Ahmad, Humzah

Bhai, Salman

Cai, Chunyu

Govil, Malvika

English

The University of Kansas: Journals@KU

Clinic Stuff35This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.org/licenses/by-nc-nd/4.0/)RRNMF Neuromuscular Journal 2024;5(1)Rhabdomyolysis and exercise intolerance in a 45-year-old manHumzah Ahmad1*, Malvika Govil BA1*, Naysa Modi2, Chunyu Cai MD3, Salman Bhai MD1*Co-First Authors1Department of Neurology, University of Texas Southwestern Medical School, Dallas, TX2University of Texas at Austin3Department of Pathology, University of Texas Southwestern Medical School, Dallas, TXABSTRACTA 45-year-old man presented to neuromuscular clinic after a first-time episode of non-traumatic rhabdomyolysis after aerobic exercise. Prior to his diagnosis, he had an extensive medical workup to evaluate for elevated transaminases and creatinine, including liver and renal biopsies. On history, the patient confirmed a lifelong history of exercise intolerance. Creatine kinase evaluation revealed an elevated baseline value. Genetic testing disclosed homozygous variants of uncertain significance and required exercise testing and muscle biopsy to identify the underlying etiology. This case demonstrates pitfalls of genetic testing and an approach to identify this form of myopathy.Section 1A 45-year-old man presented to neuromuscular clinic for an episode of non-traumatic rhabdomyolysis. He had a history of elevated transaminases for which he underwent two liver biopsies, seven years and one year prior to his clinic visit, and was diagnosed with fatty liver disease. He was noted to have an elevated creatine kinase (CK) to the 3800s U/L after his second liver biopsy. He had repeat CK values that were elevated but less than 1000 U/L. After performing routine aerobic exercise, he developed muscle weakness and dark colored urine. He was admitted for further work-up. CK was >35,000 U/L and creatinine (Cr) peaked at 6.66. A renal biopsy was performed and was normal. His CK and Cr improved with intravenous fluids. MRI of his proximal lower limbs and EMG were normal. During his initial clinic visit, he described difficulty with exercise since childhood. He had no prior identifiable episodes of rhabdomyolysis or myoglobinuria. He denied weakness, cramping, contractures, rashes, dyspnea, and dysphagia. There was no family history of muscle or metabolic disorders. The neurological exam was normal. There were no rashes and lungs were clear to auscultation bilaterally. Questions for consideration:1. What diagnoses should be considered?2. What tests would you perform next?Section 2The patient’s symptoms localize to the muscles given the elevated CK and rhabdomyolysis.  Normal EMG and strength exam do not eliminate a myopathy from the differential. The patient’s reported persistent exercise difficulty since childhood and rhabdomyolysis were most suggestive of a metabolic (glycolysis/glycogenolysis and fatty acid oxidation disorders) or mitochondrial myopathy. Typically, glycogen-storage disorders present during periods of high-intensity exercise, whereas fatty acid oxidation disorders and mitochondrial myopathies present during longer duration endurance-type activities or periods of metabolic stress such as surgery or infection. Given the non-specific history of exercise intolerance, further investigation was needed to differentiate between these. There were no systemic features which could point to a specific subtype of fatty acid oxidation disorder. There were no specific features such as proximal weakness or a rash that would suggest an inflammatory myopathy. The patient was not taking statins or cortico- or anabolic steroids, which excluded forms of drug-induced myopathy.Comprehensive testing was performed to narrow the diagnosis. Repeat CK was 609 U/L. A neuromuscular disorders gene panel (Invitae, next-generation sequencing) was obtained and revealed a pseudodeficiency allele in GAA and homozygous variant of uncertain significance in PYGM (c.403G>A [p.Gly135Arg]). Non-ischemic forearm test (NIFT) (Table 1A) and cycle exercise test (Table 1B) were performed. Cycle exercise test showed elevated heart rate (HR) and rate of perceived exertion (RPE) at low workloads with a reduction of HR (31 beats per minute from minute 8 to 16) and RPE with better tolerance to higher workloads, a physiologic response known as the second wind phenomenon, seen in McArdle disease (GSD V).36Clinic StuffTable 1A. Non-ischemic forearm testLactate response was blunted, and ammonia production was increased in the context of a baseline elevated CK value.B. Cycle exercise testThe exercise test showed reduced peak VO2, blunted lactate production, second wind phenomenon, and a defect in oxidative phosphorylation.  