assay for myophosphorylase activ- myopathic potentials can also be seen. ity reveals absent or severely reduced Histopathology reveals fiber-size activity. variability with some regenerating Molecular genetics. There are three muscle fibers, and excessive accumula- isozymes of glycogen phosphorylase: tion of glycogen in the subsarcolemmal one for muscle, one for brain, and one and intermyofibrillar regions. Staining for cardiac muscle, encoded in different for myophosphorylase is absent; how- genes (chromosomes 11, 14, and 20, ever, it may be falsely positive after an respectively).18 GSD-V results from ho- episode of myoglobinuria because of mozygous or compound heterozygous

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KEY POINT h Ramipril (2.5 mg/d), an mutations in the PYGM gene on chro- kinase (PFK), the rate-limiting enzyme angiotensin-converting mosome 11q13. More than 100 muta- in the glycolytic pathway that catalyzes enzyme inhibitor, was tions have been identified, the most the adenosine triphosphataseYdependent effective only for common in the North American popu- phosphorylation of fructose-6 phos- patients with a lation involving pArg50X in exon 1 and phate to fructose 1,6-biphosphate. polymorphism known as pGly205Ser. Significant phenotypical Clinical features. Tarui disease the deletion/deletion variability has been documented most commonly manifests as exercise angiotensin-converting among patients with the same type of intolerance with myalgias, cramps, and enzyme phenotype of mutation, and these differences seem recurrent myoglobinuria. The warm-up McArdle disease. to be at least partially explained by the phenomenon is absent, and the inci- presence of several phenotype modu- dence of myoglobinuria is less com- lators, such as the angiotensin- mon compared with McArdle disease. converting enzyme (ACE) I/D, I/I, or Other important differences compared D/D polymorphisms (with I being the with myophosphorylase deficiency in- longer allele with lower ACE activity clude worsening of muscle symptoms and D being the shorter allele with with glucose administration (the out- higher ACE activity).19 of-wind phenomenon) due to a reduc- Treatment. A Cochrane review pub- tion in availability of free fatty acids and lished in 2010 found minimal benefit ketones, and the presence in some with low-dose creatine (60 mg/kg/d), patients of jaundice (hemolytic ane- but higher doses actually resulted in mia) and gouty arthritis due to PFK worsening of clinical symptoms. deficiency in erythrocytes. Four clinical Ramipril (2.5 mg/d), an ACE inhibitor, presentations have been described: was effective only for patients with a classic form with exercise intolerance; polymorphism known as the D/D ACE severe infantile form with hypotonia, phenotype.20 A carbohydrate-rich diet progressive myopathy, cardiomyopa- resulted in better exercise performance thy, and respiratory failure; a late-onset compared with a protein-rich diet. Two form with permanent myopathy studies of oral sucrose given at different appearing around the fifth decade; and times and in different amounts before ahemolyticformcharacterizedby exercise showed an improvement in nonspherocytic anemia without muscle exercise performance. The benefits of symptoms. 75 g of oral sucrose are usually short- Laboratory. Serum CK is usually lasting, and repeated use may lead to elevated, and mild anemia and weight gain. Vitamin B6 supplementa- reticulocytosis can be present. The tion (50 mg/d to 90 mg/d) also seems nonischemic forearm exercise test to reduce exercise intolerance and en- reveals normal elevation in ammonia hance performance, according to small with no increase in lactate levels. clinical reports.21 Patients should avoid Hyperbilirubinemia and hyperurice- intense isometric exercises (eg, weight mia can also be seen. EMG may be lifting) and maximum aerobic exercises normal or show myopathic changes (eg, sprinting). They should also take (small, short-duration motor unit advantage of the second-wind phe- potentials). Muscle MR spectroscopy nomenon with a low-intensity, 5- to shows the accumulation, even with 15-minute warm-up period.22 mild exercise, of glycolytic intermedi- ates in the form of phosphorylated Type VII Glycogenosis monoesters. Muscle biopsy shows gly- GSD-VII, also known as Tarui disease, is cogen accumulation in the periphery caused by deficiency of phosphofructo- of the fibers. Biopsies of older patients

