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Metabolic Myopathies of Texas Health Science Center San Antonio, 8300 Floyd Curl Alejandro Tobon, MD Drive, San Antonio, TX, 78229, [email protected]

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Metabolic Myopathies of Texas Health Science Center San Antonio, 8300 Floyd Curl Alejandro Tobon, MD Drive, San Antonio, TX, 78229, Tobon@Uthscsa.Edu Review Article 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. Continuum (Minneap Minn) 2013;19(6):1571–1597. 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 Continuum (Minneap Minn) 2013;19(6):1571–1597 www.ContinuumJournal.com 1571 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Metabolic Myopathies 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. 1572 www.ContinuumJournal.com December 2013 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. Continuum (Minneap Minn) 2013;19(6):1571–1597 www.ContinuumJournal.com 1573 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Metabolic Myopathies TABLE 3-2 Glycogen Storage Disorders Associated With Myopathies Name of Enzyme, Gene, Static
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