WL: workload, RPE: Rate of Perceived Exertion (6-20, no exertion to maximal exertion), BP: blood pressure, HR: heart rate, VO2: oxygen consumption, Q: cardiac output, a-vO2 diff: arteriovenous oxygen difference37Clinic StuffQuestions for consideration:1. What additional testing would you obtain to de-termine the diagnosis?Section 3A lifetime of exercise intolerance, non-traumatic rhabdomyolysis, and chronically elevated muscle enzymes are all highly suggestive of a metabolic myopathy. While primary mitochondrial myopathies (PMM) and fatty acid oxidation disorders (FAOD) can present with exercise intolerance and rhabdomyolysis, the lack of lactate production on NIFT and the second wind phenomenon argue in favor of a glycogen storage disorder (GSD), specifically McArdle disease. His genetic results and absence of symptoms with fasting, illness, and exposure to cold temperatures argue against FAOD and mitochondrial myopathies. It is therefore unnecessary to order mitochondrial DNA testing or urine organic acids, serum acylcarnitine, and carnitine profiles. We pursued a vastus lateralis muscle biopsy to test for the defective enzyme in GSD V, myophosphorylase (PYGM gene). The patient’s myofibers revealed a complete absence of reactivity (Figure 1) and provided the diagnosis. His homozygous VUS was recharacterized as pathogenic per American College of A. PYGM control B. Patient PYGMC. Patient H&E D. Patient EMFigure 1: Quadriceps muscle biopsy showed a vacuolar myopathy with subsarcolemmal vacuoles (arrows) in a subset of myofibers (C), complete absence of myophosphorylase reactivity in all myofibers (B) compared to a control myophosphorylase image (A), and accumulation of free glycogen particles in subsarcolemmal space in some fibers on EM (D). Periodic acid-Schiff is not shown as there was no increased PAS staining.38Clinic StuffMedical Genetics and Genomics guidelines given the low frequency of this mutation in the population, established clinical testing, and in silico analysis. The patient was educated on the second wind phenomenon, benefits of high carbohydrate diet, and high-risk activities that could trigger rhabdomyolysis. We recommended low and moderate intensity aerobic exercises with modest use of sports drinks prior to activity. After implementing these measures, he reported an improvement in muscle symptoms and has not had a recurrence of rhabdomyolysis.DiscussionMcArdle disease1 is an autosomal recessive disorder caused by a PYGM gene defect, encoding for myophosphorylase, a muscle-specific isoform of glycogen phosphorylase that catalyzes the degradation of glycogen into glucose-1-phosphate. Nearly all mutations in PYGM lead to complete loss of enzyme activity, thus blocking glycogenolysis.2,3 In the initial stages of exercise and during intense activities, skeletal muscle predominantly depends on anaerobic glycogenolysis for energy. Thus, within minutes of starting the activity, patients describe fatigue that progresses to muscle cramps, contractures, and rhabdomyolysis if the activity is continued. Since glycogen is also needed for oxidative metabolism, patients have a low capacity for moderate exercise as well. Sustained moderate activity leads to fatigue, tachycardia, and dyspnea. After resting or maintaining a low level of activity, patients experience the pathognomonic second wind phenomenon related to greater mobilization of fatty acids to fuel oxidative metabolism.4,5,6Although exercise intolerance is present in childhood, the diagnosis is almost never made until at least the second decade of life due to misdiagnoses like “growing pains” or “being unfit.” Patients typically present in early adulthood with exercise intolerance, cramps, and recurrent rhabdomyolysis