J Neurol (1991) 238 : 265-270

Journal of

Neurology © Springer-Verlag 1991

Familial myopathy with elevated serum angiotensin-converting enzyme, creatine kinase and lactate dehydrogenase isoenzyme 5 Thomas Henze 1, Attila Bardosi 2, and Heinz R. Reichmann 3 1Neurologische Klinik and 2Institut ftir Neuropathologie der Universit~it, Robert-Koch-Strasse 40, W-3400 G6ttingen, Federal Republic of Germany 3Neurologische Klinik der Universit~it, Josef-Schneider-Strasse, W-8700 Wtirzburg, Federal Republic of Germany Received January 19, 1990 / Received in revised form July 6, 1990 / Accepted December 21, 1990

Summary. A family is r e p o r t e d in which two m e m b e r s p r e s e n t e d with proximal m y o p a t h y associated with high s e r u m levels of angiotensin-converting e n z y m e ( S A C E ) , creatine kinase ( C K ) , and lactate d e h y d r o g e n a s e isoenz y m e 5. E x a m i n a t i o n of three relatives revealed elevated S A C E levels in all of t h e m , but no m y o p a t h y . N o evidence o f sarcoidosis, the m o s t c o m m o n disease associated with high S A C E levels, could be found. Muscle biopsies of the two affected m e n revealed m y o p a t h i c features w i t h o u t g r a n u l o m a formation. Extensive b i o c h e m ical, metabolic, immunological, and microbiological studies were all n o n - c o n t r i b u t o r y . Corticosteroid and, in o n e patient, azathioprine t r e a t m e n t resulted in an imp r o v e m e n t of muscle w e a k n e s s and in a decrease of S A C E as well as C K levels.

or m y o p a t h y [12]. T h e p r e s e n t r e p o r t is, to our knowledge, the first to present a family with m y o p a t h y as well as elevated levels of S A C E and creatine kinase (CK).

Patients and methods Patients Two members of a family (cases 1 and 2; Fig. 1) with clinical signs of myopathy as well as elevated SACE and CK levels were investigated. Electromyography and muscle biopsies in these patients were performed before initiation of immunosuppressive therapy. Elevated SACE and CK levels were also present in three further persons (cases 3-5). For several reasons other members of the family could not be examined. In a control group of patients suffering from other myopathies, SACE was estimated as well.

Key words: Familial m y o p a t h y - A n g i o t e n s i n - c o n v e r t i n g e n z y m e - Creatine kinase - L D H i s o e n z y m e 5

SA CE and lactate dehydrogenase isoenzyme analyses

Introduction

SACE activity was assayed using a commercially available radioassay (Ventrex Lab., Portland, Maine, USA). Mean (2 SD) reference range was 67-145 nmol x min-1 x m1-1. Lactate dehydrogenase (LDH) isoenzymes were determined by cellulose acetate electrophoresis [3].

Elevation of serum angiotensin-converting enzyme (SACE) is a typical finding in sarcoidosis and serves as an important diagnostic tool as well as a m e a s u r e of activity during the course of the disease [2, 14]. Most diseases in which elevated S A C E levels occur - except sarcoidosis - are rare conditions, and elevation of S A C E is only occasionally o b s e r v e d in t h e m [4, 14, 15]. T h e only o t h e r disease regularly associated with high levels of S A C E is G a u c h e r ' s disease, in which the G a u c h e r cells are the origin o f the a b n o r m a l S A C E o u t p u t [9, 15]. I n v o l v e m e n t o f skeletal muscle in sarcoidosis is rare [5, 7, 13, 16-19]. In addition, it is still a m a t t e r of controversy w h e t h e r g r a n u l o m a t o u s m y o p a t h y can occur as the sole manifestation of sarcoidosis. Until recently, familial elevation of S A C E has b e e n r e p o r t e d only in one family w h o , h o w e v e r , s h o w e d no evidence of sarcoidosis

Offprint requests to: T. Henze

Electromyography The following muscles were tested in patients 1 and 2: deltoid, biceps brachii, abductor pollicis brevis (all left), vastus medialis, tibialis anterior (all right). Using a coaxial needle electrode, inser-

Fig. 1. Pedigree of the family. Numbers 1-5 denote the individual members described here

266 CK (U/t)

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tion activity as well as configuration, duration and amplitude of the motor units were analysed.

