Treatment of mitochondrial disorders

Journal of Pediatric Neurology 10 (2012) 1–11 DOI 10.3233/JPN-2012-00578 IOS Press

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Review Article

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Treatment of mitochondrial disorders

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7 8 9 10 11 12 13 14 15 16 17 18 19 20

Monika Sharmaa,*, Sheffali Gulatib and Anita Choudharyc aDepartment

of Pediatrics, Christian Medical College, Ludhiana, Punjab, India of Pediatrics, All India Institute of Medical Sciences, New Delhi, India cDepartment of Pediatrics, Advanced Pediatric Centre, Chandigarh, India bDepartment

Received 13 February 2012 Revised 9 May 2012 Accepted 30 May 2012

Abstract. Mitochondria are important intracellular organelles that are widely distributed and have a central role in metabolic activity. Production of adenosine triphosphate by oxidative phosphorylation, is the principal function of mitochondria. Defects of mitochondrial metabolism cause a wide range of human diseases. They may present as single or multisystem disease at any age. Treatment of mitochondrial disorders is a challenge, as there is only symptomatic therapy available. As few randomized and controlled studies are published, much of the experience of the treatment of mitochondrial disease is based upon anecdotal reports and small case series, which demonstrate effect of some of the measures available. In this paper, we review the various treatments studied and practiced in the context of mitochondrial disorders. We will also outline the evidence in favor or against them. Keywords: Mitochondrial disorder, oxidative phosphorylation, encephalomyopathy

21 1. Introduction 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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36 In this paper, we review the various treatments 37 studied and practiced in the context of mitochondrial The treatment of mitochondrial disorders lacks 38 disorders. We will also outline the evidence in favor evidence base and consists of a prescription of a 39 or against them. cocktail of high dose multivitamins and drugs that have been considered as useful in selected mitochondrial disorders, for example co-enzyme Q10 (Co-Q) in 40 2. The mitochondria Kearns-Sayre and idebenone in Friedrich’s ataxia. Prescriptions are based on experiential recommenda- 41 The inner mitochondrial membrane is the resting tions. None of these drugs have shown absolute ben- 42 place of five lipid enzyme complexes, complexes I-V. efit or have been without side-effects. While these 43 Production of ATP (adenosine triphosphate) by oxicocktails continue to be prescribed, and newer mo- 44 dative phosphorylation is the principal function of dalities like gene therapy or stem cell therapy are 45 mitochondria. Mitochondria are thus the powerhouses being considered and researched, there is a need to 46 of the cells. They are in abundance in structures, critically analyze prescribed agents and understand 47 which have a high consumption of energy, such as the their utility with respect to mitochondrial defects. 48 central nervous system, peripheral nervous system, 49 heart, endocrine organs, eyes and muscles. Mito___________________________________________ 50 chondrial disorders hence primarily affect either one *Correspondence: Dr. Monika Sharma, Department of Pediatrics, Christian Medical College, Ludhiana, Punjab, India. Tel.: +91 51 or all of these organs producing a wide spectrum of 52 disorders with clinical variations. 9814861205; E-mail: [email protected]. 1304-2580/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved

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M. Sharma et al. / Treatment of mitochondrial disorders

Mitochondria, also serve two other important and well-known functions. Mitochondrial membranes house certain apoptotic proteins, including cytochrome c, that play an important role in cellular apoptosis. Mitochondria also neutralize the superoxide radicals in the cytosome by enhancing their diffusion across polarity of its membrane and then dismutation with the help of manganese superoxide dismutase, inside the mitochondria. These two functions, that regulate cell proliferation and changes in the mitochondrial and cellular micro environment, have been implicated in the causation of cancers, and are a subject of continuing research [1−3]. The exact incidence or prevalence of mitochondrial disorders is only known for certain subpopulations. It has been documented as being the commonest neurometabolic disorder, with Leigh’s syndrome as being the commonest mitochondrial disorder, amongst preschool children. A large scale prevalence study from Sweden, estimates that 1 out of 11,000 live born children have a risk of developing a mitochondrial encephalomyopathy and the point prevalence for children below 16 yr of age, is one out of 21,000. This estimate was largely based on hospital records and was made with the possible exclusion of a sizeable migrating population [4]. Another significant study from South Australia has documented the prevalence of respiratory chain disorders as 13.1/100,000 population at birth and 1/7,634 when all ages of presentation were considered together [5]. There are a greater number of epidemiologic studies carried out in adult population to estimate the genetic and clinical prevalence of mitochondrial disorder [6]. Similar epidemiologic estimates of the disorder in younger ages are few. Genetic and molecular classification of mitochondrial disorders is presented in Table 1 [7]. In spite of abundant knowledge regarding the inheritance and expression of mitochondrial defects, information on therapies and evidence supporting their current use remains elusive.