that can progress to fixed proximal weakness.1 Work-up often begins at the time of non-traumatic rhabdomyolysis. CK is typically elevated to 5-10 times the upper limit of normal. Importantly, AST and ALT are present in myofibers and are not specific for liver pathology and can lead to unnecessary invasive procedures, such as liver biopsy. Significant delays in diagnosis are common, with a high rate of misdiagnosis (up to 90%). Women are substantially more likely to receive a psychiatric or psychological misdiagnosis.6NIFT is classically performed rather than ischemic forearm testing, which can lead to muscle contractures and rhabdomyolysis.7,8  During NIFT, a block in glycogenolysis is demonstrated by absent lactate and increased ammonia production. Cycle testing demonstrates and helps patients recognize the second wind phenomenon. Molecular testing may obviate the need for exercise testing and muscle biopsy in patients with the typical clinical phenotype and known pathogenic  PYGM mutations. When PYGM VUS are found, a normal NIFT can exclude GSDs. If NIFT is abnormal, a muscle biopsy should be performed to assess for myophosphorylase activity.  The goal of management is to reduce episodes of rhabdomyolysis and improve exercise tolerance. Avoidance of intense activities, especially those requiring isometric, repetitive, and eccentric actions, is recommended. Low-to-moderate aerobic exercise (no greater than approximately 70% of maximal HR) improves muscle oxidative capacity and increases the threshold for muscle injury due to exertion.9 Patients should warm-up at a low intensity for at least 10 minutes to help achieve the second wind phenomenon. Pre-exercise simple sugars improve exercise tolerance and reduce the risk of rhabdomyolysis during activity.10-12 Because McArdle disease patients are at risk of obesity, consuming sugar prior to all activity is not recommended. Additionally, carbohydrate-rich diets are beneficial by bolstering hepatic glycogen stores and glucose mobilization. Corresponding AuthorSalman Bhai, M.D.Director, Neuromuscular Disease CenterInstitute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital DallasAssistant Professor, Department of Neurology, UT Southwestern Medical Center7232 Greenville Ave. Ste. 435Dallas, TX 75231 Email: Salman.Bhai@UTSouthwestern.edu Phone: 214-345-652References1. McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951; 10:13.2. Llavero F, Sastre AA, Montoro ML, Gálvez P, Lac-erda HM, Parada LA, et al. McArdle disease: new insights into its underlying molecular mechanisms. Int J Mol Sci 2019;20. doi:10.3390/ijms20235919.3. Nogales-Gadea G, Brull A, Santalla A, et al. McAr-dle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene. Hum Mutat 2015; 36:669.4. Pearson CM, Rimer DG, Mommaerts W. A meta-bolic myopathy due to absence of muscle phos-phorylase. Am J Med 1961;30:502–17. doi:10. 1016/0002-9343(61)90075-4.5. Tarnopolsky, Mark A. “Metabolic Myopathies.” CONTINUUM: Lifelong Learning in Neurol-ogy, vol. 22, no. 6, 2016, pp. 1829–1851, https://doi.org/10.1212/con.0000000000000403.39Clinic Stuff6. Scalco RS, Morrow JM, Booth S, et al. Misdiag-nosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord 2017; 27:852.7. Kazemi-Esfarjani P, Skomorowska E, Jensen TD, et al. A nonischemic forearm exercise test for McArdle disease. Ann Neurol 2002; 52:153.8. Hogrel JY, et al. Diagnostic power of the non-ischaemic forearm exercise test in detecting gly-cogenosis type V. Eur J Neurol 2015;22;933-940)9. Haller RG. Treatment of McArdle disease. Arch Neurol 2000; 57:923.10. Vissing J, Haller R. The effect of oral sucrose on ex-ercise tolerance in patients with McArdle’s disease. N Engl J Med 2003;349:2503–9. doi:10.1056/nej-moa031836.11. Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol 2008;65:786–9. doi:10.1001/archneur.65.6.786.12. Haller RG, Vissing J. Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease oxidative mechanisms. Arch Neurol 2002;59:1395–402. doi:10.1001/arch-neur.59.9.1395

Rhabdomyolysis and Exercise Intolerance in a 45-Year-Old Man

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Rhabdomyolysis and Exercise Intolerance in a 45-Year-Old Man

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