Treatment of Mitovondrial

european journal of paediatric neurology 14 (2010) 2944
Ofcial Journal of the European Paediatric Neurology Society
Review article
Treatment of mitochondrial disorders

Josef Finsterer*
Krankenanstalt Rudolfstiftung, Vienna, Austria
article info
Article history: Received 15 April 2009 Accepted 24 July 2009 Keywords: Respiratory chain Oxidative phosphorylation Encephalomyopathy Mitochondriopathy Mitochondrial cytopathy Cerebrum Brain Spinal cord Multi-system disease
abstract
Treatment of mitochondrial disorders (MIDs) is a challenge since there is only symptomatic therapy available and since only few randomized and controlled studies have been carried out, which demonstrate an effect of some of the symptomatic or supportive measures available. Symptomatic treatment of MIDs is based on mainstay drugs, blood transfusions, hemodialysis, invasive measures, surgery, dietary measures, and physiotherapy. Drug treatment may be classied as specic (treatment of epilepsy, headache, dementia, dystonia, extrapyramidal symptoms, Parkinson syndrome, stroke-like episodes, or non-neurological manifestations), non-specic (antioxidants, electron donors/acceptors, alternative energy sources, cofactors), or restrictive (avoidance of drugs known to be toxic for mitochondrial functions). Drugs which more frequently than in the general population cause side effects in MID patients include steroids, propofol, statins, brates, neuroleptics, and anti-retroviral agents. Invasive measures include implantation of a pacemaker, biventricular pacemaker, or implantable cardioverter debrillator, or stent therapy. Dietary measures can be offered for diabetes, hyperlipidemia, or epilepsy (ketogenic diet, anaplerotic diet). Treatment should be individualized
Abbreviations: AHS, Alpers Huttenlocher syndrome; ATP, adenosine-tri-phosphate; CCT, cerebral computed tomography scan; CMCOs, cell membrane crossing oligomers; CMRI, cerebral magnetic resonance imaging; CMT, CharcotMarieTooth; CNS, central nervous system; CoQ, coenzyme Q; COX, cytochrome-c-oxidase; CPEO, chronic external ophthalmoplegia; DCA, dichloracetic acid; DDS (MTS), deafness dystonia syndrome (MohrTranebjaerg syndrome); DNA, deoxy-ribonucleic acid; DWI, diffusion weighted imaging; EEG, electroencephalogram; FA, Friedreich ataxia; GRACILE, growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload (liver hemosiderosis, hyperferritinemia, hypotransferrinemia, increased transferrin iron saturation, and free plasma iron), profound lactic acidosis, and early death; HAART, highly active anti-retroviral therapy; HTX, heart transplantation; ICD, implantable cardioverter debrillator; INR, international normalized ratio; KSS, Kearns Sayre syndrome; LHON, Lebers hereditary optic neuropathy; LTX, liver transplantation; LS, Leigh syndrome; MDS, mitochondrial depletion syndrome; MELAS, mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes; MERRF, myoclonic epilepsy and ragged red bers; MID, mitochondrial disorder; MILS, maternally inherited Leigh syndrome; MLASA, autosomal recessive sideroblastic anemia with mitochondrial myopathy and lactic acidosis; MNGIE, mitochondrial neuro-gastrointestinal encephalomyopathy; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MSL, multiple systemic lipomatosis; MTS, MohrTranebjaerg syndrome; mtDNA, mitochondrial DNA; NADH/ND, nicotine-adenine-dehydrogenase; NARP, neurogenic muscle weakness, ataxia, and retinitis pigmentosa; nDNA, nuclear DNA; nsMID, non-syndromic mitochondrial disorder; OAC, oral anticoagulation; OPA, optic atrophy; OXPHOS, oxidative phosphorylation; PDC, pyruvate-dehydrogenase complex; PNS, peripheral nervous system; POLG, polymerase gamma; PS, Pearson syndrome; RARS, refractory anemia with ring sideroblasts; RC, respiratory chain; ROS, reactive oxygen species; SANDO, sensory ataxic neuropathy, dysarthria, ophthalmoplegia; SCAE, juvenile-onset spino-cerebellar ataxia and epilepsy; SLE, stroke-like episode; SLL, stroke-like lesion; SOD, superoxide dismutase; rRNA, ribosomal ribonucleic acid; tRNA, transfer ribonucleic acid; XLASA, X-linked sideroblastic anemia; XLASA/A, X-linked sideroblastic anemia with ataxia. * Postfach 20, 1180 Vienna, Austria. Tel.: 43 1 71165; fax: 43 1 4781711. E-mail address: gs1@yahoo.de 1090-3798/$ see front matter 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2009.07.005
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because of the peculiarities of mitochondrial genetics. Despite limited possibilities, symptomatic treatment should be offered to MID patients, since it can have a signicant impact on the course and outcome. 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 1.1. Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 1.2. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 1.2.1. Mitochondrial DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 1.2.2. mtDNA mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 1.2.3. Nuclear DNA mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 1.2.4. Mitochondrial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 1.3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.1. Symptomatic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.1.1. Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.1.2. Prophylactic avoidance of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 2.1.3. Substitution of cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 2.1.4. Hemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 2.1.5. Inasive measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 2.1.6. Surgical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 2.1.7. Diatary measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.1.8. Physiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.1.9. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.2. Causal therapy (experimental) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.2.1. Somatic stem cell therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.2.2. Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 2.2.3. Germline therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 2.3. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.
