Clin Rheumatol (2002) 21:411–414 ß 2002 Clinical Rheumatology
Case Report Mitochondrial Disease Mimicking Polymyositis: A Case Report A. Corrado1, F. P. Cantatore2, L. Serlenga1, A. Amati1, V. Petruzzella1 and G. Lapadula1 1
University of Bari, Bari; 2University of Foggia, Foggia, Italy
Abstract: The authors report on a 34-year-old woman who had developed severe weakness and reduction in grip strength in both upper and lower limbs. Laboratory blood tests revealed increased levels of muscle enzyme. The presence of progressive bilateral ptosis and external ophthalmoplegia raised the suspicion of a mitochondrial disease, subsequently conﬁrmed by deltoid biopsy and genetic analysis of mitochondrial DNA that showed a deletion indicative of Kearns–Sayre syndrome. In this report we emphasise the need for a differential diagnosis between myositis and other myopathies, particularly the mitochondrial ones. Keywords: Kearns–Sayre syndrome; Mitochondriopathy; Myositis
Introduction Mitochondrial diseases are caused by alterations in endocellular organelles which have important metabolic functions, including ATP production through the respiratory chains. The pathogenic mechanisms of these disorders are generally due to mutations of either mitochondrial DNA (mDNA) or nuclear DNA (nDNA), which encode the proteins necessary for mitochondrial metabolic activity . Often mitochondrial metabolic defects affect muscular tissues, in particular sharing many clinical manifestations with other myopathies, such as myositis. Therefore, in the differential diagnosis of muscle diseases the existence of mitochondrial genetic defects must be taken into account. Correspondence and offprint requests to: Professor Francesco Paolo Cantatore, Cattedra di Reumatologia, Ospedali Riuniti, Via L. Pinto 71100, Foggia, Italy. Tel: +39881.733897; E-mail: [email protected]
Case Report A 34-year-old woman who had been suffering from severe weakness and a reduction in grip strength associated with functional muscle impairment, initially in the upper and subsequently in the lower limbs, for 1 year, was referred to our clinic. Progressive bilateral ptosis had begun at the same time. Laboratory blood tests revealed increased glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels, as well as an increase in the muscle enzymes creatine phosphokinase (CPK) and lactic dehydrogenase (LDH). Inﬂammation indices were in the normal range (erythrocyte sedimentation rate (ESR) 22 1/h, C-reactive protein (CRP) negative); other laboratory tests were normal and antinuclear antibody (ANA) and antiextractable nuclear antigens (anti-ENA) were absent. Based on clinical and biochemical ﬁndings, polymyositis had been diagnosed and corticosteroid (CS) therapy prescribed (6-methylprednisolone 20 mg/day, for a period of 6 months). However, no clinical improvement was observed and blood levels of muscular enzymes remained high. Cyclosporin A was then prescribed (150 mg/day), and the corticosteroid (prednisone) dosage was increased to 25 mg/day and then tapered to a maintenance dosage of 10 mg/day, without any clinical improvement. One year after the onset of the disease patient was admitted to our clinic. Physical examination revealed a short stature (145 cm); on examination acute muscular pain was observed on palpation, especially in the proximal muscles of both upper and lower limbs, associated with serious difﬁculty in performing normal movements. Laboratory tests revealed increased CPK and LDH values as well as concurrently normal ESR (25 mm/h), CRP (0.49 mg/dl) and acute-phase reactant, such as haptoglobin, ﬁbrinogen and a1-antitrypsyn. Full blood cell count, urinalysis, renal function tests, total serum proteins, serum calcium, phosphate, alkaline phospha-
tase, sodium, potassium, electrophoresis, C3 and C4 were normal; serum was negative for rheumatoid factor, ANA and anti-ENA. Neither diabetes mellitus nor other endocrine disorders were detected. ECG was normal; electromyography showed signs of protopathic muscular suffering, with a reduction in voltage and mean duration of motor unit action potentials, an increase in polyphasic motor unit action potentials without signs of denervation, and loss of motor units in the muscles examined (left arm biceps). Neurological examination showed limited ocular mobility in all directions. These ﬁndings, in addition to the short stature, proximal muscle weakness and bilateral ptosis, led to a diagnostic hypothesis of Kearns–Sayre syndrome. An encephalic MRI scan did not reveal the calciﬁcations of the basal