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT tend to show abnormal polysaccharide Laboratory features. Serum CK is h Unlike glycogen storage accumulation that stains intensely with normal or mildly elevated. EMG and disease type V, in PAS but is diastase resistant. Immuno- nerve conduction studies are usually glycogen storage histochemistry documents deficiency normal. An abnormal forearm exercise disease type VII the of PFK. test with a flat lactic acid curve can be administration of Molecular genetics. PFK is composed seen. Muscle biopsy results are normal glucose or fructose of three subunitsVliver (PFKL), muscle or may show increased fiber-size var- before physical activity is (PFKM), and platelet (PFKP)Vencoded iability, scattered necrotic fibers, and not beneficial, and in by different genes and expressed in a slight subsarcolemmal accumulation some patients can cause tissue-specific manner. Skeletal muscle of glycogen. Biochemical analysis re- worsening of muscle expresses only the PFKM subunit, veals decreased PBK activity. symptoms. An aerobic conditioning program is whereas, in erythrocytes, five different Molecular genetics. The functional often recommended. heterotetramers of PFKM and PFKL are muscle PBK molecule is a polymer present. The PFKM gene is located on with four subunits: alpha, beta, gam- chromosome 12, and more than 16 ma, and delta.25 The alpha subunit is different mutations have been identi- encoded on chromosome X. The fied so far.23 subunit responsible for muscle disease Treatment. Unlike in GSD-V, the is located on chromosome 16q12-q13. administration of glucose or fructose Treatment. No specific treatment is before physical activity is not benefi- available for this condition. cial in GSD-VII and in some patients can cause worsening of muscle symp- Type IX Glycogenosis toms. An aerobic conditioning pro- GSD-IX results from a deficiency of gram is often recommended. phosphoglycerate kinase (PGK), the enzyme that catalyzes the transfer of Type VIII Glycogenosis the acyl phosphate group of 1,3- GSD-VIII is caused by deficiency of the diphosphoglycerate to adenosine phosphorylase b kinase (PBK) enzyme phosphate (ADP) with formation of that catalyzes the conversion of inac- 3-phosphoglycerate and adenosine tri- tive phosphorylase to the active form. phosphate (ATP) in the terminal stage In addition, the enzyme converts gly- of the glycolytic pathway. cogen synthetase to a less active form. Clinical features. PGK deficiency Clinical features. PBK deficiency is was initially identified in 1968 in the classified in five clinical subtypes dis- erythrocytes of a homozygous female tinguished by inheritance and tissue patient with hemolytic anemia.26 Ad- involvement: liver disease, the most ditional case reports described other frequent, with X-linked inheritance symptoms, including mental retarda- pattern; liver disease with auto- tion, seizures, and stroke. Myopathy as somal recessive inheritance; liver and the predominant manifestation was muscle disease transmitted in an auto- reported in 1981 in a teenager with somal recessive trait characterized by exercise intolerance, cramps, and re- hepatomegaly and nonprogressive current hemoglobinuria. Slowly pro- myopathy in childhood; muscle dis- gressive fixed weakness has also been ease with exercise intolerance and reported. myoglobinuria in an autosomal reces- Laboratory. Serum CK is usually sive pattern; and a fatal infantile form, mildly elevated. Most patients with also autosomal recessive, with severe myopathy do not have hemolytic cardiomyopathy but no liver or skele- anemia. The forearm exercise test tal muscle involvement.24 shows a normal increase in ammonia

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KEY POINT h Potential obstetric without elevation in lactic acid levels. Treatment. No specific medical complications of EMG and nerve conduction studies treatment is available. glycogen storage are usually normal. Muscle biopsy re- disease type XI should sults may be normal or demonstrate Type XI Glycogenosis be discussed with mild diffuse glycogen accumulation Lactate dehydrogenase catalyzes the affected female that is more noticeable with electron interconversion of pyruvate and lac- patients. microscopy. tate with concomitant interconversion Molecular genetics. The human of NADH and the oxidized form of PGK gene is located on Xq13. More nicotinamide adenine dinucleotide than 20 mutations have been identi- (NAD+). fied so far. Clinical features. This is a rare Treatment. No specific medical autosomal recessive disorder charac- therapy is available for the myopathy. terized by exercise intolerance. Most cases have been described in families Type X Glycogenosis of Japanese origin. An associated Phosphoglycerate mutase (PGAM) de- generalized rash has been reported ficiency is a muscle glycogen storage in some cases. Obstetric complica- disease that results in a terminal block tions are common as a result of in glycogenolysis. PGAM catalyzes the uterine stiffness, often requiring a interconversion of 2-phosphoglycerate cesarean section. Chronic renal failure and 3-phosphoglycerate. Two subunits may develop secondary to recurrent are present: muscle (PGAM-M) and myoglobinuria. brain (PGAM-B). Laboratory. Serum CK is elevated Clinical features. Initially described during episodes, with normal lactate in 1981, PGAM deficiency leads to dehydrogenase (LDH). Forearm exer- myopathy characterized by exercise cise test reveals normal increase in intolerance, cramps and recurrent pyruvate level without a rise in lactate. myoglobinuria. Initial symptoms usu- EMG and nerve conduction studies ally develop in late childhood or are normal. Results of muscle biopsy adolescence. The disease is more are usually normal, but biochemical common in African Americans. assay reveals reduced LDH activity. On Laboratory. Serum CK is usually gel electrophoresis, less than 5% of mildly elevated between attacks. The the LDH-M isoform is present in exercise forearm test fails to show a muscle and blood. normal rise in lactate. EMG is usually Molecular genetics. LDH is a tetra- normal. Muscle biopsy reveals in- meric enzyme composed of two creased glycogen deposits by PAS or subunits, M and H. The gene encod- electron microscopy. Tubular aggre- ing the M subunit consists of seven gates have been reported in six out of exons and is located on chromosome 15 cases.27 Biochemical assay demon- 11p15.4. strates markedly diminished activity of Treatment. No specific medical PGAM. treatment is available. Potential obstetric Molecular genetics. The PGAM-M complications should be discussed with gene is located on chromosome 7p12- affected female patients. 7p13. The most common gene defect is a nonsense mutation at codon 78, Type XII Glycogenosis but different mutations have been GSD-XII is caused by deficiency of described in Italians, Japanese, and aldolase A. This enzyme catalyzes the Pakistani patients. conversion of fructose 1,6-phosphate