3.
1. Introduction
Mitochondrial disorders (MIDs) are due to mutations in the mitochondrial or nuclear DNA (mtDNA, nDNA, mitochondrial MIDs, nuclear MIDs), resulting in impaired respiratory chain (RC) or oxidative phosphorylation (OXPHOS) function. Phenotypically, MIDs present as single- or multi-system diseases, with onset between birth and senescence.1,2 Single organ affection usually turns into multi-system involvement during the disease course. MIDs predominantly manifest in tissues/organs with high-energy requirement3 and are aggravated by fever, infection, stress, toxic agents, or certain drugs.4 Systems and organs most frequently clinically or subclinically affected in MIDs are the peripheral nervous system (PNS), the central nervous system (CNS), the endocrine glands, and the heart.5 Various combinations of organ affections constitute mitochondrial syndromes (syndromic MIDs) for which well known acronyms have been adopted.6
Treatment of MIDs is a challenge since the available options are scarce, since MID patients frequently develop adverse reactions to certain mitochondrion-toxic agents, and since only few randomized and controlled studies have been carried out, which demonstrate an effect of any of the symptomatic or supportive measures. After a short introduction to phenotype, genetics, and diagnosis of MIDs, the following review aims to give an overview on recent advances and current knowledge about the treatment of MIDs.
1.1. Phenotype
Clinically, MIDs manifest as single organ disorder or as multisystem disease, affecting the peripheral nervous system, the central nervous system, the eyes, ears, endocrine organs, heart, intestines, kidneys, bone marrow, or the dermis.6 Various typical combinations of clinical manifestations resulted in the denition of various mitochondrial syndromes, for which well
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Table 1 Classication of mitochondrial disorders according to the genetic background.

mtDNA genes 1. Point mutations (maternally inherited, homoplasmic heteroplasmic) a. Genes encoding for tRNAs or rRNAs MELAS MERRF b. Genes encoding for RC subunits LHON NARP MILS 2. Single deletions/duplications (sporadic, heteroplasmic) mtCPEO PS KSS nDNA genes 1. RC subunits LS, nsMID 2. Assembly factors of RC subunits LS, GRACILE 3. Intergenomic signaling a. Breakage syndromes AD-CPEO, AR-CPEO SANDO SCAE AHS MNGIE b. Depletion syndromes nsMID AHS c. Translation defects MLASA 4. Lipid milieu Barth syndrome 5. CoQ production LS, nsMID 6. Mitochondrial transport machinery DDS (MTS) (X-linked) XLSA (X-linked) 7. Mitochondrial biogenesis CMT2A (mitofusin) or
rRNAs.7 Only the D-loop is a non-coding stretch, containing the promoters for L- and H-strand transcription. All tRNAs required for mitochondrial protein synthesis are encoded on mtDNA.8 Mitochondrial genetics differs from nuclear genetics in the following points: (1) mtDNA is maternally inherited. (2) Mitochondria are polyploid, containing 210 mtDNA copies per organelle, and each cell contains hundreds of mitochondria. (3) In the normal cell all mtDNA copies are identical (homoplasmy). The propensity of mtDNA to mutate randomly, however, results in the coexistence of wild-type mtDNA and mutant mtDNA in a single cell and organ (heteroplasmy). (4) During oogenesis mitochondria carrying mutant mtDNA are stochastically distributed to daughter cells, resulting in varying mutation loads between different oocytes, generations and tissues and increasing the phenotype variability of MIDs (bottleneck effect). (5) Because of mitotic segregation (the proportion of mutant mtDNA in daughter cells following cell division may shift due to a random drift and the phenotype may change accordingly) and polyploidy phenotypic expression is dependent on a threshold effect (usually 6090%),8 such that the load of mutant mtDNA copies needs to exceed a certain amount that the effect of a mutation can no longer be compensated