CASE REPORT Coenzyme Q 10 Improves Lactic Acidosis, Strokelike Episodes, and Epilepsy in a Patient With MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike episodes) Angel Berbel-Garcia, PhD,* Jose Ramon Barbera-Farre, PhD,† Jesús Porta Etessam, PhD,‡ Antonio Martı́nez Salio, PhD,‡ Ana Cabello, MD,§ Eduardo Gutierrez-Rivas, MD,‡ and Yolanda Campos, MD¶ Abstract: Mitochondrial encephalomyopathies encompass a group of disorders that have impaired oxidative metabolism in skeletal muscles and central nervous system. Many compounds have been used in clinical trials on mitochondrial diseases, but the outcomes have been variable. It remains controversial whether treatment of mitochondrial diseases with coenzyme Q 10 is effective. This paper describes a case of mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes, and exercise intolerance successfully treated with coenzyme Q 10. Efficacy of this therapy in this patient is correlated to control of lactic acidosis and serum creatine kinase levels. Disappointingly, larger studies with coenzyme Q 10 failed to demonstrate a clear beneficial effect on the entire study population with regard to clinical improvement or several parameters of the oxidative metabolism. They suggest that the use of coenzyme Q in treatment of mitochondrial diseases should be confined to protocols. There is a confounding variation in phenotype and genotype, and the natural history of the disorders in individual patients is not accurately predictable. The unpredictable a priori efficacy of therapy suggests that a long-term trial of oral coenzyme Q may be warranted. Key Words: coenzyme Q 10, efficacy, mitochondrial encephalomyopathies, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) (Clin Neuropharmacol 2004;27:187–191) M itochondrial encephalomyopathies encompass a group of disorders that have impaired oxidative metabolism in skeletal muscles and central nervous system.1 These condi- From the Departments of *Neurology and †Internal Medicine, Hospital Mancha Centro, Alcazar de San Juan, Ciudad Real; ‡Department of Neurology, §Department of Pathology, and ¶Investigation Centre, Hospital Doce de Octubre, Madrid, Spain. Reprints: Angel Berbel Garcia, PhD, Department of Neurology, Hospital Mancha Centro, Avenida Constitucion, 3 Alcazar de San Juan, Ciudad Real 13600, Spain (e-mail: aberbel@yahoo.com). Copyright © 2004 by Lippincott Williams & Wilkins Clin Neuropharmacol • Volume 27, Number 4, July - August 2004 tions include several syndromes such as myoclonus epilepsy with ragged-red fibers (MERFF); mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS); Kearns-Sayre syndrome; and chronic progressive external ophthalmoplegia (CPEO) syndromes.2–4 Many compounds have been used in clinical trials on mitochondrial diseases in an attempt to enhance respiratory chain function or to reduce the concentration of the toxic products of the disturbed metabolism, but the outcomes have been variable. Ubiquinone (Q 10) supplementation has been reported to have clinical or biochemical benefit,5–22 although some studies have failed to show any effect.23–25 Therefore, it remains controversial whether treatment of mitochondrial diseases with Q 10 is effective. We describe a case of MELAS with neurologic symptoms and exercise intolerance successfully treated with coenzyme Q 10 (CoQ). CASE REPORT A 22-year-old woman was examined after intermittent episodes of fatigue and dyspnea associated with mild exercise that finally became constant (grade V of Subjective Scoring of the Fatigability in Activities of Daily Living; SSFADL).10 Laboratory studies revealed metabolic acidosis with marked hyperlactatemia (5.1 mM; normal <2.0 mM) and elevated serum creatine kinase (CK) levels (800 U/L; normal <150 U/L). Clinical examination failed to reveal cardiopathy, hepatopathy, or central nervous system involvement. She did not have short stature, hearing impairment, or restriction of the extraocular movements. Her eldest brother had had dyspnea and fatigability episodes and died at 19 years; he was not studied. The rest of the family was clinically normal. Muscle biopsy revealed abundant ragged-red fibers and combined defects of the mitochondrial complexes. Genetic analysis showed the presence of a T3258C transition mutation within the tRNALeu(UUR) gene. The mutation was very abundant in muscle (96%) and less abundant in blood (57%). The patient’s 187 Clin Neuropharmacol • Volume 27, Number 4, July - August 2004 Berbel-Garcia et al 450 µg/d, cyanocobalamin 30 µg/d, ascorbic acid 600 mg/d; Becozyme C Forte; Roche Farma, Madrid, Spain) was begun. Despite this therapy, mild exercise intolerance, lactic acidosis, and elevated serum creatine kinase (CK) levels remained. Six months later the patient presented with headache, right temporal hemianopsia, and generalized tonic-clonic