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS to dihydroxyacetone phosphate and decade of life with exercise intoler- h Glycogen storage glyceraldehyde 3-phosphate. ance and episodic rhabdomyolysis. A disease type XII presents Clinical features. GSD-XII presents second-wind phenomenon has been during childhood with during childhood with hemolytic ane- described, and patients may later hemolytic anemia, mia, jaundice, proximal weakness, and develop fixed weakness. jaundice, proximal episodic rhabdomyolysis triggered by Laboratory. Serum CK is mildly weakness, and episodic febrile illness. elevated at rest and increases during rhabdomyolysis Laboratory. Serum CK is elevated attacks. The forearm exercise test triggered by febrile after exercise, febrile events, or anes- shows normal elevation of lactate with illness. thesia. Muscle pathology reveals vari- up to 4 times increase in ammonia. h Triosephosphate able fiber size, and electron microscopy Muscle biopsy may reveal abnormal isomerase deficiency is shows distorted mitochondria and oc- glycogen deposition. the most severe casional lipid accumulations. Molecular genetics. Mutations in glycolytic enzyme defect Molecular genetics. GSD-XII is an PGM1 located on chromosome 1p31.3 associated with autosomal recessive disorder second- are responsible for this disease. progressive neurologic dysfunction. ary to mutations localized to chromo- Treatment. No specific medical some 16q22-q24. therapy is available for this disease. Treatment. No specific medical treatment is available. Triosephosphate Isomerase Deficiency Type XIII Glycogenosis Triosephosphate isomerase (TPI) en- "-Enolase is a metalloenzyme responsi- zyme catalyzes the reversible intercon- ble for the catalysis of the conversion of version of the triose phosphate 2-phosphoglycerate to phosphoenol- isomers dihydroxyacetone phosphate pyruvate, the ninth and penultimate and D-glyceraldehyde 3-phosphate. step of glycolysis. Clinical features. TPI deficiency is Clinical features. A single case re- the most severe glycolytic enzyme port is available of a middle-aged man defect associated with progressive with exercise intolerance, myalgias, and neurologic dysfunction. Onset is usually no associated systemic symptoms. before 2 years of age with hemolytic Laboratory. Serum CK is elevated anemia, recurrent infections, slowly during episodes but otherwise nor- progressive proximal and facial weak- mal. Muscle biopsy reveals abnormal ness, and CNS dysfunction (including glycogen deposition in the cytoplasm. mental retardation, dystonia, cerebellar Selective "-enolase deficiency is dem- symptoms, and tremor). Some patients onstrated by immunohistochemistry. develop an associated sensorimotor Molecular genetics. Missense mu- polyneuropathy. Survival is limited, tations (Gly156Asp and Gly374Glut) with most children dying before 6 years located on chromosome 17 have been of age. identified. Laboratory. Serum CK is normal or Treatment. No specific medical mildly elevated. Nerve conduction treatment is available. studies can be normal or show changes consistent with an axonal sensorimotor Type XIV Glycogenosis polyneuropathy. EMG shows myopathic Phosphoglucomutase 1 catalyzes the potentials. Muscle pathology reveals transfer of phosphate between posi- fiber degeneration and regeneration tions 1 and 6 of glucose. with increased glycogen in some mus- Clinical features. Affected individ- cle fibers. Biochemical analysis reveals uals present during the first or second reduced TPI activity in different tissues.

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KEY POINT h Children with carnitine Molecular genetics. The TIM gene chronic hemodialysis, and malnutrition) deficiency present with is located on chromosome 12p13, and with certain medications (valproate, myopathy, elevated and the most common mutation is zidovudine). 28 creatine kinase, and Glu104Asp. Clinical features. Systemic primary cardiomyopathy, while Treatment. No specific medical carnitine deficiency is an autosomal adults present with therapy is available. recessive disorder of carnitine trans- fatigability. Pregnancy portation characterized by episodes may unmask symptoms DISORDERS OF LIPID METABOLISM of hypoketotic hypoglycemia, hepato- such as decreased Carnitine Transporter Deficiency megaly, elevated transaminases, and stamina and cardiac Carnitine transporter deficiency is hyperammonemia in infants. Children arrhythmias. the most common disorder of lipid present with myopathy, elevated CK, metabolism (Table 3-4). It can be and cardiomyopathy, while adults pres- primaryVas a result of mutations in ent with fatigability. Pregnancy may the gene codifying for the sodium- unmask symptoms such as decreased dependent carnitine transporter (OCTN2), stamina and cardiac arrhythmias. a protein responsible for the transport Laboratory. Serum CK can be normal of carnitine across cell membranesVor in almost half of affected patients, but secondary to systemic conditions (in- elevations up to 15 times normal can cluding renal Fanconi syndrome, organic also be seen. EMG may be normal or acidurias, respiratory chain defects, reveal myopathic motor unit potentials

TABLE 3-4 Disorders of Lipid Metabolism

Disorder Gene and Chromosome Neuromuscular Symptoms Primary systemic carnitine deficiency SCL22A5 Children: Proximal myopathy Adults: Fatigability and exercise intolerance Primary myopathic carnitine deficiency Unknown Proximal weakness and atrophy, neck weakness Carnitine palmitoyltransferase II CPT2 gene located Neonates: Hypotonia (CPT2) deficiency in chromosome 1p32 Adults: recurrent myoglobinuria Very long-chain acyl coenzyme A ACADVL gene located Adults: Exercise induced symptoms dehydrogenase deficiency in chromosome 17p13.1 Long-chain acyl coenzyme ACADL gene located in Infancy: Failure to thrive A dehydrogenase deficiency chromosome 2q34-q35 Adults: Exercise intolerance Medium-chain acyl coenzyme A ACADM gene located Adults: Exercise intolerance dehydrogenase deficiency in chromosome 1p31.1 Short-chain acyl coenzyme ACADS gene located Ophthalmoplegia, ptosis, facial A dehydrogenase deficiency in chromosome 12q24.1 weakness, proximal weakness or exercise intolerance Long chain 3 hydroxy/acyl LCHAD Infancy: Failure to thrive, hypotonia coenzyme A dehydrogenase Adults: Exercise induced myalgias deficiency Multiple acyl coenzyme A ETFA gene located in Proximal weakness and myalgias dehydrogenase deficiency chromosome15q24.2-q24.3 in adults