93 3. Treatment strategies 94 95 96 97 98 99

Treatments of mitochondrial disorders are based on principles that target the affected step of mitochondrial functions. These are outlined in Table 2. In addition to these treatment modalities, individuals with mitochondrial disorder may be advised to avoid drugs that could be toxic for mitochondrial functions. Cer-

100 101 102 103 104 105 106

tain treatments are based on individual requirements, for example, antiepileptic drugs for controlling seizures, insulin for hyperglycemia, surgery (blepharoplasty, transplantation), blood transfusion, dialysis, prosthetics etc. Genetic counseling for transmission and prevention of mitochondrial disorders is an essential part of therapy [8].

107 3.1. Co-Q and its analogue − idebenone 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147

Co-Q is a benzoquinone present in all animal and plant cells and is an important component of the bioenergetic processes of the respiratory chain. Within the cell, Co-Q is located on the inner mitochondrial membrane. It is an essential component of the electron transfer process [10]. Idebenone is a quinine derivative and reversibly reduces to hydroxyquinones by plasma membrane oxidoreductase and diaphorase. These reduced forms are important and useful antioxidants and help protect the mitochondrial membrane against lipid peroxidation. Their ability to act as electron acceptors and to bypass the respiratory chain complexes lends them therapeutic potential. Synthetic analogues of mitochondrial co-enzymes are said to mediate electron transfer from nitrogen to oxygen and thus result in superoxide formation [9]. Co-Q administration has been demonstrated to increase ATP production in lymphocytes both in vivo and in vitro [10]. Idebenone, analogous to Co-Q, readily enters the brain, localizes on the inner mitochondrial membrane and stimulates ATP formation. Idebenone has been widely studied in patients with Freidrich’s ataxia. Low dose idebenone (5 mg/kg/day) has been found to reduce cardiac hypertrophy in patients with Freidrich’s ataxia, whereas intermediate (30 mg/kg/day) and higher dose ranges (60−90 mg/kg/day) have been found to improve the neurological features [11]. Various other studies have not been able to document a similar positive impact on muscle strength [12,13]. Side effects were found to be mainly gastrointestinal in form of nausea, dyspepsia, loose stools, and vomiting [11]. Co-Q is one of the most widely used and the most extensively studied medical treatment of mitochondrial disorders. Co-Q deficiency has been documented in the muscles of patients with mitochondrial disorders and is also associated with cerebellar ataxias. In a study on 36 patients, Montero et al. [14] documented Co-Q deficiency in 35 patients with confirmed mitochondrial myopathies.


148 149

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Table 1 Genetic and biochemical classification of mitochondrial disorders [2] Genomes

Gene

Biochemistry

Clinical phenotype

Mitochondrial DNA Decreased protein synthesis tRNA Leu (UUR) Lys

Decreased protein synthesis

tRNA Other tRNAs

Decreased protein synthesis Decreased protein synthesis

ATPase6

Decreased ATP synthesis

ND1, ND4, ND6 ND1, ND4 Cytochrome B COX III

Kearns Sayre syndrome; ocular myopathy; Pearson syndrome Mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome Myoclonic epilepsy with ragged red fibers Multiple phenotype Neuropathy, ataxia, and retinitis pigmentosa, Maternally inherited Leigh syndrome

Decreased complex I

Leber’s hereditary optic neuropathy

Decreased complex I Decreased complex III Decreased complex IV

Encephalomyopathy Encephalomyopathy Encephalomyopathy

NUDF SDHA

Decreased complex I Decreased complex II

BCSIL

Decreased complex III

SURF1 SCO 1 SCO2 COX 10 COX 15 ATP 12 TP ANT 1 Twinkle POLG dGK TK2

Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex V Decreased Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased cardiolipin Decreased mitochondrial motility

