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Exertional Rhabdomyolysis in a Patient with Calcium Adenosine Triphosphatase Deficiency

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Exertional Rhabdomyolysis in a Patient with Calcium Adenosine Triphosphatase Deficiency Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56:823-826 823 SHORT REPORT J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.823 on 1 July 1993. Downloaded from Exertional rhabdomyolysis in a patient with calcium adenosine triphosphatase deficiency P J E Poels, R A Wevers, J P Braakhekke, A A G M Benders, J H Veerkamp, E M G Joosten Abstract Case report A patient with exertional rhabdomyolysis A 38 year old male presented with exertional and continuously elevated serum crea- myalgia and postexercise muscle weakness. tine kinase (CK) was investigated. The These symptoms of exercise-intolerance start- known causes of recurrent attacks of ed during the first decade of life. His skeletal rhabdomyolysis were ruled out by appro- muscles became stiff and painful 5 minutes priate histochemical and biochemical after the start of moderate isometric exercise. investigations. During ischaemic exer- He had many episodes of pigmenturia, espe- cise tests an abnormal K+ -efflux from cially after sport. He was not able to play a exercising muscles was observed. The volleyball match to the end because of stiffen- patient was found to have a deficiency of ing of the exercised muscles. The muscle muscular Ca2 + -ATPase. Dantrolene symptoms then lasted for at least 12 hours. sodium therapy gave relief of muscle He frequently experienced "cramping" in the symptoms and improved the exercise tol- calf muscles. Walking and cycling caused no erance. Both the CK level and the K+ - problems. When chewing firmly, the mastica- efflux in ischaemic forearm testing tory muscles became stiff and the relaxation became normal on this therapy. was impaired. The patient did not experience a second wind phenomenon. The family his- (JVNeurol Neurosurg Psychiatry 1993;56:823-826) tory was noncontributory. Physical examina- tion revealed no abnormalities. There was no muscle atrophy and no muscle weakness. Recurrent attacks of exertional rhabdomyoly- Grip and percussion myotonia were absent. sis can develop from several enzyme defects Laboratory studies showed a continuously of glyco(geno)lysis or lipid metabolism.I elevated serum CK ranging from 500 to 1500 Rhabdomyolysis has not been associated with IU/L (normal range 15-91). After sport, Ca2+ -adenosine triphosphatase (Ca2+- serum CK rose to 11 000 IU/L. A normal http://jnnp.bmj.com/ ATPase) deficiency. This rare disorder of biochemical and haematological profile was muscle function was first described by Brody obtained. Blood lactate level was within the in 1969.2 In recent years three reports have normal range and showed a fourfold rise in been published, describing patients with defi- response to exercise. EMG showed normal ciency of sarcoplasmic reticulum-ATPase.-5 conduction velocities. No myotonic dis- Exercise-induced muscle contractures and charges were observed in intrinsic hand mus- University of impaired relaxation of exercising muscles cles, quadriceps or tibialis anterior. on September 29, 2021 by guest. Protected copyright. Nijmegen, The belong to the main clinical symptoms. The Because of recurrent attacks of exertional Netherlands, deficiency causes a reduced uptake of Ca2+ in myalgia the patient was treated with dantro- Department of Neurology sarcoplasmic reticulum. Several studies have lene sodium. The dose was slowly built up to P J E Poels shown the importance of calcium ions in the 150 mg a day and continued for six months. R A Wevers contraction-relaxation cycle of striated Exercise-tolerance improved and the patient E M G Joosten muscles.2 was again able to participate in sport without Department of We describe a with exertional muscle When dantrolene sodium Biochemistry patient myal- problems. A A G M Benders gia and recurrent rhabdomyolysis. We tested was discontinued for two months, all muscle J M Veerkamp this patient with dantrolene sodium since this complaints returned. Symptoms disappeared Sophia Hospital, drug has been suggested to be useful in the again when the medication was resumed. In Zwolle, The treatment of exertional myalgia and recurrent the period without dantrolene sodium, CK Netherlands Dantrolene sodium acts level was determined twice and clearly elevat- J P Braakhekke rhabdomyolysis." Correspondence to: primarily by decreasing the sarcoplasmic ed to 1125 and 1429 IU/L respectively. Mrs Poels, Institute of reticulum calcium release and depresses the During dantrolene sodium treatment CK Neurology, University Hospital Nijmegen, PO Box trigger mechanism for the excitation- level was determined three times and had 9101, 6500 HB Nijmegen, contraction coupling, which is supposed to decreased to 105, 185, and 115 IU/L