by wild-type mtDNA. (6) All coding sequences are contiguous with each other without introns.9 (7) The mtDNA genetic code slightly differs from the universal genetic code. (8) Expression of mtDNA genes relies not only on the mitochondrial transcription machinery but also on the interplay between nuclear encoded transcription and translation factors with mitochondrial tRNAs and rRNAs. (9) Phenotypic variability is additionally dependent on the pathogenicity of a mutation, the affected gene, and the reliance of an organ on mitochondrial energy supply. So far, w200 mtDNA point mutations have been reported.10 (10) mtDNA is normally not methylated.8
1.2.2. mtDNA mutations

mtDNA mutations can be classied as single large-scale rearrangements (partial deletions or duplications) or point mutations. Large-scale rearrangements usually are sporadic, while point mutations usually are maternally inherited. Large-scale rearrangements affect several genes and are invariably heteroplasmic, whereas point mutations affect mit and sin genes and can be heteroplasmic or homoplasmic, like in LHON or certain tRNA(Ile) mutations.2,7,9,11,12 Phenotype expression of mtDNA mutations often requires the inuence of nuclear modier genes, environmental factors, or the presence of mtDNA haplotypes (polymorphisms). Clusters of mtDNA variants may act as predisposing haplotypes, increasing the risk of disease. Most frequently, mtDNA mutations are heteroplasmic and only rarely homoplasmic. Pathogenic nDNA mutations are likely to be more numerous than pathogenic mtDNA mutations.10
known acronyms have been coined (MELAS, MERRF, LHON, NARP, MILS, KSS, mtCPEO, PS, LS, AD-CPEO, AR-CPEO, GRACILE, MNGIE, SANDO, SCAE, MLASA, XLASA, DDS (MTS), AHS, IOSCA, MEMSA, MIRAS, DIDMOAD, ADOAD, LBSL) (Table 1). In the majority of MIDs, however, the phenotype does not t into one of these syndromes (non-syndromic MIDs (nsMIDs)).
1.2. Etiology
MIDs may have a genetic etiology or may be acquired. The actual review mainly deals only with genetic MIDs, which may be either due to mtDNA or nDNA mutations.
1.2.1. Mitochondrial DNA

Human mtDNA is a 16.5 kb circular minichromosome built up of the complementary H and L strands. mtDNA contains 13 genes encoding for subunits of RC complexes (RCC) I (ND1-4, ND4L, ND5-6), III (cytochrome b), IV (COXI-III), and V (ATPase6, ATPase8), and 24 genes encoding for 22 tRNAs and two
1.2.3. Nuclear DNA mutations

nDNA mutations are classied as follows: (1) Mutations in nuclearly encoded RC subunits (LS). (2) Mutations in ancillary proteins, such as RC subunit assembly factors (LS, GRACILE). (3) Mutations in genes affecting the maintenance or expression of mtDNA leading to faulty intergenomic communication
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and thus breakage syndromes (AD-CPEO, AR-CPEO, MNGIE, SANDO, SCAE, AHS), depletion syndromes (MDS, nsMID, myopathy, encephalomyopathy, multi-system disease), or translation defects (MLASA). (4) Mutations in biosynthetic enzymes for lipids or cofactors (Barth syndrome). (5) Mutations in genes involved in the coenzyme-Q (CoQ) metabolism (LS). (6) Mutations in genes resulting in defective mitochondrial trafcking or transport machinery (DDS/MTS, XLASA). (7) Mutations in genes encoding proteins involved in the mitochondrial biogenesis, such as fusion or ssion of mitochondria (OPA, CMT2A) (Table 2).13 The genotypephenotype-correlation in MIDs is generally poor.7 Whether mutated RC proteins represent new targets for the immune system remains speculative. However, there are indications that some mtDNA mutations create new antigens due to altered hydrophobicity.14
ions from the Krebs cycle or beta-oxidation are transferred to either NAD, generating NADH or to avin adenine dinucleotide (FAD) from succinate in the Krebs cycle, generating FADH2. NADH transfers electrons to RCCI. FADH2 transfers electrons from succinate to RCCII or from the reduced electron transfer protein to CoQ.