Leigh’s syndrome Leigh’s syndrome Growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload Leigh’s syndrome Hepatoencephalomyopathy Cardioencephalomyopathy Nephroencephalomyopathy Cardioencephalomyopathy Fatal infantile multisystem disease Mitochondrial neuro-gastrointestinal encephalomyopathy AD PEO plus* AD PEO plus* AD /AR PEO plus* Hepatocerebral syndrome Myopathy; spinal muscular atrophy

Nuclear DNA

TKZ OPA1

150 151 152 153 154

Barth syndrome AD optic atrophy

* Plus refers to “proximal weakness, neuropathy, psychiatric disorder and Parkinsonism”. AD = Autosomal dominant; AR = Autosomal recessive; PEO = Progressive external ophthalmoplegia. Table 2 Principles of treatment Principle Reduce free radical damage Circumvent the block in electron transport chain Boosting of the oxidative process/Supplements Acceleration of excretion of toxic metabolites Replacing the defective mitochondria

Drugs used Co-enzyme Q, idebenone Vitamin C, menadione Riboflavin, thiamine, folate, carnitine Dicholoroacetate, dimethyl glycine (for treating lactic acidosis) Gene therapy, stem cell therapy

155 156 157 Co-Q has been successfully used in several mito158 chondrial disorders. There are several reports citing 159 improved cardiac functioning in mitochondrial car160 diomyopathies, improvement in metabolic derange-

161 162 163 164

ments in the brain, muscle and blood in various mitochondrial cytopathies including Kearns-Sayre syndrome, improvement in muscle strength, ataxia, chorea, ophthalmoplegia, cognitive functions and de-

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165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198


crease in stroke like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome with Co-Q and idebenone therapy [15−23]. Though Co-Q continues to be used widely for mitochondrial disorders, evidence favoring prolonged used is debatable. In a study on 17 patients with chronic progressive external ophthalmoplegia, authors were able to demonstrate a transient elevation in serum levels of Co-Q, while evaluation at 10−15 mo after therapy revealed that levels had returned to the previous baseline [24]. In an earlier study on two patients with mitochondrial myopathies, no change in the muscle level of Co-Q or muscle strength was demonstrated in spite of a year of therapy [25]. In a recent clinical trial, combined therapy of high dose idebenone and high doses of vitamin C and riboflavin were studied in Leber’s hereditary optic neuropathy. This study failed to show any visual improvement after one yr of therapy [26]. Cortelli et al. [27] had also earlier documented the usefulness of idebenone in Leber’s hereditary optic neuropathy, though the study was of the opinion that administration of the drug early in the course of the illness had a better outcome. Co-Q has also been tried in patients with muscular dystrophy, in doses lower than those used for mitochondrial disorders. A few trials have reported improved sense of well being and muscle strength. None has reported any side effects [28]. Co-Q is available as simple and sustained release tablets. Both result in comparable elevations in serum levels of Co-Q [29]. Dizziness, rashes and gastrointestinal symptoms are known side-effects [30].

199 3.2. Vitamins for mitochondrial disorders 200 201 202 203 204 205 206 207 208 209 210 211 212 213

3.2.1. Vitamin K3 (menadione) and vitamin K1 (phytonadione) Menadione and phytonadione are lipid soluble naphthoquinones. Menadione bypasses the respiratory chain defects by entering the electron transport pathway at cytochrome b [31]. Both these analogues are nearly equally active after alkylation. Menadione reverts complex III deficiency. In rat model, menadione has been shown to improve oxygen utilization by mitochondria and improve muscle function [32]. Argov et al. [33] have reported encouraging results in a patient with mitochondrial myopathy treated with a combination of high done menadione and ascorbic acid. They were able to demonstrate some improve-

214 215 216 217 218 219

ment in muscle strength. The biochemical improvement in lactic acidosis was however marginal. Menadione is known to result in hyperbilirubinemia and hemolytic anemia, especially in neonates, with a safer profile in adults. No such side effects are known with phytonadione [30].

220 221 222 223 224 225 226 227

3.2.2. Ascorbic acid Ascorbic acid is another electron transfer mediator and has been used in doses up to 4 g per day. Ascorbic acid has been used in combination with menadione. Combined use of both these vitamins has been reported to significantly improve muscle function as mentioned earlier though another large clinical trial, did not support this result [34].