Histochemical and electron microscopic preparation of muscle biopsies Biopsy specimens were either frozen in isopropanol and cooled in liquid nitrogen for light microscopic examination, or immersed in 0.1 M cacodylate-buffered 2% glutaraldehyde solution for electron microscopy. Sections (61am thick) were cut using a cryostat and stained with haematoxylin and eosin, periodic acid-Schiff (PAS), oil red 0 (ORO) and modified Gomori trichrome. The enzyme histochemical methods used were: NADH-tetrazolium reductase ( N A D H - T R ) , menadion-linked glycerophosphate dehydrogenase, amylophosphorylase, myoadenylate deaminase, alkaline and acid phosphatase, unspecific esterases and cytochrome-c-oxidase. Staining for myosin ATPase activities was performed at pH 9.5, pH 4.5 and pH 4.3. For electron microscopic examination, specimens of fixed muscle tissue were postfixed in osmium, dehydrated, and embedded in Araldite. Thin sections were cut with an ultramicrotome, doublestained with uranyl acetate and lead citrate and viewed with a Zeiss EM 10 electron microscope.

Case

reports

Case 1 This 27-year-old man complained of muscle weakness and pain in his left upper arm that had slowly developed 8 weeks previously and was combined with occasional angina-like sensations. After swimming 1000 m he said that he could hardly walk and his urine was of brown colour the following day. No history of other acute illness, particularly infection, had preceded the onset of these symptoms. On examination there was no swelling or atrophy of muscles, but a slight decrease of muscle strength of the biceps and triceps brachii as well as the deltoid and neck muscles was obvious. After five knee-bends he could not continue and both quadriceps muscles were hardened and painful to pressure. An elevated S A C E level was found during biochemical examinations, but there were no clinical signs of sarcoid myopathy. Muscle weakness and CK levels increased from 1987 onwards. Although examinations of skin, tung, heart, liver, and central nervous system revealed no evidence of systemic sarcoidosis, the patient was treated with prednisone. While on this treatment his muscle pain

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Fig. 2. Course of serum angiotensinconverting enzyme (SACE) and creatine kinase (CK) levels in case 1 during and after corticosteroid treatment

1989

and angina-like complaints diminished and muscle strength normalized. CK and SACE levels decreased (Fig. 2). Because of increased body weight and uncontrollable sweating, prednisone was gradually reduced and then discontinued, after 7 months of treatment. Only a few weeks later, all his previous complaints returned, so that the patient was forced to give up his job as a miner and find a less fatiguing occupation.

Table 1. Normal laboratory findings in cases 1 and 2

Biochemical studies Erythrocyte sedimentation rate, white blood cells, red blood cells, thrombocytes, haemoglobin, haematocrit, partial thromboplastin time, thrombin time, fibrinogen, Na + , K + , Ca 2 + , P O -3 , Mg 2 + , CI-, Cu 2., iron, blood glucose, serum creatinine, urea, uric acid, cholesterine, triglyceride, alkaline phosphatase, gamma-glutamyltransferase, direct and indirect bilirubin, serum electrophoresis, carcino embryonic antigen. Thyroid hormones, cortisol, A C T H , vitamin B12, folic acid, whole catecholamines, hydroxyindoleacetic acid, methylprotocatechuric acid

