Turk J Gastroenterol 2002; 13 (1): 56-59

McArdle’s disease: case report and review of the literature McArdle hastal›¤›: olgu sunumu ve literatürün gözden geçirilmesi

Ahmet TÜZÜN1, Ahmet ERD‹L1, Sait BA⁄CI1, Erol BOLU2, Önder ÖNGÜRÜ3, ‹smail KURT Pharm4, Zeki YEfi‹LOVA1, Kemal DA⁄ALP1 Gülhane Military Medical Academy, Departments of Gastroenterology1, Endocrinology2, Pathology3 and Biochemistry4, Ankara

McArdle’s disease, or myophosphorylase deficiency, is one of the McArdle hastal›¤› veya myofosforilaz eksikli¤i en yayg›n kas most common muscle glycogenoses and typically presents in glikojenozlar›ndan biridir ve tipik olarak çocukluk veya adole- childhood or adolescence with exercise intolerance, myalgia, san dönemde egzersiz intolerans›, myalji, myoglobinüri ve egz- myoglobinuria, and cramps in the exercising muscle. ersiz yap›lan kaslarda kramplar ile kendini gösterir. Bu makalede biz karaci¤er enzim yüksekli¤i olan 21 yafl›nda erkek We report the case of a 21-year-old male patient with bir hasta tan›mlad›k. Hastam›z›n çocuklu¤undan beri devam elevation who had a history of weakness, exercise intol- eden güçsüzlük, egzersiz intolerans› ve kas kramplar› mevcut erance, and muscle cramps since childhood. His sister (a three- idi. 3 yafl›ndaki k›z kardeflinin de benzer yak›nmalar› mevcut year-old) suffered from similar symptoms. Laboratory results idi. Laboratuvar testlerinde serum kreatinin fosfokinaz düzey- showed that serum creatinine phosphokinase levels were elevat- leri yüksek idi, iskemik egzersiz testinde serum laktat› yük- ed serum lactate did not rise on ischemic exercise testing, while selmedi ve kas biyopsisinde subsarkolemmal ve intermyofibril- muscle biopsy showed subsarcolemmal and intermyofibrillar er glikojenle dolu periodic acid schiff-pozitif vakuoller sap- periodic acid schiff-positive vacuoles filled with . This tand›. Sonuç olarak karaci¤er enzim yüksekli¤i olan hastalar- case report underlines the importance of taking into account da kas glikojenozlar› gibi nadir metabolik hastal›klar da rare metabolic diseases such as muscle glycogenoses in the eval- düflünülmelidir. uation of patients with elevated liver . Anahtar kelimeler: McArdle hastal›¤›, myofosforilaz eksikli¤i, Key words: McArdle’s disease, myophosphorylase glikojen depo hastal›¤› tip V. deficiency, type V.

INTRODUCTION Prolonged elevations of serum alanine amino- recessive autosomal trait (4). However, a few fam- (ALT) and aspartate aminotrans- ilies with an autosomal dominant mode of inheri- ferase (AST) are often attributed to hepatic dis- tance have also been documented (5). The gene for eases. However, these enzymes are also present in myophosphorylase has been cloned, sequenced, a variety of extrahepatic tissues, including skele- and localized to chromosome 11q13 (2,6). tal muscle. McArdle disease (type V glycogen stor- Although symptoms usually start in childhood or age disease) is an uncommon hereditary metabol- adolescence (4), there are occasional reports of ic disease characterized by muscle individuals diagnosed in late adulthood, who were deficiency (1). Myophosphorylase, an important relatively asymptomatic in their youth (7-9). enzyme of metabolism, converts Patients experience exercise intolerance with pre- glycogen to -1-phosphate (2). Deficiency of mature fatigue, myalgia, and cramps (contrac- this enzyme in muscle limits ATP generation by tures) in response to exercise (1,10). and results in glycogen accumula- Electromograms are often normal between tion (3). attacks of myoglobinuria. Electrical silence usu- Myophosphorylase deficiency is transmitted as a ally occurs when voluntary activity is followed by

Address for correspondence: Dr. Ahmet TÜZÜN Manuscript received: 29.5.2001 Accepted: 7.8.2001 G.A.T.A., Gastroenteroloji Klini¤i, Etlik, Ankara McArdle’s disease 57