1.3. Diagnosis
The golden standard of diagnosing MIDs is genetic testing, why all effort should be taken to nd the genetic defect. Due to the huge amount of undetected nDNA genes involved in mitochondrial metabolism, however, search for the genetic cause of MID often remains unsuccessful. In such cases the diagnosis relies on the documentation of a biochemical defect in the RC or another mitochondrial metabolic pathway. Diagnostic work-up starts with a comprehensive individual and family history, followed by a clinical neurologic, ophthalmologic, otologic, endocrinologic, cardiologic, gastroenterologic, nephrologic, hematologic, or dermatologic investigation. Instrumental investigations should be additionally applied to detect subclinical phenotypic manifestations of MIDs. Emergency laboratory should include glucose, lactate, ammonia, arterial blood gases, acyl-carnitine, amino acids in the serum, and organic acids in the urine.15 Based upon this information the clinician then decides whether the individual phenotype conforms to any of the syndromic MIDs or represents a nsMID. If a syndromic MID, such as CPEO, KSS, or PS is suspected a Southern blot or RFLP should be carried out to look for single or multiple mtDNA deletions. If multiple mtDNA deletions are detected, a search for mutations in the POLG1, POLG2, PEO1, ANT1, TYMP, or OPA1 genes should follow. If a syndromic MID, such as MELAS, MERRF, LHON, NARP, or MILS is suspected, DNA-micro-arrays, real-time PCR, single-gene sequencing of an affected tissue should be carried out. If no mutation is detected, mtDNA sequencing is the next step. If the phenotype suggests a syndromic MID due to a nDNA gene mutation (GRACILE, ADCPEO, AR-CPEO, SANDO, SCAE, AHS, MNGIE, LS, MLASA, Barth syndrome, DDS, XLASA, or CMT2A), the corresponding genes should be sequenced. In the presence of a non-syndromic phenotype, biochemical investigations of the most affected tissues should clarify if a single or multiple biochemical defect(s) is (are) present. In case of a single autosomally inherited biochemical defect, sequencing of genes encoding for structural subunits or assembly factors of RCCI, RCCIII, RCCIV, and RCCV, or for enzymes of the coenzyme-Q biosynthesis should be undertaken. If the single biochemical defect is maternally inherited, one should proceed with mtDNA sequencing. If multiple autosomally inherited biochemical defects are present, a Southern blot should clarify if there is depletion of mtDNA. If Southern blotting detects mtDNA depletion and the primary affected organ is the skeletal muscle, sequencing of genes such as TK2, SUCLG1, SUCLA2, or RRM2B is recommended. If Southern blotting detects mtDNA depletion and the primary affected organ is the liver, sequencing of genes such as POLG, PEO1, DGUOK, or MPV17 is recommended. If Southern blotting detects no mtDNA depletion sequencing of mutated genes involved in the mitochondrial protein synthesis machinery is necessary.
1.2.4. Mitochondrial function

The main function of mitochondria is the production of energy in form of heat or ATP. To accomplish this goal ingested carbohydrates are metabolized via aerobic glycolysis, with pyruvate as the end-product and fat is hydrolyzed. Pyruvate enters the mitochondrion through a symport system in the wake of hydrogen ions, which ow into the matrix along their electrochemical gradient. There pyruvate is oxidized via the PDH complex into acetyl-CoA, which enters the Krebs cycle. Free fatty acids (FFA) enter the mitochondrion via a complex carrier system provided by carnitine-palmitoyltransferase I and II. Inside the mitochondrion FFA undergo beta-oxidation, with acetyl-CoA as the end-product. Hydrogen
Table 2 Therapeutic concepts for MIDs.

A. Symptomatic therapy Drugs Specic drug therapy (antiepileptics, antispastics, analgetics, bone marrow stimulating factors, iron substitution, etc.) Non-specic drug therapy Removal of noxious metabolites Antioxidants (quinones, vitamin E, lipoic acid, steroids, vitamin C, glutathione, others) Lactate lowering agents (bicarbonate, dichloracetate) Electron donors/acceptors (riboavin, succinate, quinones) Alternative energy sources (creatin-hydrochloride) Cofactors (L-arginine, L-carnitine, aspartate, thiamine, folic acid, other vitamins) Avoidance of certain drugs (Table 3) Others (copper intravenously, pyridoxine, steroids) Substitution of cells (XLASA, PS) Hemodialysis Invasive measures (pacemaker, biventricular pacemaker, ICD) Surgery Physiotherapy Dietary measures (ketogenic diet, anaplerotic diet, high-carbohydrate, high medium-chain triglyceride diet, high-fat diet) Miscellaneous B. Causal therapy (experimental) Stem cell therapy Genetic therapy Germline therapy
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2. Treatment
There is no causal treatment of MIDs in humans, only symptomatic therapy of various manifestations can be offered so far. Because of the involvement of multiple organs, variable expression, and chronic progressive course of MIDs, an individualized, integrated, multi-disciplinary approach needs to be adopted. This includes specialist nurses, speech, occupational, or physiotherapists, as well as medical professionals for neurology, psychiatry, ophthalmology, oto-rhino-laryngology, endocrinology, cardiology, gastroenterology, nephrology, dermatology, surgery, or anesthesiology.16 Since only few evidence-based data for the effectiveness of remedies for MIDs are available, recommendations for a therapy often rely only on personal experiences from single cases or small case series (class C evidence) why treatment recommendations reach only levels IIb or III. Generally, a number of clinical MID manifestations can be effectively relieved by symptomatic therapy with drugs for specic or non-specic manifestations, invasive interventions, surgery, dietary measures, or physiotherapy. Care should be taken with local anesthetics and elective generalized anesthesia. Causal therapy in the form of gene therapy is not available in the clinical routine, but various promising attempts in cell or animal models have been undertaken or are ongoing.