Biochemical and histochemical studies of muscle N A D H dehydrogenase, N A D H cytochrome c reductase, succinate dehydrogenase, succinate cytochrome c reductase, cytochrome c oxidase, citrate synthetase, fumarase, malate dehydrogenase, phosphorylase, hexokinase, phosphofructokinase, aldolase, glycerinaldehyde phosphate, phosphoglycerate kinase, phosphoglyceratemutase, enolase, lactate dehydrogenase, protein

Immunological studies Complement C3 and C4, immunoglobulins (G, M, A), haptoglobin, rheumatoid factor, LE test, antibodies against smooth and skeletal muscle, single (ss-) and double (ds-) stranded D N A , Sin, UI-nRNP (ENA), heart muscle, mitochondria, and the acetylcholine receptor

Microbiological studies Cysticerci, echinococcus, trichinosis, Toxoplasma gondii, hepatitis A and B, RS virus, mumps, measles, herpes simplex 1 and 2, varicelia zoster, coxsackievirus, Epstein-Barr virus, parainfluenza 1-3, rubella, HIV, leptospira, brucella, mycoplasma, Treponema palli-

dum, Borrelia burgdorferi Cerebrospinal fluid Cell count and cell differentiation, whole protein, immunoglobulins G, A, and M, lactate

267

Table 2. Laboratory findings in cases 1 and 2 (CK, CK-MB, L D H , GOT, GPT, myoglobin in serum, SACE)

CK (0-70 units/l) a CK-MB (6% o f C K , units/l) L D H (80-200 units/l) G O T (0-15 units/l) GPT (0-22 units/l) Myoglobin (0-70 ng/ml) S A C E (67-145 nmol × min 1 × ml-1) a

Case 1

Case 2

332-3500 25- 70 218- 336 41- 100 59- 118 864-1042 151- 227

200-1200 13- 20 210- 300 16- 88 21- 158 337 141- 203

Values in parentheses represent normal range

Table 3. L D H isoenzyme patterns, pyruvate and lactate levels in cases 1, 2, and 5

LDH-1 (20-30 rel. %)a LDH-2 (28-44 rel. %) LDH-3 (16-25 rel. %) LDH-4 (0-18 rel. %) LDH-5 (0-16 rel. %) Lactate (1-1.78 mmol/1) Pyruvate (0.041-0.068 mmol/1) a

Case I

Case 2

Case 5

28 33 6 12 21 3.39 0.142

25 36 14 3 22 3.35 0.182

24 37 20 12 17 2.19 0.141

Values in parentheses represent normal range

The patient's normal laboratory findings are given in Table 1, myoglobin, muscle and liver enzymes are listed in Table 2 and L D H isoenzymes in Table 3. Creatinine clearance was decreased to 61ml/min. S A C E was elevated to 227nmol × m1-1 × min -1 (normal range 67-145). Titres of antibodies against thyreoglobulin and thyroidal microsomes were normal. An ischaemic forearm test revealed only slightly increased initial serum lactate levels, with a decrease during muscle ischaemia.

Electromyography. Insertion activity in all muscles tested was normal as were configuration, duration and amplitude of the motor units during innervation. Only in the deltoid muscle were occasional positive sharp waves detected. There were no fibrillations, bizarre high-frequency discharges, myotonic or pseudomyotonic patterns. Muscle morphology. Light microscopic features were as follows. Routine histological staining of the muscle biopsy specimen taken from the right biceps muscle revealed atrophied muscle fibres of less than 10 gm diameter, some of them with basophilic sarcoplasm and enlarged vesicular nuclei, suggesting regeneration (Fig. 3 a). Occasionally, necrotic fibres appeared, surrounded by macrophages, plasma cells and lymphocytes. In serial sections no signs of diffuse inflammatory infiltrations or granuloma were observed. The NADHT R reaction revealed a disorganized intermyofibrillar network, resulting in a moth-eaten appearance. Acid and alkaline phosphatase reactions showed an increased enzyme activity in the degenerated and regenerated fibres. ATPase reactions revealed no selective atrophy of muscle fibres. Ragged red fibres were not seen. The endomysial connective tissue was not increased. A later biopsy of the left vastus medialis showed fibre atrophy particularly of type-1 fibres. In further enzyme histochemical reactions the activities of cytochrome-c-oxidase, amylophosphorylase and myoadenylate deaminase enzymes were normal. Electron microscopic findings were as follows. Ultrastructural examination revealed evidence of a degenerative process. The degenerating regions displayed dilated sarcoplasmic vesicles and