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT with increased insertional activity in the Clinical features. Phenotypical ex- h In adults, carnitine form of fibrillations, positive sharp pression of CPT II deficiency is depen- palmitoyltransferase II waves, or complex repetitive dis- dent on the severity of enzyme deficiency is the most charges, especially in severe cases. Liver deficiency and has been described in common cause of enzymes are also elevated in the pri- a severe neonatal form, severe infan- recurrent myoglobinuria. mary systemic form. Echocardiogram tile form, and, more commonly, an may reveal a dilated or hypertrophic adult myopathic form. cardiomyopathy. Reduced carnitine The lethal neonatal form begins levels in plasma, liver, heart, and muscle during the first few days of life with are present. Muscle biopsy demonstrates encephalopathy, cardiomyopathy, hy- vacuoles as well as abnormal accumula- poglycemia, hepatomegaly, and sei- tion of lipid in the subsarcolemmal zures. Death usually occurs during and intermyofibrillar regions. Electron the first week. Fasting or infection microscopy also reveals lipid deposition. usually triggers the severe infantile Type I fibers are preferentially affected. form; common manifestations include Muscle carnitine levels are severely de- hypoglycemia, hepatomegaly, cardiac creased (less than 2% to 4% of normal arrhythmias and cardiomyopathy, hy- levels) in patients with the primary form, potonia, and weakness. In adults, CPT compared with secondary causes in II deficiency is the most common which free levels are moderately re- cause of recurrent myoglobinuria. duced (25% to 50%). Diagnosis can be Usual manifestations include myalgias confirmed through genetic testing or and cramps after intense or prolonged skin biopsy with assessment of carnitine exercise, febrile illness, or fasting transport in skin fibroblasts (less than (Case 3-3). Medications like valproate 10% of normal levels). sometimes can trigger these symp- Molecular genetics. This disorder toms. Physical examination usually is transmitted in an autosomal reces- shows normal findings between sive pattern, and is due to mutations attacks. of the SLC22A5 gene located on chro- Laboratory. Serum CK is normal or mosome 5q23. More than 100 muta- mildly elevated between attacks and tions have been reported so far. increases significantly during episodes Treatment. Patients may benefit of rhabdomyolysis. Serum carnitine from oral carnitine 50 mg/kg/d to levels are normal or mildly decreased. 400 mg/kg/d divided in three doses.29 Forearm exercise test findings are Common side effects include diarrhea normal, and EMG can be normal or and abdominal discomfort. During show myopathic units. Muscle pathol- acute episodes, IV glucose may be ogy can be normal or reveal increased helpful. Patients should follow a low- lipid content, especially with electron fat diet and avoid fasting. microscopy. Tandem mass spectrom- etry of serum/plasma acylcarnitines Carnitine Palmitoyltransferase (ie, the acylcarnitine profile) helps to II Deficiency reach a diagnosis. The finding sugges- CPT II is a peripheral inner mitochondrial tive of a defect in mitochondrial beta- membrane protein that catalyzes the oxidation (and therefore suspect transesterification of palmitoylcarnitine for CPT II deficiency) is an elevation back into palmitoylYcoenzyme A (CoA), of C12 to C18 acylcarnitines (in which which is now an activated substrate C stands for the number of carbon for beta-oxidation inside the matrix atoms), notably of C16 and C18:1. The (Figure 3-5). differential diagnosis for an elevation

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FIGURE 3-5 Schematic illustration of the oxidation of fatty acids in mitochondria. Short- and medium-chain fatty acids (SMCFA) freely cross the mitochondrial membrane, whereas long-chain fatty acids (LCFA) require a specific transporter system. Acyl coenzyme A (acyl-CoA) synthetase transforms the LCFA into acyl-CoA, and the coenzyme A (CoA) is exchanged for carnitine by carnitine palmitoyltransferase I (CPT I). Acylcarnitine is then transported across the inner mitochondrial membrane by carnitine acylcarnitine translocase (CAT). Carnitine is removed from acylcarnitine by carnitine palmitoyltransferase II (CPT II) to form acyl-CoA, which can undergo beta oxidation.

Modified with permission from van Adel BA, Tarnopolsky MA, J Clin Neuromuscul Dis.1 B 2009, Lippincott Williams & Wilkins. journals.lww.com/jcnmd/Abstract/2009/03000/Metabolic_Myopathies__Update_2009.3.aspx.

of C12 to C18 acylcarnitines includes cise and fasting. A small case study glutaric acidemia type II and carnitine- with bezafibrate 200 mg 3 times a acylcarnitine translocase deficiency, day showed significant increase in which can be excluded by additional palmitoyl L-carnitine levels and reduced screening of urinary metabolites such frequency of attacks.30 Another small as glutaric and 3-OH-glutaric acids. study with triheptanoin diet (30% of Diagnosis is confirmed by detection daily calories) demonstrated increased of reduced CPT II enzyme activity in exercise tolerance.31 skeletal muscle homogenates or cultured skin fibroblasts. Very-Long-Chain Acyl–Coenzyme Molecular genetics. CPT II deficiency ADehydrogenaseDeficiency is caused by mutations on chromosome Very-long-chain acyl-CoA dehydroge- 1p32 (most commonly p.Ser113Leu, nase (VLCAD) is involved in the initial p.Pro50His, and p.Lys414ThrfsX7). If step of mitochondrial beta-oxidation, none or only one of these mutations is and is active toward CoA esters of identified, sequence analysis of the longer-chain substrates: arachidoyl-CoA, entire coding region can be performed. behenoyl-CoA, and lignoceroyl-CoA. Treatment. Patients are advised Clinical features. Three phenotypes to follow a low-fat diet with frequent have been identified: an infantile form meals and to avoid prolonged exer- with recurrent hypoketotic hypoglycemia,

