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 medication an excessive increase of serum potassium was found immediately after ischaemic exercise (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.

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 of this enzyme may explain the main present- deficiency. The diagnosis is established by ing symptoms in this disease: problems in measuring the microsomal Ca2+-uptake,24 relaxation of muscles, aggravated by exercise, quantifying the activity of Ca2+-ATPase in muscle stiffness and exertional myalgia. muscle homogenate'4 or by immunochemical When sarcoplasmic reticulum Ca2+-uptake tests.4 17 cannot keep pace with Ca2+-release, then an K+-efflux from exercising muscle is consid- accumulation of Ca2+ in muscle cytosol will ered a normal physiological phenomenon.'6 18 occur. If at a critical level, a sustained eleva- The efflux of K+ in the venous return blood tion in cytosolic Ca2+-concentration will be of the exercising forearm was excessive in this damaging to muscle cells, and will result in patient. The normal values found for muscle cell necrosis and pigmenturia. Na+/K+-ATPase activity excluded a reuptake Myoglobinuria has not yet been associated disorder of K+ as cause of its excessive efflux. with Ca2+-ATPase deficiency, which may be The K+ efflux may be explained by the effect attributed to the very small number of case of a disturbed Ca2+-homeostasis on the Ca2+- reports up till now. The degree of deficiency activated K+-channels.10 This hypothesis is of Ca2+-ATPase may be important for the supported by the strongly reduced activity of development of muscle damage. Verapamil sarcoplasmic reticulum Ca2+-ATPase that and dantrolene sodium are the therapeutic was found in the muscle homogenate of this drugs that have been successfully used in the patient. treatment of exertional myalgia. In the patient Electron microscopic findings showed nor- described by Taylor dantrolene sodium mal structures of triad and tubular elements reduced the pain, but produced unacceptable of sarcoplasmic reticulum, but swollen mito- weakness.5 Verapamil proved to be effective. chondria with crystals. Crystalline mitochon- The therapeutic use of dantrolene sodium in drial inclusions are often seen under preventing muscle necrosis has been reported pathological conditions concerned with ener- before in animal experiments.6 Its beneficial gy metabolism. These crystals may be consid- effect in humans has also been reported by us ered as a secondary effect of the disturbed and others in treating exertional myalgia and calcium homeostasis on mitochondria. preventing recurrent attacks of rhabdomyoly- To date four case reports of Ca2+-ATPase SiS.8 917 In our patient dantrolene sodium also deficiency have been published. The first case had a positive effect upon exercise tolerance described by Brody in 1969 had considerable and muscle complaints; moreover, CK level problems with relaxation of exercising mus- and plasma potassium efflux from ischaemic cles.2 Karpati et al described 4 male patients exercising muscles became normal. with similar complaints about exertional mus- Recurrent rhabdomyolysis in metabolic cle stiffness and contractures. CK level in myopathies is mainly precipitated by exercise. only one of them was slightly elevated. The The number of recognised metabolic defects http://jnnp.bmj.com/ mode of inheritance in this family was auto- has increased in the past two decades, but in somal recessive.4 Danon et al described four about half of the cases the biochemical cause family members with impaired muscle relax- of recurrent rhabdomyolysis remains ation and an autosomal dominant mode of unknown.' We suggest that account Ca2+- inheritance.' Taylor et al reported a Ca2+- ATPase deficiency as a metabolic cause of ATPase deficiency in a patient with an exer- recurrent exertional rhabdomyolysis should