Open-angle glaucoma requires adequate therapy with betablockers.22 Many MID patients with endocrine disturbances may prot from substitution of hormones for hypopituitarism, hypothyroidism, hypoparathyroidism, hypoinsulinism, hypocorticism, or hypogonadism. Hyperthyroidism requires adequate drug therapy or even radiotherapy. If there is adrenal insufciency patients may prot from hydrocortisone, in addition to coenzyme Q (CoQ) or L-carnitine.23 Recombinant human growth hormone therapy improved growth and muscle strength in a MERRF patient24 but the increased metabolic demand may overburden the already challenged metabolism.24 Cardiac drug therapy is indicated in case of rhythm abnormalities or heart failure. Oral anticoagulation may be inevitable in case of atrial brillation, frequently found in MIDs or severe systolic dysfunction. Anti-emetic drugs are indicated if there is vomiting, domperidone or cisapride if there is gastrointestinal dysmotility. Exocrine pancreas insufciency (PS) requires replacement therapy with digestive enzymes.24 Patients may also prot from the substitution of potassium or sodium in case of hypokalemia or hyponatremia from renal failure or hypoaldosteronism. In case of anemia or pancytopenia iron, transfusions, or hematopoetic cell stimulators may be benecial.
2.1. Symptomatic therapy

Symptomatic measures for MIDs are important since patients often need specic treatment for various manifestations of the disease and since symptomatic measures are often the only help, which can be provided to these patients. Symptomatic measures may be divided into specic and nonspecic drug therapy, hemodialysis, invasive measures, surgical therapy, dietary measures, and physiotherapy. A classication of non-specic drug therapy is challenging since some of these agents have an antioxidative effect and serve also as electron donors/acceptors or cofactors of RC functions, such as riboavin, vitamin C, vitamin E, or quinones.
2.1.1.2. Non-specic drug therapy. Non-specic drug therapy can be categorized according to the type of action into drugs, which remove noxious metabolites (antioxidants, lactate lowering agents), electron donors/acceptors, alternative energy providers, cofactors, and other agents. 2.1.1.2.1. Drugs, which remove noxious metabolites. 2.1.1.2.1.1. Reactive oxygen species (free radical) scavengers (antioxidants). Reactive oxygen species (ROS) derive from the
reaction of electrons with O2 by generating superoxide anions (O-2).24 Superoxide anions are physiologically cleared by superoxide dismutase by generating H2O2.24 In the presence of metal ions H2O2 can be further reduced to the hydroxyl radical (OH). H2O2 itself can be detoxied by glutathione peroxidase or by catalase.24 Reduction of increased oxidative stress in MIDs can be enhanced by the administration of ROS-scavengers. Particularly benecial in MIDs are quinones, vitamin E, lipoic acid, corticosteroids, vitamin C, melatonin, or glutathion.25,26 ROS-scavengers may not only be benecial in primary MIDs (RC/OXPHOS defects) but also in neurodegenerative diseases due to other mitochondrial defects.24,27 Antioxidative therapy may be particularly effective in FA since deciency of frataxin is associated with mitochondrial iron accumulation, increased sensitivity to stress, decit RC activity, or impaired tissue energy metabolism.28
2.1.1. Drugs 2.1.1.1. Specic drug therapy. Specic symptomatic drug therapy comprises antiepileptics for seizures (avoid valproic acid for its inhibition of the carnitine uptake17), cholinesterase-inhibitors for dementia (antidementiva), sedatives for states of excitation, neuroleptics for psychotic episodes (antipsychotics), serotoninergic and adrenergic agents for depression, DOPA-antagonists and dopamine receptor antagonists for Parkinson disease,18 antispastics, such as baclofen,19 tizanidine, or botulinum toxin, in case of focal or generalized spasticity, dopamine receptor antagonists in case of restless-leg-syndrome, botulinum toxin in case of dystonia, analgesics or muscle relaxants, in case of myalgia or muscle cramps, gabapentin, pregabalin, carbamazepine, or lamotrigine in case of neuropathic pain from polyneuropathy or neuralgia. Aripiprazole has been shown to be effective in FA patients with psychosis.20 Concerning antiepileptic drug therapy, there are several reports about patients in whom the established antiepileptic drug therapy was ineffective.21
2.1.1.2.1.1.1. Quinones. Quinones (CoQ, idebenone, decylubiquinone, duroquinone) are among the few compounds, which are effective in single MID cases and are meanwhile frequently given.16,2931 Quinones not only have an antioxidative effect but exhibit their effect also as electron donors/ acceptors (Table 3).32 Their effect appears to depend on their side chain, which presumably governs their interaction with the RC.33
2.1.1.2.1.1.1.1. Coenzyme Q. CoQ, also known as coenzyme Q10, ubiquinone, or vitamin Q10, is a fat-soluble vitamin-like
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Table 3 Drug effects on mitochondrial functions. Substance

Corticosteroids
Effect on mitochondrial function

Increase mitochondrial membrane potential, generate ROS, reduce antioxidants, induce apoptosis Inhibits OXPHOS, induces apoptosis of microglia, sequesters carnitine, reduces RC activity Inhibits mitochondrial ATPase
Antiepileptics Valproic acid
Phenytoin Anesthetics Intravenous Barbiturates Volatile Halothane Isourane Sevourane Local anesthetics Bupivacain Articain Lipid lowering drugs Fibrates Statines Antidiabetics Biguanides Thiazolidinediones Antiarrhythmics Amiodarone b-blockers Neuroleptics Haloperidol Chlorpromazine Quetiapine Risperidone Antibiotics Chloramphenicol