228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244

3.2.3. Thiamine Thiamine acts as a free radical scavenger. It is a cofactor for several steps in glucose oxidation. Thiamine deficiency decreases the thiamine dependent enzymes, altering mitochondrial function, creating oxidative stress and thus resulting in neurodegeneration. Thiamine deficiency results in selective neuronal degeneration, with the subthalamic nucleus being most sensitive to the deficiency [35,36]. Low cerebrospinal fluid (CSF) thiamine levels have also been reported in patients of Friedreich’s ataxia [37,38]. Administration of high doses of thiamine reportedly improves the lactate to pyruvate ratios and reverses the neurodegenerative process due to thiamine deficiency. Its usefulness has been documented in some cases of lactic acidosis, MELAS, mostly in conjunction with other high dose vitamins [39,40].

245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261

3.2.4. Riboflavin Riboflavin is a precursor of flavin monophosphate and flavin adenine dinucleotide, which are cofactors for complex I and complex II. Its therapeutic effect is related to activation of the enzyme system, stimulation of synthetic process or reducing complex I degradation [41,42]. Bugiani et al. [42] studied three patients with complex II deficiency over a period of 4.5 yr. These patients were treated with riboflavin and demonstrated a stable course of the disease. They have demonstrated a near normalization of lactic acidosis in one of the three children observed [41]. Several authors, report near complete resolution of myopathic symptoms, with reversal of lactic acidosis in patients with complex I defects. A parallel improvement in brain and muscle histopathology has also been documented [43].


262 263 264 265 266

Co-administration of nicotinamide (1 mg qid) along with riboflavin has been associated with improvement in encephalopathy and nerve conduction in patients with MELAS [44]. Riboflavin has not been shown to cause any serious side effects [40,41].

267 3.3. Accelerating the excretion of toxic metabolites

5

309 310 311 312 313

drome described from Quebec, associated with facial dysmorphism, ataxia and lactic acidosis. This trial was not able to demonstrate significant alteration in the blood lactate levels or the clinical status of the children, compared to a placebo [47].

314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341

3.3.3. L-Carnitine Carnitine is widely found in foods from animal sources and is endogenously synthesized, from methioneine and lysine. Skeletal muscles contain high amounts of carnitine [48]. Carnitine functions in the transfer of long chain fatty acids across the mitochondrial membrane with the help of enzyme carnitine palmitoyl transferase that conjugates the long-chain fatty acids with carnitine and transports it by the carnitine transporter protein. Carnitine thus, has an importance in the transfer of acyl coA into the mitochondria. Of the two isoforms of carnitine (L and D), the L isomer is biologically active. It improves cognitive function and muscle activity [49]. Carnitine is also known as a modulator of intracellular stress responses [50]. Carnitine is recommended as a maintenance therapy in combination with dietary modification and micronutrient supplementation, in treatment of glutaric aciduria [51]. Carnitine is also one of the few drugs approved by Food and Drug Administration for treatment of inborn errors of metabolism. Carnitine helps in enhancing excretion of toxic metabolites and has been found to be efficacious in treatment of methyl malonic acidemias [52,53]. Side effects are usually reported with the use of higher doses. These are gastrointestinal, a fishy odor, alopecia and rash [30].

342 343 344 345 346 347 348 349 350 351 352

3.3.4. Creatine Creatine increases the bioavailability of creatine phosphate in the muscle. Creatine phosphate is a storage form of high-energy phosphate bonds and improves oxidative metabolism and exercise tolerance in patients with mitochondrial myopathies. As it inhibits platelet aggregation, it may be beneficial in patients with stroke like episodes [30]. The results of studies using creatine, are contradictory and do not offer definite suggestions on their routine use [54,55].