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 3-3 h Infants with the more severe forms of A 20-year-old college student presented to the emergency department very-long-chain with progressive, severe incapacitating pain in both thighs, inability to acylYcoenzyme A walk, and dark urine. The day before, she had been asymptomatic and dehydrogenase are participated in a strenuous 3-hour soccer practice. She had a history of typically placed on a occasional muscle cramps during exercise but never as severe. She denied low-fat formula, with any drug use, and her personal and family history were unremarkable. supplemental calories Examination revealed severe tenderness to palpation of both quadriceps provided through muscles, and mild tenderness to palpation of the gastrocnemius muscles. medium-chain Strength was 5/5 in upper extremities, 2/5 hip flexion and knee extension triglycerides. with significant limitations due to pain, and 5/5 strength distally. Deep tendon reflexes, sensory examination findings, and coordination were normal. Initial laboratory tests were remarkable for mild leukocytosis, with 12,500 white blood cells/6L; creatine kinase (CK) 210,000 U/L; aspartate aminotransferase (AST) 9600 IU/L; creatinine 2.4 mg/dL; and blood urea nitrogen (BUN) 32 mg/dL. MRI showed diffuse swelling of the quadriceps muscles with blurred margins and hyperintense signal on short T1 inversion recovery (STIR) and T2-weighted images, and hypointense to isointense signal on T1-weighted image. After hydration and rest, her kidney function and serum CK gradually normalized. Later, a forearm exercise test was performed, with normal results. Serum carnitine levels were normal, and acylcarnitine profile showed a high ratio of palmitoyl carnitine (C16:0) and oleoyl carnitine (C18:1) to acetylcarnitine (C2). Muscle biopsy performed 6 weeks after the episode showed mild fiber type 2 predominance, and carnitine palmitoyltransferase II (CPT II) activity was very reduced (less than 10% of normal levels). Comment. CPT II is the most common cause of myoglobinuria in adults. Usual trigger factors include prolonged strenuous exercise or fasting. The forearm exercise test helps to exclude certain glycogen storage disorders such as McArdle disease. Serum carnitine is normal or mildly decreased, and the acylcarnitine profile helps to narrow the differential diagnosis. CPT II enzyme activity or genetic testing are confirmatory.

hepatomegaly, cardiomyopathy, hypo- reduced. In addition, VLCAD protein tonia, and very high mortality; a hepatic activity in fibroblasts is decreased. form with episodic hypoglycemia, hepa- Molecular genetics. VLCAD defi- tomegaly but no systemic involvement, ciency is an autosomal recessive dis- and low mortality rate; and a rare order secondary to mutations in the myopathic form in children or adults gene ACADVL located on chromo- with episodic myalgias, rhabdomyolysis, some 17p13.1. and variable systemic features. Treatment. Infants with the more Laboratory. Serum CK is normal severe forms are typically placed on a except in cases of myoglobinuria. Free low-fat formula, with supplemental plasma carnitine level is normal or calories provided through medium- mildly decreased. Acylcarnitine profile chain triglycerides (MCT). A variety of shows elevated tetradecanoic acid strategies for the low-fat diet are used, (C14:1). Muscle biopsy results are ranging from 13% to 39% of calories as normal or may show increased lipid total fat, with an additional 15% to deposition. VLCAD immunostain is 18% of calories supplied as MCT oil for

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patients most strictly restricted from of children with LCAD deficiency after long-chain fats. Extra MCT have dem- exercise.32 onstrated benefit in older patients with long-chain defects who have Medium-Chain Acyl–Coenzyme exercise intolerance. Triheptanoin A Dehydrogenase Deficiency has been used in a few individuals Medium-chain acyl-CoA dehydroge- with the goal of providing calories as nase (MCAD) works in the degrada- well as anaplerotic (ie, alternative tion of fatty acyl-CoA derivatives substrate) carbons; however, its efficacy whose acyl residues contain four to remains controversial. 14 carbon atoms. Clinical features. MCAD is the Long-Chain Acyl–Coenzyme A most common form of acyl-CoA defi- Dehydrogenase Deficiency ciency, but it is rarely associated with Long-chain acyl-CoA dehydrogenase skeletal muscle or cardiac disease. (LCAD) acts on fatty acyl-CoA deriva- Typical presentation is very similar to tives whose acyl residues contain LCAD, presenting before 2 years of more than 12 carbon atoms; patients age with lethargy, hypoketotic hypo- with LCAD deficiency, therefore, have glycemia, hepatomegaly, and enceph- impaired ability to metabolize long- alopathy. Older children and adults chain fatty acids. can have exercise-induced symptoms Clinical features. Phenotypical var- or mild myopathy. iation is significant, but most patients Laboratory. CK level is usually present during infancy with failure to normal. Carnitine levels are low. thrive, hepatomegaly, cardiomegaly, Dicarboxylic, adipic, and sebacic acids nonketotic hypoglycemia, and en- are increased in urine. MCAD activity cephalopathy. Other presentations in- is diminished to less than 10% in clude exercise-induced rhabdomyolysis muscle, fibroblasts, and liver. in adults or progressive limb-girdle Molecular genetics. Mutations in weakness. the gene ACADM located on chromo- Laboratory. Serum CK is normal some 1p31.1 are responsible for this between attacks. Total and free carni- disorder (K304E is the most common). tine levels are reduced, but long-chain Treatment. Patients should avoid acylcarnitine esters are increased. Oil fasting for more than 12 hours, and Red O staining of muscle biopsies infants affected should have frequent demonstrates increased lipid deposi- feedings and receive 2 g/kg of uncooked tion. Diagnosis can be confirmed with cornstarch at bedtime. A relatively low- reduced LCAD enzyme activity in fat diet may also be beneficial. cultured fibroblasts. Molecular genetics. LCAD deficiency Short-Chain Acyl–Coenzyme A is an autosomal recessive disorder Dehydrogenase Deficiency caused by mutations of the ACADL gene Short-chain acyl-CoA dehydrogenase located on chromosome 2q34-q35. (SCAD) enzyme acts on fatty acyl-CoA Some patients previously diagnosed derivatives whose acyl residues contain with LCAD deficiency may actually have four to six carbon atoms. VLCAD deficiency, a much more com- Clinical features. Affected infants mon disorder. present with failure to thrive and non- Treatment. MCT supplementation ketotic hypoglycemia. Older patients during periods of increased activity may present with ophthalmoplegia, pto- may improve the metabolic control sis, facial weakness, and cardiomyopathy,