Inhibit RCCI, reduce mitochondrial protein synthesis and function Inhibits RCCI Inhibits RCCI Inhibits the RC electron transport Inhibits RCCI Inhibits RCCI Inhibit RCCI Reduce coenzyme Q10, inhibit RCCI Inhibit RCCI, cause lactacidosis Inhibit RCCI Inhibits b-oxidation Inhibit ATPase and stage-3-respiration, inhibit RCCI Inhibits Inhibits Inhibits Inhibits RCCI RCCI RCCI RCCI
gastrointestinal discomfort, arterial hypotension, or hypoglycemia.34 There is conjection about the lowering effect of INR in patients on OAC and the depletion of CoQ following statin or doxorubicin therapy. The reduced form of CoQ (ubiquinole) decreases lipid peroxidation by acting as a chainbreaking antioxidant and indirectly by recycling vitamin E.32 CoQ also reacts with other ROS.32 Paradoxically, CoQ is also involved in the production of superoxide by the RC.32 CoQ is one of the most widely used supplements in MIDs.24 CoQ (3001500 mg/d) is highly effective in CoQ-deciency (COQ2, PDSS2 mutations) presenting as exercise intolerance, lactacidosis, or cerebellar manifestations.24,3540 CoQ has been also reported benecial in RCCII and RCCIII defects, clinically presenting as MILS.41,42 CoQ substitution is also effective in FA associated with primary CoQ-deciency, presenting as exercise intolerance, lactacidosis, or cerebellar manifestations.36,37,43,44 In an open-label pilot trial it has been shown that CoQ (400 mg/d) and vitamin E 2100 IU/d improved cardiac and skeletal muscle bioenergetics during a four year therapy in 10 patients with FA.45 CoQ showed also a benecial effect on the symptoms and signs in patients with MELAS, MERRF, and KSS.20,46,47 In these later studies the maximum effect was observed not before six months of continuous treatment. In a patient with MERRF syndrome administration of CoQ (90 mg/d) resulted in complete resolution of myoclonic seizures. CoQ (210 mg/d) plus tocopherol was not only effective in patients with MELAS but also in patients with nsMID.48 CoQ is less effective in patients with renal failure and primary CoQ-deciency.24 UbiQGel, a special type of CoQ was granted US FDA orphan drug status for the treatment of MIDs.34
Inhibits RCCI, reduces mitochondrial protein synthesis and functions Tetracyclines Inhibit b-oxidation Nucleoside reverse transcriptase inhibitors Zidovudine mtDNA depletion, reduces RCCI, IV activity, induces oxidative stress, apoptosis, impairs bioenergetics Chemotherapeutics Carboplatin Causes mtDNA mutations Doxorubicin Causes mtDNA mutations Ifosamide Causes mtDNA mutations Interferon Impairs mtDNA transcription Others Acetyl-salicylicInhibits RC electron transport acid
ROS: reactive oxygen species, RC: respiratory chain.
2.1.1.2.1.1.1.2. Idebenone. Only limited experiences exist with substances like idebenone29,30 and the results on the effectiveness of idebenone are conicting. In FA idebenone appeared to be particularly effective for hypertrophic cardiomyopathy.49 Additional pilot studies have shown a potential effect of idebenone, coenzyme Q, and vitamin E also for neurological manifestations of FA.29,50,51 Idebenone (0.5 mg/ kg) over three months improved muscle force, tolerability of workload, mobility, speech coordination, and reduction of fatigue. Long-term therapy with idebenone also prevented the progression of FA in pediatric and adult patients.52 Idebenone (5 mg/kg/d) in 48 genetically conrmed FA patients resulted in the improvement of neurological functions and activity of daily living scores.53 Idebenone was also effective in single LHON patients.24 On the contrary, idebenone was not effective in preventing the second eye in LHON patients from being also affected.54 2.1.1.2.1.1.2. Vitamin E (alpha-tocopherol). There are conicting results concerning the effect of vitamin E in MIDs.31,55 This is due to lack of well-designed studies on the effect of vitamin E in MIDs and the fact that vitamin E is usually not given alone but together with a varying number of other cocktail ingredients. Mice treated with vitamin C and vitamin E exhibited signicantly less oxidative damage from zidovudine-induced ROS than controls.56 On the contrary, vitamin E was ineffective to protect cardiomyocytes from doxorubicin-induced toxicity.57
ubiquitous compound, vital to a number of activities related to energy metabolism with the highest concentrations in tissues with high-energy demand, such as muscle, brain, heart, liver, endocrine glands, or kidney.34 CoQ is vital for the proper transfer of electrons from RCCI and RCCII to RCCIII.35 CoQ also increases ATP production, has antioxidant properties by preventing lipid peroxidation, and is an indirect stabilizer of calcium-channels.34 Potential side effects of CoQ include
35
2.1.1.2.1.1.3. Lipoic acid. Alpha-lipoic acid is a dithiol

compound functioning as an essential cofactor for mitochondrial bioenergetic enzymes. In addition to its enzymatic function lipoic acid also seems to act as a micronutrient with various pharmacologic and antioxidant properties.58 Lipoic acid scavenges glycemic control, diabetic polyneuropathies, and effectively mitigates toxicities from heavy metal poisoning. As an antioxidant, lipoic acid terminates free radicals, chelates transition metal ions, increases cytosolic glutathione and vitamin C levels, and prevents toxicities associated with their loss.58,59 Lipoic acid is particularly effective in neuropathic pain in MID patients with polyneuropathy, although no well-designed studies have been carried out to support single observations.