268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299

3.3.1. Dicholoroacetate Dicholoroacetate (DCA) is a biochemical often found in contaminated ground water, chlorinated water and as a metabolite of several pharmaceutical agents. It rapidly concentrates in the inner mitochondrial membrane. The principal site of action is at the first rate limiting step of aerobic oxidation of glucose, lactate and pyruvate. Pyruvate dehydrogenase enzyme complex (PDC) catalyses the decarboxylation of pyruvate to acyl co-enzyme A (acyl coA). This reversible reaction is irreversibly blocked by DCA, as it inhibits the kinase enzyme that inactivates pyruvate dehydrogenase (PDH) [45]. Thus, DCA improves the efficiency of mitochondria in converting lactate and pyruvate into sources of energy. DCA is partly plasma bound after rapid absorption on oral administration and takes nearly a wk to clear from the body after stopping the drug. DCA has been widely used and studied in congenital and acquired lactic acidosis and mitochondrial diseases particularly associated with PDC defects [45]. In a randomized cross over study in 11 patients with various mitochondrial disorders, DCA was found to result in metabolic improvement. Clinical and neurological findings however remained unchanged [46]. In animal studies, DCA has been found to cause hepatotoxicity and induce various kinds of neoplasm. This however has not been reported in humans. It is known to cause irreversible peripheral neuropathy. Mild sedation has been noted transiently after administration.

300 301 302 303 304 305 306 307 308

3.3.2. Dimethyl glycine Dimethyl glycine is present in certain health foods and has been associated potential toxicities, probably related to the presence of dicholoroacetate in available formulations. In its pure form, it is not readily available. Dimethyl glycine acts as a source of electrons entering the respiratory chain at the level of Co-Q [47]. 353 3.3.5. Citrate and succinate There is a single clinical trial using dimethyl gly- 354 Citrate and succinate are intermediates in the citric cine in a specific cyclooxygenase deficiency syn- 355 acid cycle. Succinate is a source of electrons for

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356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400


complex II and is said to improve the electron flow from complex III to complex IV. Clinically successful use of long-term succinate therapy in patients with MELAS has been reported in a few case reports (in adults), however further evaluation on their efficacy and side effect profile is needed on a larger scale [56]. Succinate is usually available as a sodium salt and can cause hypernatremia. Citrate and aspartate drip was reported to be useful in reduction of lactic acidosis in a patient with PDC deficiency. It however, did not improve the neurologic problems [57].

401 402 403 404 405 406 407 408 409 410 411 412 3.3.6. L-arginine 413 L-arginine, a nitric oxide-precursor, showed im- 414 provement in endothelial dysfunction and may be particularly beneficial for stroke like episodes in 415 patients with MELAS [58]. The exact role of L-arginine is so far unclear. Being a precursor of 416 nitric oxide, its pulmonary arteriodilatory properties 417 have been suggested as a possible explanation for it 418 role in management of pulmonary arterial hyperten- 419 sion, which has been reported in some children with 420 421 MELAS [59]. 422 3.4. Folic acid 423 424 Use of folate supplementation in mitochondrial 425 disorders is extrapolated from its co relation with 426 cerebral folate deficiency disorders. Cerebral folic 427 acid deficiency has long been associated with mito- 428 chondrial DNA deletion syndromes like Kearns-Sayre 429 syndrome, progressive external ophthalmoplegia and 430 Pearson syndrome and a lot of other mitochondrial 431 neuropsychiatric disorders [60,61]. Low levels of 432 5-methyl tetrahydrofolate are detected in the CSF in 433 presence of normal levels in the blood. Profound de- 434 ficiencies correlate well with the possibility of mito- 435 chondrial diseases. CSF estimation of 5-methyl tet- 436 rahydrofolate can in fact be a useful screening test in 437 various unqualified neurodevelopmental disturbances, 438 where levels can help differentiate folate transport or 439 metabolic defects [62,63]. Lifelong supplementation 440 with folic acid has been noted to improve CSF levels 441 and clinical symptoms over time [64,65]. 442 443 3.5. Corticosteroids 444 445 The role and mechanism of action of steroids in 446 mitochondrial diseases is not clear and hence steroids 447 have not been routinely recommended. A possible 448