Fig. 3a, b. Muscle morphology of cases I and 2 showing single basophilic atrophied fibres (arrow) and hypertrophic fibres with an increased number of central nuclei (arrowheads). a Right biceps brachii muscle, × 720; b left biceps brachii muscle, x 285. a,b H & E staining

rarefied, disorganized myofibrils. In some degenerated fibres partially lysed myofibrils were present. Focal degeneration of the contractile apparatus was shown by disorganized, aberrant myofibills with disintegration of sarcomeres and Z-disc streaming. The triads showed altered localization and proliferation, resulting in pentads and heptads. Cytoplasmic glycogen was not increased in the interfibrillar and subsarcolemmal regions of muscle fibres.

Further investigations. Chest radiographs were normal on repeated examinations, as were electrocardiography, echocardiography, pulmonary function, sonography and computed tomography of liver, spleen and brain.

Case 2 The 49-year-old father of the first patient suffered from two transient ischaemic attacks in the area of the left middle cerebral artery in July 1986 and April 1987. There was no history of arterial hypertension, diabetes mellitus, hyperlipidaemia or nicotine abuse. At that time he did not complain of weakness or show any clinical signs of an underlying myopathy, but the CK level was elevated to 349 units/l. During the following months his muscle strength decreased and myalgia appeared in the neck as well as in the proximal muscles of upper and lower extremities. Muscles were painful to pressure, especially after exercise. Biceps and triceps brachii muscles of both arms seemed to be slightly atrophic. Unfortunately,

268 S A C E levels were not estimated at that time. He was treated with corticosteroids (50mg/day) and his condition improved slowly. During treatment, CK levels were markedly lowered. At this point, S A C E levels were estimated because of his son's history and were found to be elevated, too. In order to avoid the hazards of longterm steroid medication, azathioprine was begun (2.5 mg/kg body weight per day), leading to a further decrease of CK and S A C E levels as well as myalgia, but not to complete resolution of muscle weakness. Because of the limited clinical improvement, the patient refused to continue immunosuppressive therapy. Medication was stopped and CK and S A C E levels increased again, followed by progressive muscle weakness a few weeks later. Sace was then elevated to 175.1nmol × ml 1 × min 1. An ischaemic forearm test showed no evidence of glycolytic enzyme deficiency. Serum aldosterone was increased to 598 pg/ml (normal range 100-350). Titres of antibodies against thyreoglobulin and thyroidal microsomes were 1:5120 and 1:40, respectively. For other laboratory findings, see Tables 1-3.