a cramp (11). The severity and duration of the symptoms are related to the amount of exercise and symptoms are relieved by rest (9). Elevated serum levels of cytoplasmic muscle enzymes and myoglobinuria occur after particu- larly intense and/or prolonged physical activity. Myoglobinuria occurs in about half of the cases of McArdle’s disease (4,9,11) and about half of these patients have acute renal failure (12). The diagnosis is established by the lack of eleva- tion of serum lactate after exercise, and by histo- chemical demonstration of an absence of phospho- rylase activity in a muscle biopsy specimen. Figure 1. Subsarcolemmal vacuoles are seen in many of the myofibrils (Hematoxylen-Eozin, X 200). Muscle pathology often shows subsarcolemmal and intermyofibrillar vacuoles filled with glyco- gen. In this study, we report a patient with McArdle’s Disease who presented with raised serum amino- plete blood cell count, chest roentgenogram, ESR, transaminases. This case report emphasises the creatinine, urea, sodium, potassium, uric acid, importance of considering muscle disease in the serum calcium, glucose, cholesterol, triglyceride, differential diagnosis of raised serum amino- direct bilirubin, indirect bilirubin, alkaline phos- transaminases, as it may negate the need for phatase, g-glutamyl transpeptidase, amylase, invasive investigations such as liver biopsy. total , albumin, serum copper, ferritin, peripheral blood smear, urinalysis, stool analysis, CASE REPORT ANA, Anti ds DNA, Anti Sm Ab, HBsAg, A 21-year-old male patient was admitted with AntiHCV, HCV RNA, Anti-HIV, Rubella IgM, liver enzyme elevation. He had a history of weak- Rubeola IgM, Toxoplasma IgM, Toxoplasma IgG, ness, exercise intolerance, and muscle cramps Anti RNP, Anti Scl-70, Anti Jo-1, ACA IgG, ACA (contractures) since childhood which generally IgM, p ANCA, c ANCA, and thyroid function tests. occurred after exercise and improved a little with Abnormal serum chemistry was as follows: CPK rest. There was no history of dark-colored urine 5706 U/L (31-221), AST 94 U/L (8-40), ALT 93 U/L He reported that no diagnosis could be made and (5-40), LDH 351 U/L (91-232), Rubella IgG 211 (0- no cause for the raused liver enzymes had been 20), Rubeola IgG 2.9 (0-1). Serum myoglobin and found despite repeated medical investigations. myoglobinuria could not be investigated due to His sister (a three-year-old) was suffering from technical problems. Upper abdominal ultrasonog- similar symptoms. His mother had diabetes melli- raphy was normal. tus while his father had bronchitis and heart dis- The findings defined in the EMG were considered ease. The patient presented with no neurological nonspecific for myopathy. Later, a forearm abnormalities including muscle atrophy and ischemic exercise (lactate) test was carried out as weakness. Gower's sign was negative. Physical described by Munsat (13). Serum lactic acid levels examination was entirely normal. remained unchanged after the ischemic forearm Initially elevated aspartate aminotransferase exercise test, but ammonia levels were markedly (AST) (94 U/L) and alanine aminotransferase raised (basal 34 and maximum 229 mmol/L). (ALT) (93 U/L) values on admission decreased to Myoadenilate deaminase and respiratory chain levels of 54 U/L and 32 U/L respectively within enzyme deficiency were excluded as a result of four weeks. However, elevated levels of creatinine these findings. All data was thought to support phosphokinase (CPK) and lactic dehydrogenase the presence of glycogen storage disease involving (LDH) continued, which prompted us to consider striated muscle. whether hypertransaminasemia was related to an A muscle biopsy was taken from the right thigh extrahepatic cause. region. Variation of the diameter of fibers, random Normal laboratory investigations included com- atrophy, hypertrophy and occasional internal 58 TÜZÜN et al. nuclei were observed. Subsarcolemmal vacuolisa- intermyofibrillar PAS-positive vacuoles filled with tions were present in many of the myofibrils glycogen seen in the muscle biopsy material in (Figure-1). Accumulation Periodic Acid Schiff particular that led to consideration of McArdle’s (PAS) positive substance was noted in some of the disease. As it is known that McArdle’s disease is these vacuoles. Myocyte necrosis and fibrosis were basically a disease of skeletal muscle, it was not not seen. The histopathological findings were considered to be necessary to perform any inva- found to be compatible with the diagnosis of sive procedure such as liver biopsy. Glycogen storage disease (Type V myopathy). From the clinical point of view, Mc Ardle’s disease and Tarui disease (muscle phosphofructokinase DISCUSSION deficiency, Type VII glycogen storage disease) Persistent hypertransaminasemia unrelated to may have similarities. Most patients with muscle hepatic viral infection is a common cause for refer- phosphofructokinase deficiency may also have ral to the hepatologist. However, these enzymes moderate hemolytic anemia, arthritis and clinical are also present in a variety of extrahepatic tis- manifestations of gout. Hyperuricemia is common sues, including skeletal muscle. There have been and becomes more marked after exercise (1). Our occasional reports in which elevated serum amino- patient had neither clinical manifestations of gout transferase activities have led to the diagnosis of nor arthritis; complete blood cell count, serum suspected muscle disease (14). urate and bilirubin levels were all within normal As many patients know their exercise capacity, ranges whenever we checked them. they limit their exercise before appearence of Due to its rarity, McArdle’s disease can easily be symptoms. In our patient, there was a history of missed by physicians and sometimes the diagno- weakness, exercise intolerance, muscle cramps sis can not be made until renal failure develops and pain since childhood, with of the severity and (12). Likewise, our patient had a history of symp- duration of symptoms being related to the amount toms since childhood but was only diagnosed dur- of exercise, thus the patient had never physically ing his military service, although his renal func- exerted himself greatly. Transaminase levels of tions were normal. Many life-long sufferers are our patient were therefore only slightly higher than normal. Determination of increased CPK finally diagnosed in their 50’s and 60’s (8,9). It is levels suggested that elevation of transaminases now believed that many cases may go unnoticed. may have an extrahepatic cause. In conclusion, this case report demonstrates that Serum aminotransferase measurements are often occult muscle diseases should be taken into included in blood screening panels performed for a account in the evaluation of patients with unex- variety of reasons. In contrast, serum CPK mea- plained chronic hypertransaminasemia. surement is infrequently included in such screen- Measurement of serum creatine kinase activity ing although it is the most useful marker of mus- and muscle biopsy should be performed at an cle disease. A careful physical examination in early stage for the correct diagnosis of McArdle’s addition to CPK determination will identify the disease. Identification of subjects with this dis- majority of these cases (1,11). Indeed, the diagno- ease is important since they may benefit signifi- sis in our patient was made by muscle biopsy and cantly from a high-protein diet (15), avoidance of forearm ischemic exercise test without any need certain physical activities and genetic counseling. for liver biopsy. It was the absence of a rise in Early diagnosis will also make it possible to avoid serum lactate levels in the forearm ischemic exer- exercise-induced rhabdomyolysis and acute renal cise test and observation of subsarcolemmal and failure.

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