impact of membrane stabilizing effect has been suggested. There have been anecdotal and hypothetical suggestions of their utility in certain multisystem mitochondrial disorders on the basis of a favorable response to steroids [66]. Recent research has also linked mitochondrial diseases to the etiology of infantile spasms where steroid treatment is a wellknown and successful treatment modality [67]. Steroids have also been found to benefit in acute emergent situations in certain mitochondrial, disorders such as MELAS and myoclonic epilepsy with ragged red fibers. Various authors have reported benefits with use of dexamethasone, methylprednisolone and prednisolone in various doses [68−71]. 3.6. Diet In mitochondrial disorders, oxidative metabolism and therefore utilization of energy substrate is impaired. Depending on what enzymatic step is blocked, the kind of impairment can be predicted and diet may be tailored accordingly. For example; carbohydrate utilization may be affected in PDH defects and fat utilization in acyl coA defects. Though a specific diet cannot really be recommended, single or multiple diet component manipulations or alternative feeding methods can be suggested. These strategies keep in mind the vital nutritional needs of growing patients, besides taking care of immune integrity that is so important in preventing infections. Thus, the aim of diet manipulations is to optimize energy production and decrease production of toxic byproducts [30]. One example of the diet manipulation is limiting long chain fatty acids and substitution with medium chain fats/oils in patients with very long chain acyl coA deficiency. Ketogenic diet, induction of artificial starvation like state, has been studied in patients with low PDH activity as it is said to bypass the PDC deficiency. Ketogenic diet has been recommended for children with refractory epilepsy due to PDC deficiency [66]. In most mitochondrial disorders, fasting and hypoglycemia should be avoided and hence frequent small meals and addition of complex carbohydrates are recommended [72,73]. Addition of cornstarch at bedtime prevents hypoglycemia and is useful in patients who cannot stand prolonged fasting. Cornstarch has been shown to decrease the incidence of hypoglycemia and improve levels of serum aminotransferases [74].


449 450

Table 3 Drugs to be avoided in mitochondrial disorders [75] Drugs Zidovudine Valproic acid Phenytoin Tetracyclin, amiodarone Statin Carboplatin, ifosamide, doxorubicin Interferon alpha Corticosteroid

Mechanism of mitochondrial toxicity Mitochondrial depletion, oxidative stress, direct inhibition of mitochondrial bioenergetics machinery, mitochondrial depletion of L-carnitine Sequester carnitine, inhibits oxidative phosphorylation, induces apoptosis of microglia Inhibits mitochondrial ATPase Inhibit mitochondrial beta oxidation enzymes Reduces co-enzyme Q, inhibit respiratory chain complex I Induces mitochondrial mutation Decrease synthesis and stability of mitochondrial transcript Increase mitochondrial membrane potential, reduce antioxidants, induce apoptosis

451 452 3.7. Drugs to be avoided 453 454 455 456 457

Certain drugs should be avoided in mitochondrial disorders as they may cause mitochondrial mutation, inhibit mitochondrial replication, inhibit beta-oxidation, reduce mitochondrial protein synthesis and reduce respiratory chain enzyme activity (Table 3) [75].

458 3.8. Gene therapy 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484

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Mitochondrial genetics displays what is called as heteroplasmy, where the disease manifests when more than a certain threshold proportion of defective mitochondrial DNA are present. As muscles tend to have a smaller proportion of mutated DNA, inducing local necrosis and inducing regeneration to produce mutation deficient cells is one suggested method for heteroplasmic shifting. This approach is not likely to be of help in the more generalized form of the disorder [8]. Another strategy proposed is the induction of mitochondrial fusion. Mitochondrial fusion and fission are normal processes in eukaryotic cells that regenerate and rejuvenate the organelle. Induction of the same in mutated mitochondria with the help of agents such as ethacrynic acid and N-ethylmaleimide has been studied [76]. Ethacrynic acid disrupts the organelle membrane and produces mega mitochondria, thus trying to produce more homoplasmy [76]. Where a specific component of the respiratory chain is deficient, therapy targeted at supplying the deficient component through allogenic or isogenic transplantation has been suggested [8]. Gene repair experiments on mutation bearing yeast and mice encourage the possibility of ‘manufacture’ of an oral drug that could help treat mitochondrial disorders. So far, however, this has not been possible [77,78].

485 3.9. Stem cell therapy 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500

Stem cell therapy consists of injecting stem cells capable of restoring enzyme defects. The wide variety of mitochondrial enzyme defects known, makes it difficult for stem cell therapy to be easily designed, but has been a subject of research for some time. Allogenic stem cell therapy was first attempted for mitochondrial neuro-gastro intestinal encephalomyopathy in 2006 wherein stem cells capable of restoring thymidine pyrophosphate activity were injected in two subjects with mitochondrial neuro-gastro intestinal encephalomyopathy, with partial success [79]. A combination of stem cell therapy and gene therapy is also being researched for disorders where certain effected organ systems can be easily targeted e.g. cardiomyopathies [80].