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT or exercise-induced symptoms and pro- structural, biochemical, or genetic de- h The most common gressive weakness. fects in the mitochondria. The most neuromuscular feature Laboratory. Serum CK is usually common neuromuscular feature of mi- of mitochondrial disease normal apart from episodes of rhab- tochondrial disease is myopathy, causing is myopathy, causing domyolysis. Urinary excretion of proximal weakness often accompanied proximal weakness ethylmalonate and methylsuccinate is by exercise intolerance out of propor- often accompanied by increased. tion to the weakness. Ptosis and chronic exercise intolerance out Molecular genetics. Mutations in progressive external ophthalmoparesis of proportion to the the ACADS gene located on chromo- are also common manifestations, often weakness. some 12q24.31 are responsible for this associated with dysphagia.33 Peripheral disorder. neuropathies are common. Table 3-5 Treatment. Patients should avoid shows the most frequent mitochondrial fasting for long periods of time. disorders associated with myopathy. Given the considerable heterogeneity Multiple Acyl–Coenzyme A of these disorders, a detailed descrip- Dehydrogenase Deficiency tion of each mitochondrial disorder is (MADD) beyond the scope of this article, and Electron-transfer-flavoprotein alpha- only some of the most common entities polypeptide (ETFA) participates in cat- are reviewed. alyzing the initial step of the mitochondrial fatty acid beta-oxidation. It Myoclonic Epilepsy With shuttles electrons between primary Ragged Red Fibers flavoprotein dehydrogenases and the Myoclonic epilepsy with ragged red membrane-bound electron transfer fla- fibers (MERRF) is a multisystem disorder voprotein ubiquinone oxidoreductase. characterized by myoclonus followed by Clinical features. MADD most generalized epilepsy, ataxia, weakness, commonly affects adults in the third and dementia.34 or fourth decade of life, with proximal Clinical features. Myoclonus is usu- weakness and myalgias. A severe neo- ally the first symptom, most commonly natal form is characterized by acidosis, emerging during late adolescence or hypoglycemia, and high mortality rate. young adulthood. Myoclonus can be Laboratory. Serum CK is usually stimulus-sensitive or present at rest, elevated 2 to 20 times above normal. and generalized seizures may frequently EMG shows myopathic changes. Car- occur. nitine levels are reduced while urine Other common manifestations in- glutaric and ethylmalonic acids are clude ataxia, sensorineural hearing loss, elevated. short stature, dementia, optic atrophy, Molecular genetics. MADD is caused muscular weakness, and atrophy. An by mutations in the gene codify- associated sensorimotor polyneuropathy ing ETFA located on chromosome with pes cavus can be seen. Clinical 15q24.2-q24.3. features and age of onset are variable, Treatment. Riboflavin (100 mg/d) and not all patients present with the full seems to be beneficial in some patients. syndrome. Other, less common systemic The effect of carnitine supplementation features include cardiac arrhythmias with and coenzyme Q10 is controversial. conduction block, pigmentary retinopathy, pyramidal signs, and multiple MITOCHONDRIAL MYOPATHIES lipomatosis. This condition is inherited The mitochondrial myopathies are a in a mitochondrial pattern, which is also complex group of diseases related to known as maternal inheritance.

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TABLE 3-5 Most Common Mitochondrial Disorders Associated With Myopathies

Disease Genetics Clinical Features Myoclonic epilepsy with A8344G; T8356C; G8363A; G8361A Epilepsy (myoclonic and tonic-clonic), ragged red fibers (MERRF) myoclonus, cognitive decline, Maternal sensorineural hearing loss, ataxia, optic atrophy, multiple lipomatosis, weakness, and muscle atrophy Mitochondrial encephalopathy, A3243G; T3271C; A3260G Strokelike episodes, headaches, lactic lactic acidosis, and strokelike acidosis, myopathy, cognitive decline, Maternal episodes (MELAS) sensorineural hearing loss, ataxia, optic atrophy, polyneuropathy Kearns-Sayre syndrome Deletion of mitochondrial DNA Progressive external ophthalmoplegia, (most common 4977 base pigmentary retinopathy, cardiac pairs from 8488 to 13,460) conduction block, endocrinopathies, sensorineural hearing loss, ataxia, Sporadic and familial myopathy, and cognitive decline Progressive external Deletions of mitochondrial DNA Slowly progressive ophthalmoplegia ophthalmoplegia and bilateral ptosis, proximal Sporadic myopathy, sensory ataxic neuropathy, Maternal (transfer RNA Leu, transfer cardiomyopathy, and parkinsonism RNA Ile, transfer RNA Asn) Autosomal dominant (POLG, C10ORF2, ANT1) Autosomal recessive (POLG) Mitochondrial neurogastrointestinal Deletions of mitochondrial DNA Ptosis, progressive external encephalopathy (MNGIE) Autosomal recessive TYMP mutations ophthalmoplegia, gastrointestinal dysmotility, peripheral neuropathy, myopathy, and leukoencephalopathy