A. Corrado et al.
ganglia that are commonly seen in Kearns–Sayre syndrome. A biopsy of the deltoid muscle was carried out and the histological examination, using Gomori trichrome (Fig. 1) and succinic dehydrogenase – SDH – stains, revealed several ragged red ﬁbres in addition to many cytochrome C oxidase – COX – (Fig. 2)- negative muscle ﬁbres, which are features strongly suggesting of mitochondriopathy. The diagnosis of mitochondrial myopathy was conﬁrmed by molecular genetic analysis of both total mDNA extracted from the muscle sample and peripheral blood cells by Southern blotting, which, in addition to wildtype mDNA, detected a deletion of 16.6 kilobases signiﬁcant for Kearns–Sayre syndrome. The proportion of mutant versus total amount of mDNA, evaluated by scanning densitometry, was roughly 55%.
Fig. 1. Deltoid muscle biopsy. The modiﬁed Gomori trichrome histochemical stain showed the presence of abnormal ﬁbres staining red in the subsarcolemmal region, the so-called ‘ragged red ﬁbers’ (RRF), which are considered the distinguishing morphological feature of mitochondrial myopathies.
Fig. 2. Speciﬁc staining for COX on deltoid muscle biopsy. The presence of scattered COX-negative ﬁbres suggests an mDNA mutation.
Many muscle diseases can give similar clinical and laboratory features, so in the differential diagnosis it is essential to discriminate as early as possible the inﬂammatory diseases from others, such as degenerative and mitochondrial myopathies, in order to choose the most appropriate therapy. Because physical and laboratory investigations often provide only indirect evidence of myopathy, muscle biopsy has an essential role in making the correct diagnosis. Mitochondrial encephalomyopathies are relatively rare disorders caused by dysfunctions of the mitochondria, intracellular organelles which perform several metabolic functions of vital importance, such as the production of ATP by oxidative phosphorylation . Altered mitochondrial function may occur at various levels of metabolic activity in these organelles, and can determine a large variety of both clinical manifestations and laboratory ﬁndings [2–4]. Mitochondrial DNA (mDNA) encodes 13 proteins which are subunits of respiratory chain complexes ; any alteration of these genes can determine clinical features involving virtually every tissue and organ. Several types of mDNA defect have been described [1,5,6,7], each of these being associated preferentially with deﬁnite syndromes. When the mutation affects the germinal cells, multiple copies of mDNA pass on progeny cells via the cytoplasm, by maternal inheritance ; when the mDNA mutation occurs in somatic cells, the defects do not pass on progeny and the disease is sporadic. Normal and mutant mDNA can coexist in the same cells; this phenomenon is called ‘heteroplasmy’ . The ratio between normal and mutant mDNA varies widely in tissues from the same patient, and when the proportion of mutant mDNA exceeds a certain threshold cellular functions can be impaired, thereby resulting in disease. Many of these metabolic mitochondrial defects can often produce incomplete syndromes or even be asymptomatic in different individuals from the same family, as a
consequence of heteroplasmy and the threshold effects described above. Tissues that require a greater oxidative metabolism, such as muscle and brain, are those in which mitochondrial metabolic defects primarily determine impairment. In the case presented here the presence of high serum levels of muscle enzymes and the severe weakness of the proximal limb muscles led to the diagnosis of myositis, but some aspects were inconsistent with this muscle disease, in particular the unresponsiveness to corticosteroid and immunosuppressive therapy, which usually determine a signiﬁcant improvement in myositis; the absence of autoantibodies typical of myositis, such ANA and anti-ENA; the relatively low values of ESR, CPR and other markers of inﬂammation, which are usually high in cases of myositis; the electromyographic ﬁndings; and ﬁnally, the appearance of ptosis accompanying the onset of muscular symptoms and the presence of ophthalmoplegia, as typically the ocular extrinsic musculature is uninvolved by myositis, strongly questioning the initial diagnosis. These