501 3.10. Palliative therapy 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517

Antiepileptic drugs are indicated for seizure control. Valproic acid should be avoided due to potential mitochondrial toxicity. For reducing spasticity baclofen, tizanidine and botulinum toxin should be used. Patient with hearing impairment may benefit from hearing aid. Blood transfusion is required in cases of anemia and thrombocytopenia. Ptosis may require ophthalmic surgery. Endocrine dysfunction requires replacement hormonal therapy. In conclusion, Co-Q and its analogues continue to be one of the most frequently used treatments for mitochondrial disorders. In spite of reports of clinical and biochemical improvements, most studies have not been able to show a sustained improvement with prolonged therapy. There are still no definite guidelines for how long Co-Q therapy should be continued

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518 519

Table 4 Commonly used drugs and their doses Agent

Dosage

Co-enzyme Q Idebenone Vitamin K3 Vitamin C Riboflavin Thiamine Carnitine Creatine Dicholoracetate Succinate Dimethyl glycine Citrate Folic acid Steroid

Reference no.

5−15 mg/kg/day in 3 divided doses up to 1 g in documented deficiency 90−675 mg/day, 5−90 mg/kg/day 5−30 mg/day in three doses 100−500 mg three doses daily, up to 4 g 50−100 mg/day 50−100 mg/day 50−100 mg/kg/day in divided doses 8−35 mg/kg/day 25−100 mg/kg/day 2−6 g/day 50 mg/kg/day for 3 doses in children 33 kg 7.5 mmol/kg/day 0.5−1 mg/kg/day Dexamethasone 6−12 mg/kg/day Prednisolone 2 mg/kg/day Methylprednisolone 1 g/kg in 3 divided doses

520 521 522 523

17−25, 30 11 33, 34 33, 34 41, 42 39, 40 52, 53 54, 55 46 56 47 57 64, 65 68

Table 5 Summary of studies on treatment of mitochondrial disorders References

Disease

Number of Duration patients (months)

Drugs

Outcome

Barbiroli et al. (1999) [17]

Mitochondrial cytopathy

10

6

Co-Q 150 mg/day

All brain magnetic resonance spectroscopy-measurable variables and rate of muscle mitochondrial respiration remarkably improved Normalization of venous lactate/ pyruvate ratio in three patients Improvement in electrocardiography and neurological symptoms

Chan et al. (1998) [18]

Mitochondrial myopathy

9

6

Co-Q 150 mg/day

Ogasahar et al. (1986) [19] Choie et al. (2000) [20]

Kearns Sayre syndrome

5

14

Co-Q 120−150 mg/day

Kearns Sayre syndrome

1

16

Co-Q 100 mg/day

Ihara et al. (1989) [21]

MELAS

2

7

Co-Q and idebenone

Bendahan et al. (1992) [23] Hanisch et al. (2003) [24] Zierz et al. (1990) [25] Barnils et al. (2007) [26]

Mitochondrial encephalomyopathy

2

10

Co-Q 150 mg/day

Transient improvement in pyruvate metabolism at one month after therapy. No sustained improvement Improvement in muscle weakness and peripheral nerve damage in one case Improvement in mitochondrial function

Mitochondrial chronic progressive external ophthalmoplegia Mitochondrial myopathy

17

12−15

2

12

Co-Q 0.60-1.8 mg/kg/day Co-Q

Transient rise in Co-Q serum level, no clinical improvement No improvement

Leber’s hereditary optic neuropathy

2

12

No improvement in visual function

Cortelli et al. Leber’s hereditary optic neurop(2003) [27] athy

1

12

Idebenone 270 mg/day, vitamin C 500 mg/day, riboflavin 700 mg/day Idebenone 135 mg tid

Improvement in paraparesis


9

Table 5, continued Argov et al. (1986) [33] Matthews et al. (1993) [34] Tanaka et al. (1997) [40]

524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539

540 541 542 543 544

Mitochondrial myopathy

1

12

Mitochondrial disease

16

2

Mitochondrial encephalomyopathy

9

6−42

Bernsen et al. Mitochondrial myopathy, associ(1993) [41] ated with a complex I (NADH dehydrogenase) deficiency Bugiani et al. Complex II deficiency (2006) [42] De Stefano et Mitochondrial disorders al. (1995) [46] Liet et al. Saguenay-Lac-Saint-Jean cyto(2003) [47] chrome-c oxidase deficiency