tional muscle pain syndrome.5 Our patient be considered. on September 29, 2021 by guest. Protected copyright. had exercise-induced myalgia, recurrent The authors thank Dr Th M N Breuer, for his cooperation attacks of myoglobinuria and a constantly and Mrs G Steenbergen for her assistance in this study. elevated CK level. Relaxation of muscles was This investigation is part of the research programme sometimes difficult but not the patient's main "Disorders of the Neuromuscular System" at the University of problem. Nijmegen. The clinical picture of muscle relaxation problems in these patients resembles myotonic dystrophy or myotonia congenita. 1 Tonin P, Lewis P, Serveidi S, DiMauro S. Metabolic causes of myoglobinuria. Ann Neur 1990;27:181-5. However, these patients do not demonstrate 2 Brody IA. Muscle contracture induced by exercise. A syn- clinical or electrical myotonia. Their delayed drome attributable to decreased relaxing factor. The New Eng JMed 1969;281:187-92. muscle relaxation is painless in contrast to 3 Danon MJ, Karpati G, Charuk J, Holland P. muscle contractions in myotonia syndromes. Sarcoplasmic reticulum adenosine triphosphatase deficiency with probable autosomal dominant inheritance. Conversely, Ca2+-ATPase deficiency shows Neurology 1988;38:813-15. a resemblance with McArdle's disease and 4 Karpati G, Charuk J, Carpenter S, Jablecki C, Holland P. Myopathy caused by a deficiency of Ca2+-adenosine phosphofructokinase deficiency because of triphosphate in sarcoplasmic reticulum (Brody's dis- the electromyographical silence during relax- ease). Ann Neurol 1986;20:38-49. ation. 5 Taylor DJ, Brosnan MJ, Arnold DL, et al. Ca2+-ATPase deficiency in a patient with an exertional muscle pain The main difference between our patient syndrome. J Neurol Neurosurg Psychiatry 1988;51: 1425-33. and the previous cases2-5 is the exertional 6 Amelink GJ. Exercise induced muscle damage. Thesis 1990, recurrent rhabdomyolysis, confirmed by ele- Utrecht, The Netherlands. 826 Poes, Wevers, Braakhekke, Benders, Veerkamp, Joosten

7 Bertorini T, Palmieri G, Bhattacharya G. Beneficial 13 Everts ME, Andersen JP, Clausen T, Hansen 0. effects of dantrolene sodium in exercise-induced muscle Quantitative determination of Ca2+-dependent Mg2+- pains: calcium mediated? Lancet 1982;i:616-7. ATPase from sarcoplasmic reticulum in muscle J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.823 on 1 July 1993. Downloaded from 8 Haverkort-Poels PJE, Joosten EMG, Ruitenbeek W. biopsies. Bwochj 1989;260:443-8. Prevention of recurrent rhabdomyolysis by dantrolene 14 Norgaard A, Kjeldsen K, Hansen 0. Na+ + K+-ATPase sodium. Muscle Nerve 1987;10:45-6. activity of crude homogenates of rat skeletal muscle as 9 Lopez JR Dantrolene sodium is able to reduce the resting estimated from their K+-dependent 3-0-methylfluores- calcium ion intracellular concentration in muscle from cein phosphatase activity. Biochimica et Biophysica Acta humans with malignant hyperthermia. Muscle Nerve 1984;770:203-209. 1987;10:77-9. 15 Sinkeler SP, Wevers RA, Joosten EMG. Improvement of 10 Scholte HR, Jennekens FGI, Bouvy JJBJ. Carnitine palmi- screening in exertional myalgia with a standardized toyltransferase HI deficiency with normal carnitine ischemic fore arm test. Muscle Nerve 1986;9:731-7. palmitoyltransferase I in skeletal muscle and leukocytes. 16 Wevers RA, Joosten EMG, Van de Biezenbos JBM, Neurol Sci 1979;40:39-5 1. Theeuwes AGM, Veerkamp JH. Excessive plasma K+ 11 Parvin R, Pande SV. Microdetermination of (-)carnitine increase after ischemic exercise in myotonic muscular and camitine acetyltransferase activity. Anal Biochem dystrophy, Musde Nerve 1990;3:27-32. 1977;79:190-201. 17 Brumback RA, Gerst JW. A reply. Muscle Nerve 12 Trijbels JMF, Sengers RCA, Ruitenbeek W, et al. 1984;7:593-4. Disorders of mitochondrial chain: clinical manifesta- 18 Sj0gaard G. Role of exercise-induced potassium fluxes tions and diagnostic approach. Eur Paediatr underlying muscle fatigue: a brief review. Can Physiol 1988;148:92-7. Pharmacol 1991;69:238-45. http://jnnp.bmj.com/ on September 29, 2021 by guest. Protected copyright.