aspects, associated with the clinical, serological and instrumental ﬁndings described above, associated with a permanent elevated serum lactic acid, raised the suspicion of a mitochondrial disease, later conﬁrmed by muscle biopsy which revealed the presence of RRF and the absence of a typical feature of myositis. A deﬁnitive diagnosis of mitochondrial myopathy was then conﬁrmed by genetic analysis of mDNA, which showed a deletion indicative of Kearns–Sayre syndrome. Progressive external ophthalmoplegia, pigmentary degeneration of the retina and a cardiac conduction block represent the leading features of Kearns–Sayre syndrome, a sporadic, progressive neuromuscular disease associated with abnormal mitochondrial structure and function, described by Kearns in 1965 . The mDNA defects determining the syndrome are single deletions and duplications. Other clinical features are small stature, weakness of the facial, pharyngeal, trunk and extremity muscles (Table 1), and speciﬁc laboratory ﬁndings such as elevated levels of blood lactate and pyruvate. High levels of muscle enzymes are uncommon
laboratory ﬁndings, raising some difﬁculties in the present patient for the differential diagnosis with inﬂammatory muscle disease. The diagnosis of mitochondrial diseases is conﬁrmed by muscle biopsy; a modiﬁed Gomori trichrome histochemical stain allows the detection of abnormal deposits in mitochondria by light microscopy , revealing in the subsarcolemmal region abnormal ﬁbres that stain red – the so-called ‘ragged red ﬁbres’, which are considered the distinguishing morphological features of mitochondrial myopathies [1,2]. Speciﬁc staining for COX and SDH is also important, as the presence of scattered COX-negative ﬁbers suggests an mDNA mutation . A deﬁnite diagnosis of Kearns–Sayre syndrome requires speciﬁc molecular genetic analysis. The mDNA deletions and point mutations are demonstrated using polymerase chain reaction and restriction fragment length analysis by Southern blotting, which allows the detection of these molecular defects in all tissues examined. The size and the location of the deletions, and the proportion of deleted mDNA, differ between patients  and do not appear to be correlated with the presentation or the severity of the disease. To date, adequate drug therapies for these disorders have yet to be discovered . One possibility is to supply respiratory chain components, such as coenzyme Q10 and l-carnitine: this approach is supported by several reports of beneﬁcal results. Interesting results have been provided from attempts to remove toxic metabolites, such as lactic acid, using dichloroacetate (an experimental agent) . The application of various new therapeutic agents, such as antioxidants, radical scavengers and cofactors such as vitamin K3, vitamin C, riboﬂavin and thiamine, have not reached any realistic clinical result. Gene therapy should be a future possibility for intervening in mitochondriopathies, but so far appears only theoretical . In this report we emphasise the need for a differential diagnosis between myositis and other myopathies, particularly mitochondrial ones. Despite some common similar clinical aspects, there are several laboratory and clinical features that distinguish each disease, as
Table 1. Clinical features of Kearns–Sayre syndrome CNS
Action tremor Ataxia Cerebral and cerebellar atrophy Leukoencephalopathy (infrequent) Increased levels of cerebrospinal ﬂuid proteins Basal ganglia calciﬁcations Hyporeﬂexia Sensorineural hearing loss Muscle weakness Ptosis Progressive external ophthalmoplegia Dysphagia Retinal pigmentation Congenital glaucoma
CNS, central nervous system; PNS, peripheral nervous system.
Short stature Insulin-dependent diabetes mellitus Adrenal insufﬁciency
Cardiac conduction block Cardiomyopathy Fanconi’s syndrome
Increased serum levels of lactate Increased serum levels of CPK and LDH (uncommon)
previously discussed. Muscle biopsy is extremely important in reaching the correct diagnosis and could be performed in each case of suspected myopathy, even when clinical and laboratory ﬁndings seem to suggest a speciﬁc disease.
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Received for publication 13 November 2001 Accepted in revised form 15 April 2002