(30 mg/twice a day) intravenously for two weeks may decrease the intensity of T2-hyperintensities of SLL.48 Edaravone can block free radicals but is not able to rescue neurons within the primary lesion of a SLL.48 Angiotensin-II-inhibitors have been shown to be benecial since they enhance mitochondrial energy production and protect mitochondrial structures by the inhibition of ROS.73 As a precursor of an antioxidant Nacetyl holds promise for improving mitochondrial functions.74 MitoQ is an orally active antioxidant with the ability to target mitochondrial dysfunction.75 MitoQ mimics the role of CoQ but also augments the antioxidative capacity of CoQ and has been proven useful in tissue cultures to reduce oxidative stress and apoptotic cell death.75
2.1.1.2.1.1.4. Corticosteroids. Corticosteroids may have benecial or detrimental effects in MIDs. In a 27 year old male with MELAS syndrome due to the 3243A > G mitochondrial tRNA mutation, manifesting as recurrent tonic-clonic seizures, intractable headaches, and stroke-like episodes (SLEs), corticosteroids resulted in a signicant improvement of these manifestations, but could not prevent death from the intractable epileptic state one year after initiation of therapy.60 Corticosteroids were also effective in a female with MELAS, CPEO, and secondary carnitine-deciency61 and a 12 year old MELAS male patient with a wide range of clinical manifestations.62 Together with a cocktail of other agents, however, corticosteroids were hardly effective in another MELAS patient63 but together with Larginine, glycerol and edaravone were highly effective in a 16 year old girl with MELAS.64 Corticosteroids have been reported benecial to prevent visual loss in a 7 year old LHON patient.65 Corticosteroids have been also proven useful to treat eosinophilia in MID.66 Another patient with nsMID developed respiratory failure six months after the initiation of corticosteroids for initially suspected granulomatous myositis.67
2.1.1.2.1.2. Lactate lowering agents. Lactacidosis is one of the hallmarks of MIDs and is toxic to all types of cells, particularly if their metabolism is already impaired.24 Correction of acidosis is a major goal in MIDs with lactacidosis. It is usually carried out with two agents, while glucose supply should be limited in these patients.15 2.1.1.2.1.2.1. Bicarbonate. Buffering of lactate is possible with bicarbonate but has only a transient effect and may actually exacerbate cerebral dysfunction.24 2.1.1.2.1.2.2. Dichloracetic acid. Dichloracetic acid (DCA), a potent lactate lowering agent, relieves clinical manifestations in 3243A > G mutants. DCA acts by inhibiting the PDC complex, keeping pyruvate-dehydrogenase in the dehydrogenated (active) form.24 In a group of four patients carrying the 3243A > G mutation, DCA resolved headache, abdominal pain, weakness, and the frequency of SLEs. DCA, however, had no effect on short stature, deafness, mental status, or the electrophysiological abnormalities.76 In a single patient cytochrome-c had no positive effect on the function of RCCs in platelets, whereas their function improved under DCA.77 Initially, adverse reactions included only mild liver dysfunction or hypocalcemia.76 Recent studies with a dosage of 25 mg/ kg/d, however, had to be discontinued because of marked peripheral nerve toxicity.78 Since DCA may cause polyneuropathy in adult patients some authors proposed to reduce its dosage in adults as compared to children and adolescents,79 whereas others did not recommend DCA for the treatment of 3243A > G mutants at all. Recent studies in children suggest that DCA may have a benecial effect in PDCdeciency.80 2.1.1.2.2. Electron transfer mediators (electron donors or acceptors). Electron transfer mediators bypass the defective
site within the RC.55 The most important representatives of this group are quinones; their effect as electron transfer mediators has been described already above. The other representatives of this group are riboavin and succinate.