Electromyography. As in case 1, all findings in muscles tested in the second patient were normal and, in contrast to his son, no positive sharp waves were detected. Muscle morphology. Light microscopic features were as follows. Routine histological staining of a muscle biopsy specimen taken from the left biceps muscle revealed variation of muscle fibre diameter with atrophied muscle fibres of 10 ~tm diameter and hypertrophic muscle fibres with a diameter of 90gm (Fig. 3b). Basophilic regenerated muscle fibres appeared occasionally. The number of internal nuclei was increased (15%). Using the PAS reaction, areas of the sarcoplasm were shown to contain accumulated, positively stained material. However, vacuolar storage of glycogen was not observed. Here and there the N A D H - T R reaction revealed focal disorganization of intermyofibrillar network, resulting in so-called minicores. Some muscle fibres showed subsarcolemmal accumulation of the enzyme substrate, particularly in typed fibres. In the Gomori trichrome staining rare ragged red fibres appeared, showing an increased lipid content in the O R O staining. As in case 1, no selective fibre atrophy or predominance were present. In serial sections diffuse inflammatory infiltrations as well as granuloma were absent. All other enzymes showed normal histochemical activities. Electron microscopic findings were as follows. Ultrastructural examination revealed evidence of a degenerative process similar to that seen in muscle tissue of case 1. Additionally, cytoplasmic glycogen was increased in the interfibrillar and subsarcolemmal regions of many muscle fibres. However, intralysosomal storage of glycogen particles was not observed. Mitochondrial alteration was also present, showing degeneration with an increase of density and thickness, as described by Bardosi et al. [1] in a mitochondrial myopathy caused by deficiency of triosephosphate isomerase enzyme. Splitting of the inner or outer membrane and an increase in the number of mitochondria were observed, too. Embedded between accumulated glycogen particles, aggregates composed of mitochondria of normal structure appeared in the subsarcolemmal and interfibrillar regions. However, mitochondria containing crystalloid inclusions were not present. Mononuclear cells such as lymphocytes or macrophages could also be identified as an accompanying cellular component of fibre degeneration and necrosis.

Further investigations. Cranial computed tomography, digital subtraction angiography of cerebral vessels, and repeated chest radiographs were all normal.

Cases 3 - 5 None of these patients (case 3: aged 41 years, male; case 4: aged 43 years, male: case 5: aged 24 years, female) ever complained of muscle pain, weakness or symptoms of central or peripheral nervous system disorders. On clinical examination, no pareses or atro-

Table 4. Laboratory findings in cases 3-5

ESR (mm/1 h; mm/2 h) G O T (units/l) 0-18 GPT (units/l) 0-22 CK (units/l) 0-60 L D H (units/l) 80-200 Gamma-glob. (11-20%) SACE (67-145 nmol × ml 1 x min 1)

Case3

Case4

Case5

5/12 21 32 118 146 22.6 169.3

5/14 8 10 34 115 22.7 173.7

25/44 9 11 22 149 17.6 154.6

Table 5. SACE levels of patients with different myopathies (control group). (Normal range: 67.0-145.0nmol × m1-1 × min 1) n

Range (nmol

Dystrophic myopathies Mitochondrial myopathies Polymyositis/systemic lupus erythematosus Myasthenia gravis Polymyalgia rheumatica Sarcoid myopathy CNS sarcoidosis (without myopathy)

Median x

m1-1 × min -1)

5 6

74.1-114.5 62.5- 92.7

94.0 80.1

7 14 8 3 3

80.0-122.5 56.9-135.5 85.5-149.4 76.7-194.8 134.6-189.0

100.5 95.7 106.6 139.5 157.4

phy of muscles were present. Case 3 had a history of medical treatment with prednisone in a sanatorium for pulmonary diseases. Case 4 was said to suffer from a "shadow on the lungs". No treatment had been instituted in this patient. No former diagnosis for either patient 3 or 4 could be elucidated. Patient 5 had no history of pulmonary disease. She was suffering from a common cold at the time of blood sampling. The results of the three patients' laboratory examinations are listed in Table 4. In all patients, elevated SACE levels were detected. Rheumatoid factor, LE test and antibodies against D N A were negative in all patients. Immunoelectrophoresis and levels of immunoglobulins G, M, A were normal. In case 5 serum aldosterone was elevated (667pg/ml), while values for cortisol, adrenocorticotrophic hormone, testosterone, luteinizing hormone, follicle-stimulating hormone, human growth hormone and prolactin showed normal values. For several reasons the other members of the family (Fig. 1) could not be examined.

Control group In none of the control patients suffering from several forms of myopathy tested were elevated SACE levels detected (Table 5).