The Netherlands. play a key role in the development of muscle respectively. Received 28 February 1992 and in final revised form pain and stiffness.69 The effect of dantrolene 1992. sodium on muscle symptoms and on Special studies Accepted 14 July 1992 ischaemic exercise tests is discussed. A muscle biopsy from the vastus medialis was 824824~~~~~~~~~~~~~~~~~~~~~Poels,Wevers, Braakhekke, Benders, Veerkamp, Joosten processed according to standard procedures cells there was no deficiency of glycolytic for histochemistry and electrornmicroscopy. enzymes. The activity of alpha-glucosidase J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.823 on 1 July 1993. Downloaded from Gamitine palmitoyltransferase I and II activi- in the leukocytes and in the muscle was ties were measured in leukocytes and in mus- normnal. Free and esterified carnitine in cle homogenate with the exchange assay.'0 serum and muscle were normal. Muscle The activity of aipha-glucosidase was deter- homogenate showed a normal oxidation rate mined in leukocytes and in muscle. of [1_'4C]pyruvate and [U_'4C]malate, no Concentrations of free and esterified carnitine defect in ATP metabolism and normal activi- were determined in blood and muscle tis- ties of mitochondrial enzymes. sue." An extensive biochemical study of The Ca2+-dependent 3-O-MFPase activity mitochondrial metabolism and enzymes was in muscle was significantly reduced to 589 performed according to standard proce- pmol/minute per mg protein compared with dures.'12 the control value of 1134 ± 227 (n = 14). A In muscle homogenates (1% w/v) the Ca2+_ normal activity was found for K+-dependent dependent Mg2+-ATPase of sacroplasmic 3-O-MFPase of 414 pmollminutes per mg reticulum was investigated by measurement protein versus 382 ± 73 (n = 14). of the Ca2+-dependent 3-0-methylfiuorescein phosphatase (3-0-MFPase) activity accord- MORPHOLOGICAL STUDIES ing to the method described by Everts et al.'13 Histological studies of the muscle biopsy The Na+/K+-ATPase activity was estimated showed 19% central nuclei (normal <3%), from the K+-dependent 3-0-MFPase activity some necrotic fibres and an increased varia- according to Norgaard et al.'14 tion of fibre diameter. Myophosphorylase and To exclude a glyco(geno)lytic enzyme myoadenylate deaminase staining reactions defect glycolytic enzymes in erythrocytes were were positive. A trichrome stain was negative determined and ischaemic forearm tests were and no ragged red fibres were seen. carried out under standardised conditions.'" Histochemical study revealed a slight amount Two ischaemic forearm tests were performed of subsarcolemmal PAS-positive material. during dantrolene therapy and two tests with- Electrornmicroscopy showed muscle fibres out medication. In the blood samples taken with an increased amount of glycogene. A before and immediately after exercise, substantial number of subsarcolemmal mito- changes in plasma electrolyte levels were chondria were swollen and contained crystals studied.'16 (fig 1). The structures of t-he triad and the tubular elements of sarcoplasmic reticulum Results were normal. Laboratory investigations Normal values were found for camnitine ISCHAEMIC FOREARM TESTS palmitoyltransferase I and II in leukocytes All four ischaemic exercise tests showed a and in muscle homogenate. In red blood normal rise of venous lactate and ammonia. During the two forearm tests without medica- tion an excessive increase of serum potassium was found immediately after ischaemic exer- cise (fig 2). The K+-efflux was normal in the two ischaemic forearm tests at dantrolene http://jnnp.bmj.com/ sodium treatment. Change in I + (MM)1 *without DaNa ,Awith DaNa o controls 03 on September 29, 2021 by guest. Protected copyright. 3- 0 2. 00 El 0 0 o3 0 0 ..46.. -~Change in [lactate] (mM) Figure 2 Abnormal increase of serum potassium in relation to the concentration lactate during the ischaemic forearm test. During dantrolene sodium (DaNa) Figure 1 Electron microscopy. A number of subsarcolemmal mitochondria which are medication the K+ release was in the normnal range of the swollen and contain crystalline inclusions. Bar= 1 im. controls. Exernional rhabdomyolysis in a patient with calcium adenosine tnphosphatase deficiency 825 Discussion vated CK levels. For muscle relaxation to Ca2+-ATPase deficiency is a rare inborn error occur, Ca2+-ions released into cytosol during J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.823 on 1 July 1993. Downloaded from of metabolism. Its clinical presentation is not contraction, must be taken up into the sar- specific. Impaired muscle relaxation, muscle coplasmic reticulum lumen through activity contractures and exertional muscle pain are of Ca2+-ATPase located in the sarcoplasmic the main features. Hitherto rhabdomyolysis reticulum membrane. The partial deficiency has not been associated with Ca2+-ATPase
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