Laboratory. Serum CK is normal or may lack cytochrome oxidase activity. mildly elevated. Lactate and pyruvate On electron microscopy, an increased are commonly elevated at rest and number of enlarged mitochondria with increase with physical activity. Brain- abnormal cristae and occasional inclu- imaging studies may reveal cerebral sions can be seen. and cerebellar atrophy. Nerve conduc- Molecular genetics. The mitochon- tion studies may demonstrate an axo- drial DNA (mtDNA) gene MT-TK nal polyneuropathy, and EMG often encoding transfer RNA (tRNA) lysine shows myopathic potentials. Muscle is the gene most commonly associated biopsy reveals subsarcolemmal accu- with MERRF. Four MT-TK mutations mulation of abnormal mitochondria, (m.8344A9G, m.8356T9C, m.8363G9A, best seen on the modified trichrome and m.8361G9A) account for approxi- stain, giving the characteristic appear- mately 90% of cases.35 ance of ‘‘ragged red’’ fibers (Figure 3-6). Treatment. No specific treatments These fibers may be more basophilic are available. Seizures should be man- and granular with hematoxylin aged with appropriate anticonvulsants. and eosin, and they react intensely Aerobic exercise is helpful, and physical with succinic dehydrogenase and therapy might improve some impaired NADHYtetrazolium reductase (TR) and motor abilities.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT h Common clinical features of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome include headaches, seizures, hearing loss, muscle weakness with exercise intolerance, and strokelike episodes, which typically improve or FIGURE 3-6 Ragged red fibers revealed by the modified Gomori one-step trichrome stain (A) fluctuate (usually cortical and combined cytochrome oxidase/succinate dehydrogenase stain (B). They are formed by the subsarcolemmal accumulation of abnormal mitochondria. blindness, hemianopia, hemiparesis). Attacks may Courtesy of Derek A. Mathis, MD. be precipitated by exercise or infection. Mitochondrial lactate levels. Serial brain MRI shows Encephalomyopathy, lesions that are not restricted to Lactic Acidosis, and Strokelike arterial territories and migrate over Episodes Syndrome time. They often affect the occipital/ Mitochondrial encephalomyopathy, parietal regions. Deep gray matter lactic acidosis, and strokelike episodes structures like the thalami can also (MELAS) syndrome is a metabolic be affected. Brain lesions tend to disorder that usually presents with affect the cortical ribbon with relative seizures and strokelike events in sparing of the deep white matter. young people. It is a prototypical EMG may be normal, although, in mitochondrial disorder in that it ex- patients with severe weakness, it can hibits a maternal pattern of inheritance show myopathic potentials. Muscle and features a variable proportion of biopsy findings in MELAS syndrome mutated mitochondria in different are similar to those described in tissues over time (heteroplasmy). It MERRF. affects tissues of high metabolic de- Molecular genetics. MELAS syn- mand (brain, muscle), and a given drome is caused in approximately tissue appears to require a certain 80% of cases by a mitochondrial RNA level of affected mitochondria before (mtRNA) Leu (MTTL1)mutation clinical symptoms occur (threshold (A3243G). Other, less common muta- effect).36 tion foci include T3271C and A3252G. Clinical features. Common clinical Mutations in MTTV, MTTK, MTTF, features of MELAS syndrome include MTTS1, MTND5, MTND4, and MTCYB headaches, seizures, hearing loss, have all been described with MELAS muscle weakness with exercise intoler- syndrome. ance, and strokelike episodes, which Treatment. Different treatment ap- typically improve or fluctuate (usually proaches have been tried in patients cortical blindness, hemianopia, with MELAS syndrome, with mixed hemiparesis). Attacks may be precipi- results. A 3-year randomized study tated by exercise or infection. with dichloroacetate was stopped early Laboratory. Serum CK may be because of a very high incidence or elevated or normal. The majority of worsening of polyneuropathy. Coen- patients have raised CSF and serum zyme Q10 is considered safe but has