Discussion Two members of the family described here demonstrated m y o p a t h y , d i a g n o s e d o n t h e basis o f m u s c l e p a i n a n d weakness, especially after exercise. In both patients, the symptoms were accompanied by raised CK levels and m y o p a t h i c f e a t u r e s in m u s c l e b i o p s y s p e c i m e n s . T h r e e o t h e r f a m i l y m e m b e r s h a d n o c o m p l a i n t s o f m u s c l e fat i g u e , b u t s h o w e d slightly e l e v a t e d S A C E l e v e l s as well. In t h e s e i n d i v i d u a l s , a s u b c l i n i c a l c o u r s e o f m y o p a t h y

269 may exist but, unfortunately, muscle biopsies could not be taken from them. Other diagnostic features were elevations of lactate, pyruvate, L D H isoenzyme 5 and aldosterone. Electromyography in cases i and 2 was negative in respect to the diagnosis of myopathy, since the finding of occasional positive sharp waves in the first patient does not fulfil the electromyographic criteria of myopathy, which include raised insertion activity, small amplitudes and short duration of muscle action potentials, or fibrillations. If elevations of SACE levels are detected, many diseases, especially sarcoidosis, have to be considered. The only other report of familial elevation of S A C E described four members of a Japanese family, one of whom presented with an occlusion of the left central retinal vein. None of them showed evidence of any underlying disease. The significance of this laboratory finding remained unclear [12]. Muscle involvement in sarcoidosis is rare [5, 7, 13, 16-19]. Patients usually complain of proximal muscle weakness and pain. In some, nodules within affected and unaffected muscles can be palpated [7]. There are five distinct clinical categories of sarcoid myopathy, according to Engel and Banker: (1) asymptomatic; (2) acute myositis; (3) chronic myositis; (4) peripheral neuropathy with denervation atrophy of muscle; and (5) nodular myositis [7]. It is still a matter of controversy whether sarcoid myopathy can occur without involvement of other tissues. In those cases, the term "granulomatous myopathy" should be used [8]. Abnormal laboratory findings have rarely been reported. CK levels are usually normal [8, 10], as are those of other muscle enzymes. Electrophysiological studies usually reveal myopathic changes. Two of the patients described here presented with weakness and pain of proximal muscles (cases 1 and 2). CK levels were increased to a maximum of 3 500 units/1 and 900 units/l, respectively. In both individuals, SACE was above the normal range on repeated occasions. Further investigations revealed no signs of sarcoidosis. There were no myopathic patterns in electromyography, and biopsy evaluation with serial sections of skeletal muscle failed to show granuloma formation. In addition, three other relatives showed no muscle weakness or pain or any other clinical abnormalities, but all presented with increased S A C E levels. Histochemical and biochemical analyses as well as the ischaemic forearm test revealed no evidence of defective muscle metabolism. Lactate and pyruvate were elevated in the three patients tested (cases 1, 2, and 5), without lactic acidaemia. In contrast to the very high CK levels, total L D H enzyme activity was only slightly increased. L D H isoenzyme determination showed elevated L D H isoenzyme 5 in all three patients tested (cases 1, 2 and 5). LDH-5 is the tetramere of the M (muscle) subunit, predominantly derived from skeletal muscle [6]. In human hereditary muscular dystrophies, LDH-5 in muscle tissue is usually decreased [6], whereas skeletal muscle necrosis is associated with an elevation of this isoenzyme [11, 20]. In the biochemical analysis of muscle tissue we found a normal concentration of whole L D H activity, so that one of the rare types of genetically determined deficiency of L D H H or