seizures that disappeared in a week. Lamotrigine therapy, 100 mg BID (Lamictal, GSK, Tres Cantos, Spain) was started. Three months later, she had another transient episode of headache followed by left temporal hemianopsia. Magnetic resonance of the brain revealed a reversible strokelike lesion in the right occipital cortex not corresponding to the territory of larger arteries. Both episodes were related to an increase in lactic acidosis and CK levels (Fig. 1). RESULTS FIGURE 1. Clinical and metabolic changes. Basal serum levels of lactate (mM), CK (U/L ⳯ 100) and bicarbonate (mM). Serum concentrations of CK and lactate increased and bicarbonate decreased during strokelike episodes (March 2001 and June 2001). Once CoQ therapy was started (July 2001), serum concentrations of CK, lactate, and bicarbonate improved (sustained for 30 months, December 2003). Horizontal bars depict normal serum values of bicarbonate (superior), CK, and lactate (inferior). mother and 2 asymptomatic brothers had the mutation in blood but the mutation was less abundant than in the patient (19, 30, and 48%, respectively); muscle biopsy was not performed. For more details of histochemistry and molecular genetic studies see Campos et al.26 A combined therapy of bicarbonate at a dosage of 2 gr/d (Bicarbonato; Novartis, Barcelona, Spain), carnitine 3 gr/d (Carnicor; Sigma Tau, Alcala de Henares, Spain), and multiple vitamins (vitamin B1 45 mg/d, vitamin B2 45 mg/d, nicotinamide 150 mg/d, pyridoxine 30 mg/d, biotin Finally therapy with CoQ 300 mg/d was started (Decorenone 50, Italfarmaco SPA, Milan, Italy). Progressive improvement of exercise intolerance (grade II on SSFADL),10 metabolic acidosis, and serum CK levels was documented. New strokelike episodes or seizures did not appear. The patient has been asymptomatic for 30 months. For more details in the evolution of clinical and metabolic findings, see Figure 1 and Table 1. DISCUSSION Coenzyme Q 10 plays a pivotal role in the mitochondrial respiratory chain. It distributes the electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Based on our present understanding of the role of quinones in the mitochondria, we should distinguish attempts aiming at restoring electron flow, providing electrons to the chain, or increasing mitochondrial antioxidant defenses. Therapeutic studies of mitochondrial diseases are difficult to perform. It is hard to find a sufficient number of patients to give adequate statistical power to a study. Although appropriate treatment has not been established, therapeutic trials TABLE 1. Metabolic Changes: Basal Serum Levels of Lactate (mM), Creatine Kinase (CK), pH, and Bicarbonate (mM) pH Bicarbonate CK Lactate Symptoms 11-00 03-01 04-01 06-01 09-01 12-01 12-02 12-03 7.23 12 800 6 D/EI 7.16 8.7 1500 18 Stroke 7.27 19 1000 8 D/EI 7.23 10 1400 15 Stroke 7.31 18 600 10 EI 7.39 23 100 1.5 Oligo 7.42 23 180 1.8 Oligo 7.45 21 150 2.1 Oligo Periods without neurologic symptoms previous to coenzyme Q administration show intermediate metabolic alterations (from November 2000 to March 2001 and from April 2001 to June 2001). Serum concentrations of CK and lactate increased and pH and bicarbonate decreased during strokelike episodes (March 2001 and June 2001). Once coenzyme Q therapy was started (July 2001), serum concentrations of CK, lactate, pH, and bicarbonate improved (sustained for 30 months, December 2003). D; dyspnea; EI, exercise intolerance; oligo, oligosymptomatic. 188 © 2004 Lippincott Williams & Wilkins Clin Neuropharmacol • Volume 27, Number 4, July - August 2004 Coenzyme Q in MELAS TABLE 2. Trials in Coenzyme Q 10 Therapy for Mitochondrial Diseases Trial Remes et al5 Barbiroli et al6 Shinkai et al7 Abe et al8 Goda et al9 Chen et al10 Patients Encephalopathy 7 patients (A3243G) 4 CPEO 2 LON (11778) 1 MELAS (A3243G) 2 MELAS (A3243G) 1 MELAS Abe et al11 Yamamoto et al12 Berio and Piazzi13 4 MERFF (8344) 3 MELAS (3243) 1 CPEO 1 MELAS 1 MELAS 1 Kearns-Sayre Calatayud et al14 1 Kearns-Sayre Ihara et al15 2 MELAS Desnuelle et al16 Bresolin et al17 Ogasahara et al18 Dosage CoQ/ Other Drugs 3 mg/kg/d + nicotinamide 50 mg/kg/d 150 mg/d Time Biochemical Efficacy Clinical Improvement 6 mo Serum L and P improvement No improvement 6 mo Muscle, brain MR-S improvement CSF L and P decreased No improvement 70 mg/d 200 mg/d 300 mg/d 1y Noninvasive oximetry improvement Serum L and P improvement 160 mg/d 3 mo Exercise lactate test improved High doses 90 mg/d 30 mg/d, controlled carbohydrate intake 150 CSF L and P decreased 1y 6 mo 3y 2 Kearns-Sayre 7 CPEO 5 Kearns-Sayre 210 mg/d and idebenone 90 mg/d 150 mg/d 120 mg/d 120–50 mg/d 3 mo 2y 1y 3–4 mo Ogasahara et al19 1 Kearns-Sayre 120 mg/d 3 mo Nishikawa et al20 Maldergem et al21 Chan et al22 1 COX deficiency 2 Leigh disease 9 Kearns-Sayre High doses 300 mg/d 150 mg/d 2y Matthews et al23 300 