5

7−84

2

54

11

0.25

5

3 days

Klopstock et al (2000) [54] Komura et al. (2003) [55] Oguro et al. (2004) [56] Koga et al. (2005) [58]

Chronic progressive external ophthalmoplegia /mitochondrial myopathy Mitochondrial encephalomyopathy MELAS

16

1

5

9−48

1

30

MELAS

6

18

Vitamin K3 40 mg/day and vitamin C Co-Q with vitamin K3 and vitamin C, riboflavin, thiamine and niacin Cardiocrome, containing cytochrome c 6.25 mg/day, flavin mononucleotide, 12.5 mg/day and thiamine diphosphate 25 mg/day Riboflavin

Riboflavin 50−100 mg/day Sodium dichloroacetate 25 mg/kg bid

Clinical improvement No significant clinical improvement Improvement in muscle symptom and severity of stroke like episodes

Clinical improvement in two patient with myopathy and one patient with encephalomyopathy Stabilization of symptoms Decrease in lactate level, no adverse effect

Dimethylglycine No change in oxygen consumption 50 mg/kg per day for 3 doses in children 33 kg Creatine monohydrate No significant effect 20 g/day Creatine monohydrate 0.08 g−0.35 g/kg /day Succinate 6 g/day L-arginine 0.15−0.3 g/kg/day

Improved aerobic oxidative function No stroke like episode Improved stroke like episodes

Co-Q = Coenzyme Q; MELAS = mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes.

545 the role of coenzyme Q10, gene and metabolic regulation. 546 Mitochondrion 2004; 4(5-6): 779-89. 547 [3] Punj V, Chakrabarty AM. Redox proteins in mammalian cell 548 death: an evolutionarily conserved function in mitochondria 549 and prokaryotes. Cell Microbiol 2003; 5(4): 225-31. 550 [4] Darin N, Oldfors A, Moslemi AR, Home E, Tulinius M. The 551 incidence of mitochondrial encephalomyopathies in child552 hood: clinical features and morphological, biochemical and 553 DNA abnormalities. Ann Neurol 2001; 49(3): 377-83. 554 [5] Skladal D, Halliday J, Thorburn DR. Minimum birth preva555 lence of mitochondrial respiratory chain disorders in children. 556 Brain 2003; 126(Pt 8): 1905-12. 557 [6] Chinnery PF, Turnbull DM. Epidemiology and treatment of 558 mitochondrial disorders. Am J Med Genet 2001; 106(1): 94559 101. 560 [7] DiMauro S. Mitochondrial diseases. Biochim Biopys Acta 561 2004; 1658: 80-8. 562 [8] Schon EA, DiMauro S. Medicinal and genetic approaches to 563 the treatment of mitochondrial diseases. Curr Medicinal 564 Chem 2003; 10(23): 2523-33. 565 [9] Genova ML, Pich MM, Biondi A, Bernacchia A, Falasca A, 566 Bovina C, et al. Mitochondrial production of oxygen radical References 567 species and the role of Coenzyme Q as an antioxidant. Exp 568 Biol Med (Maywood) 2003; 228(5): 506-13. [1] Oberley TD. Mitochondria, manganese superoxide dis569 [10] Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM. mutase, and cancer. Antioxid Redox Signal 2004; 6(3): 483570 Cofactor treatment improves ATP synthetic capacity in pa7. 571 tients with oxidative phosphorylation disorders. Mol Genet [2] Linnane AW, Eastwood H. Cellular redox poise modulation; 572 Metab 2004; 81(4): 263-72. in patients with mitochondrial disorders. High doses of vitamins with antioxidant properties have shown good clinical response. However, most of the clinical reports have noted a sudden recurrence of symptoms on withdrawn of therapy, requiring the vitamins to be continued. DCA and dimethyl glycine are particularly useful in disorders with lactic acidosis. Routine use of DCA is not recommended due to its potential complications. Generally, used doses of these drugs are summarized in Table 4. Most of the evidence available on the use of these drugs is based on case reports or studies on a small group of patients (Table 5). Organized research on a larger scale is necessary to come out with clear guidelines [81].

10

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