M subunit reported recently [4] is not present in this family. Myopathic changes were seen in muscle biopsy specimens of both patients, showing atrophied and basophilic muscle fibres and architectonic changes with disturbance of the interfibrillar network. Additionally, rare ragged red fibres and accumulation of glycogen were observed in the muscle biopsy of case 2. Because of the latter finding, glycolytic enzymes and phosphofructokinase were analysed without finding abnormal levels. Because of ultrastructurally observed pathological changes of mitochondria, enzymes of the respiratory chain were analysed, again without detection of an enzyme defect. Control patients suffering form several forms of myopathy showed no elevation of SACE. This finding therefore may present a special feature of the familial myopathy described here. SACE catalyses the conversion from angiotensin ! to angiotensin II by hydrolysis of the carboxyl-terminal dipeptide histidine-leucine from angiotensin I and therefore plays an important role in blood pressure regulation. It is also an inactivator of the hypotensive peptide bradykinin. SACE has a molecular weight of 150000 and is mainly synthesized within endothelial cells. It has been demonstrated especially in the lungs' huge vasculature. At present there is no known effect on skeletal muscle cells [2]. The wide spectrum of quite different pathological changes of muscle fibres in the two patients described here suggests non-specific morphological alterations of muscle tissue. The increased number of central nuclei is often seen in muscular hypertrophy, appearing also in myositis. However, with respect to the normal erythrocyte sedimentation rate and the absence of immunoserological abnormalities, the latter diagnosis could not be confirmed further. Degeneration of muscle fibres, glycogen accumulation as well as local increase and degeneration of mitochondria seen in one patient may suggest a probably secondary disturbed muscle metabolism; a distinct defect could not be demonstrated. In conclusion, the significance of S A C E elevation in the myopathy described here remains unclear. Since immunosuppressive treatment resulted in a rapid clinical improvement as well as a decrease of S A C E and CK levels, however, these findings may be causally related to this myopathy.

References

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270 6. Emery A E H (1968) Muscle lactate dehydrogenase isoenzymes in hereditary myopathies. J Neurol Sci 7 : 137-148 7. Enget AG, Banker BQ (1987) Myology. Basic and clinical. McGraw-Hill, New York 8. Jerusalem F, Imbach P (1970) GranulomatOse Myositis und Muskelsarkoidose. Dtsch Med Wochenschr 95:2184-2190 9. Lieberman J, Beutler E (1976) Elevation of serum angiotensin-converting enzyme in Gaucher's disease. N Engl J Med 294:1442-1444 10. Matthews WB (1979) Neurosarcoidosis. In: Vinken P, Bruyn W (eds) Handbook of clinical neurology, vol 38. Elsevier, Amsterdam, pp 521-542 11. Mauck JD, Davis JE (1980) Clinical enzymology. In: Sonnenwirth AC, Jarrett L (eds) Gradwohl's clinical laboratory methods and diagnosis. Mosby, St Louis, pp 305-323 12. Okabe T, Fujisawa M, Yotsumoto H, Takaku F, Lanzillo JJ, Fanburg BL (1985) Familial elevation of serum angiotensin converting enzyme. Q J Med 5 : 55-61 13. Pongratz D, Burg D (1979) Sarkoidose. Neurologische OrganManifestationen. Miinch Med Wochenschr 121 : 853-854

14. Romer FK (1984) Clinical and biochemical aspects of sarcoidosis. Acta Med Scand 690 [Suppl] : 63-68 15. Romer FK (1985) Angiotensin-converting enzyme activity in sarcoidosis and other diseases. Sarcoidosis 2 : 25-34 16. Silverstein A, Siltzbach LE (1969) Muscle involvement in sarcoidosis. Asymptomatic, myositis, and myopathy. Arch Neurol 21 : 235-241 17. Stern B J, Krumholz A (1986) Neurosarcoidosis. Presentation and management. Ann NY Acad Sci 465 : 345-348 18. Stjernberg N, Cajander S, Truedsson H, Uddenfeldt P (1981) Muscle involvement in sarcoidosis. Acta Med Scand 209 : 213216 19. Turiaf J, Battesti J-P, Basset F (1975) Sarcoidoses musculaires hypertrophiques et nodulaires. Ann Med Intern 126 : 503-508 20. Vladutiu AO, Venuto RC (1977) Creatine kinase MB and lactate dehydrogenase 5 isoenzymes in rhabdomyolysis. Clin Chem 23 : 1366