mg/d and multiple vitamins 2 mg/kg/d 2 mo Bresolin et al24 4 MERFF 7 Myopathy 44 patients Zierz et al25 2 CPEO 6 mo 6 mo 1y Serum L improved Serum L and P and VEP improved EEG Serum L/P improved Serum L/P improved Serum L and P CSF L and P, ECG defects, improved Serum L/P, conduction ECG bocks improved MR-S, SEP improved Basal and alter exercise Serum L/P improved L and P, MR-S, exercise testing, unchanged 25% postexercise lactate levels decreased Serum L, mitochondrial activity, unchanged Psychiatric signs Transient blindness disappeared Weakness Weakness, seizures Weakness Ophthalmoparesis Ophthalmoparesis Weakness, WAIS Ophthalmoparesis Weakness Weakness, ophthalmoparesis Ophthalmoparesis No improvement Weakness, growth No improvement No improvement No improvement Reports in coenzyme Q 10 therapy and its clinical or biochemical efficacy. In parentheses: mitochondrial DNA mutations. COX, cytochrome-c-oxidase; CPEO, chronic progressive external ophthalmoplegia; CSF, cerebrospinal fluid; ECG, electrocardiogram; EEG, electroencephalogram; L, lactate; LON, Leber optic neuropathy; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke; MERFF, myoclonus, epilepsy, red-ragged fibers; MR-S, magnetic resonance-spectroscopy; P, pyruvate; SEP, somatosensory evoked potentials; VEP, visual evoked potentials; WAIS, Wechsler Adult Intelligence Scale. with Q 10 have been reported to be beneficial clinically or biochemically in several studies.5–22 Conversely some studies have failed to show any effect.23–25 Moreover there is a confounding variation in phenotype and genotype, and the natural history of the disorders in individual patients is not accurately © 2004 Lippincott Williams & Wilkins predictable. A direct comparison of the effect of CoQ in these studies is difficult because of different methods with different metabolic parameters to evaluate response; the lack of quantitative assessment or scores; the inclusion of different syndromes with variable genetic backgrounds; the variable sever- 189 Berbel-Garcia et al ity of symptoms; time of trial; and dosage of CoQ and combination of several drugs (Table 2). Disappointingly, larger studies with CoQ failed to demonstrate a clear beneficial effect on the entire study population with regard to clinical improvement or several parameters of the oxidative metabolism.23–25 Authors postulated that variability in the natural history of the disorders was the responsible for the initial lactate changes and that treatment with CoQ did not actually improve oxidative functions.23 They concluded that the use of CoQ in treatment of mitochondrial diseases should be confined to protocols designed to assess possible benefits.23 Conversely, others studies suggested that a trial of oral CoQ 10 may be warranted but should last much longer than 6 months and test higher doses.5,9,10,11,17 Except for those with CPEO, most of these patients have showed only mild, shortterm subjective clinical improvement. Moreover, the principal endpoint was biochemical or neurophysiologic efficacy. Our patient showed a dramatic improvement of exercise intolerance and neurologic symptoms once CoQ therapy was started. Clinical and biochemical effects last for 30 months. Several hypotheses have been postulated to explain the etiology of the strokelike episodes and an individual cellular dysfunction related to the abnormality in the respiratory chain of the mitochondria seems to be the most plausible.15 Fluctuations of neurologic symptoms were correlated to increase of systemic lactic acidosis; strokelike episodes and seizures disappeared with control of lactic acidosis. Unfortunately cerebrospinal fluid, neurophysiologic, or magnetic resonance spectroscopy findings are not available to prove that neurologic symptoms could be attributed to systemic metabolic changes and are not due to changes in brain mitochondrial metabolism. Exogenous CoQ is known not to be able to pass the blood-brain barrier (BBB),15 but some trials have proved clinical, biochemical, or physiological efficacy in the central nervous system.5,11,12,18,20 A broken BBB11 has been proposed to explain a relatively freely pass into the brain tissue. In cases of nervous central system dysfunction, concomitant therapy with idebenone is recommended.15,27,28 Efficacy of this therapy in our patient could be attributed to control of lactic acidosis, because out of the strokelike episodes a broken BBB is not demonstrable. The ultimate mechanism of CoQ in our patient is unknown. In conclusion, appropriate treatment of mitochondrial encephalomyopathies has not been established. Larger trials conclude that the use of CoQ in treatment of mitochondrial diseases should be confined to protocols. Nevertheless our patient shows a long-term efficacy of therapy with CoQ. 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