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KEY POINT h Recommended poor CNS penetration and has been Treatment. Recommended strategies strategies for treatment tried in several small studies with for treatment include the placement of of Kearns-Sayre variable success. L-Arginine showed cardiac pacemakers in individuals with syndrome include the promise in the acute treatment of cardiac conduction blocks, cochlear im- placement of cardiac strokelike episodes, but additional data plants and hearing aids for sensorineural pacemakers in are required.37 hearing loss, hormone replacement for individuals with cardiac endocrinopathies, folic acid supplemen- conduction blocks, Kearns-Sayre Syndrome tation in individuals with KSS with low cochlear implants and The diagnosis of Kearns-Sayre syndrome CSF folic acid, administration of coen- hearing aids for (KSS) is based on three classic features: zyme Q10 and L-carnitine, and rehabili- sensorineural hearing progressive externalophthalmoplegia, tation services. loss, hormone pigmentary retinopathy, and heart block. replacement for Mitochondrial endocrinopathies, folic Clinical features. Symptoms usually Neurogastrointestinal acid supplementation in develop before the second decade of individuals with low CSF life. Accompanying features may in- Encephalopathy folic acid, administration clude proximal myopathy, short stat- The main clinical components of of coenzyme Q10 ure, dementia, ataxia, sensorineural mitochondrial neurogastrointestinal en- and L-carnitine, and hearing loss, and endocrinopathies. cephalopathy (MNGIE) include severe rehabilitation services. This condition is generally not in- gastrointestinal dysmotility, cachexia, herited but arises from mutations in ptosis, external ophthalmoplegia, the body’s cells that occur after con- sensorimotor polyneuropathy, and ception. Rarely, it can be transmitted leukoencephalopathy. with a maternal inheritance pattern. Clinical features. Patients develop Laboratory. Serum CK is usually muscle weakness and atrophy, more normal. Serum lactate and pyruvate are prominent distally. Sensation is com- commonly elevated, and CSF reveals monly lost in a stocking and glove high protein and homovanillic acid levels pattern, and patients are hyporeflexic with very low 5-methyltetrahydrofolate. or areflexic. Ptosis and ophthalmoparesis Conduction defects can be seen on are present in most patients. Other ECG. EMG may be normal or demon- accompanying symptoms may include strate myopathic potentials. Nerve con- pigmentary retinopathy, sensorineural duction studies are normal unless an hearing loss, facial weakness, and associated axonal sensory or sensori- dysarthria (Case 3-4). The earliest motor polyneuropathy is present. Mus- and most common symptoms are cle biopsy shows ragged red fibers, related to gastrointestinal dysmotility: with most fibers being cytochrome dyspepsia, bloating, cramps, intoler- oxidase (COX)Ynegative. ance of large meals, nausea, vomiting, Molecular genetics. More than and diarrhea.38 This condition is 150 different mtDNA deletions have transmitted in an autosomal recessive been associated with KSS. A deletion pattern. of 4977 base pairs known as Laboratory. Brain MRI reveals prom- m.8470_13446del4977 is encountered inent white matter changes even in the most frequently. The same mutation absence of significant hemispheric and numerous other types of deletions symptoms. Serum CK is normal or of varying length have been identified mildly elevated. Plasma thymidine levels in Pearson syndrome (sideroblastic greater than 3 6mol/L and deoxyuridine anemia and exocrine pancreas dys- concentration greater than 5 6mol/L function) and progressive external can be sufficient to confirm the diagno- ophthalmoplegia (PEO). sis. Thymidine phosphorylase enzyme

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 3-4 A 26-year-old woman was admitted to the hospital for evaluation of nausea, vomiting, and progressive weight loss. Symptoms had been present intermittently over the past 9 months, and she had lost at least 20.4 kg (45 lbs). A neurologic consult was requested as she also reported proximal and distal weakness affecting the lower extremities, mild distal paresthesia, and increased difficulty walking. Her medical and family history were unremarkable, and she had no history of drug or toxic exposure. Neurologic examination was positive for mild bilateral ptosis with restriction of horizontal eye movements. No muscle atrophy was evident, and strength examination showed Medical Research Council (MRC) grade 4/5 bilaterally in the hip flexors, abductors, and knee extensors, with grade 4+/5 in the tibialis anterior and gastrocnemius. Deep tendon reflexes were mildly decreased (1+) symmetrically in both lower extremities. Sensory examination showed mildly decreased vibratory sensation in both feet. Serum creatine kinase was normal, and both serum lactate and pyruvate were mildly elevated. Nerve conduction studies revealed a mild mixed axonomyelinic polyneuropathy. Needle EMG showed some chronic reinnervation changes in distal muscles but also myopathic motor unit potentials without fibrillations or positive sharp waves in the iliopsoas, quadriceps, and gluteus medius. Muscle biopsy of the right vastus lateralis showed ragged red fibers (Figure 3-6A)withcyclooxygenase-negative fibers and succinic dehydrogenaseYpositive fibers. Thymidine phosphorylase enzyme activity in leukocytes was less than 10%. Comment. The combination of gastrointestinal dysmotility, polyneuropathy, myopathy, ptosis, and external ophthalmoplegia is consistent with mitochondrial neurogastrointestinal encephalopathy (MNGIE). A mitochondrial myopathy is confirmed with muscle biopsy findings, and a definite diagnosis could be reached by measuring thymidine phosphorylase activity or plasma thymidine and deoxyuridine levels, or with molecular testing. activity in leukocytes less than 10% can in 100% of individuals with enzymatically also be confirmatory. Nerve conduction proven MNGIE disease. POLG1 muta- studies show demyelinating or mixed tions may cause MNGIE-like syndrome axonomyelinic changes. EMG varies without leukoencephalopathy and nor- according to muscle selection with mal thymidine plasma levels.39 possible denervation and chronic Treatment. Early attention to swal- reinnervation changes, while in proxi- lowing difficulties and airway protection mal muscles a myopathic pattern can are very important, and nutritional be seen. Muscle biopsy demonstrates support should be provided. No specif- ragged red fibers, increased NADH and ic medical therapy is available for this succinic dehydrogenase staining, and disease. Liver transplantation remains COX-negative staining. Reduced COX controversial, and stem cell transplanta- and other respiratory complex activi- tion shows some promising results. ties are demonstrable on biochemical assays of muscle tissue. CONCLUSIONS Molecular genetics. Mutations are The discovery of the basic genetic and detected in genomic DNA by sequenc- biochemical changes responsible for the ing the TYMP exons and flanking regions development of metabolic myopathies

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