2.1.1.2.1.1.5. Vitamin C (ascorbic acid). Vitamin C is an important antioxidant, which enters mitochondria in its oxidized form via Glut1 and protects mitochondria from oxidative injury.68 Since mitochondria contribute signicantly to intracellular ROS, protection of mtDNA and mitochondrial membranes may have pharmacological implications against a variety of ROS-mediated disorders.68 There is only anecdotal evidence for vitamin C to be effective in MIDs31,55 and most studies in which vitamins have been applied did not report a benecial effect. On the contrary, vitamin C has been shown to be effective in a mouse model of oxidative stress.69 Also in mice vitamin C had a benecial effect on zidovudine-induced oxidative damage of cardiac mitochondria.56 2.1.1.2.1.1.6. Glutathione. Glutathione is an endogenous ROSscavenger that has been tried only rarely in humans but has been shown to be effective in various animal models and cell systems.70 Particularly in patients with glutathione deciency due to isolated or combined RCC defects exogenous glutathione may supplement the endogenous deciency.71 2.1.1.2.1.1.7. Other antioxidants. Anecdotal reports also showed a benecial effect of other antioxidants, such as NADH,72 edaravone, or angiotensin-II-inhibitors. Edaravone
2.1.1.2.2.1. Riboavin. Most frequently riboavin is administered together with other cofactors or antioxidants why its therapeutic effect cannot be sufciently assessed. However, there is anecdotal evidence for riboavin to be effective in MIDs,31,55 particularly in secondary riboavin deciency in mitochondrial fatty acid disorders.81 Riboavin also has
36
electron donor/acceptor properties and may thus directly interfere with the RC.82 Riboavin was highly effective in three children with rare isolated RCCII defect. In two of them neurological abnormalities remained stable under riboavin; in the third growth retardation and lactacidosis markedly improved.83 Riboavin has been also tried in patients with ethylmalonic encephalopathy with some effect.84
2.1.1.2.4.3. Aspartate. Aspartate (10 mmol/kg(1)/d(1)) and citrate (7.5 mmol/kg(1)/d(1)), together with continuous drip feeding in a patient with pyruvate-dehydrogenase complex (PDC)-deciency resulted in a dramatic reduction of elevated lactate and keton bodies. Plasma amino acids normalized except for L-arginine, but did not prevent mental retardation, tetraspasticity, or epilepsy.21 2.1.1.2.4.4. Thiamine. Reports about the effect of thiamine in MID patients are conicting. Some reports describe thiamine treatment to be benecial in single cases with sideroblastic anemia,55 PDC-deciency, and single patients carrying the 3243A > G mtDNA mutation.95 In two siblings and their mother, carrying the mitochondrial 3243A > G mutation, manifesting clinically as myopathy, lactic acidosis, cardiomyopathy, and thiamine deciency, thiamine treatment resulted in the lowering of serum lactate and pyruvate in one of the three.95 Thiamine deciency was attributed to malabsorption of thiamine in these patients.95 Thiamine was also effective in a patient with RCCI defect due to a mutation in the megaloblastic anemia gene SLC19A2.96 Other studies, however, did not conrm this effect [personal communication]. 2.1.1.2.4.5. Folic acid. Folic acid has been shown to be benecial in KSS patients, in whom CSF folic acid concentrations may be decreased.24 Folic acid (12.5 mg/kg/d) particularly improved leucencephalopathy on MRI and increased CSF concentrations of folic acid, which is why it is recommended in KSS patients.24 2.1.1.2.4.6. Other vitamins. The effect of other vitamins, such
as riboavin, vitamin C, or vitamin E, has been discussed already above. Concerning the effect of niacin, pyridoxalphosphat, or vitamin K in MIDs, there are only few reports available. There is anecdotal evidence for niacin to be effective in MIDs.31,55 Only in single cases of XLASA it has been shown that pyridoxine has a benecial effect.97 There is also anecdotal evidence for vitamin K (phylloquinon, menadione) to be effective in MIDs.31,55 Menadione, a synthetic vitamin K1 analogue, has been shown to restore Ca oscillations and cardiomyocyte contractility after blocking of RCCI with rotenone in cultured cardiomyocytes.98
2.1.1.2.2.2. Succinate. In a patient with RCCI defect due to

a single mtDNA deletion respiratory function markedly improved upon the simultaneous administration of succinate (6 g/d) and CoQ (300 mg/d).24 Whether succinate or CoQ or the combination of both was more effective remains questionable. Succinate also proved useful in a MELAS patient in whom dementia, myoclonus and hemiparesis resolved during a followup of 30 months under a monotherapy with succinate (6 g/d).85
2.1.1.2.3. Alternative energy sources. 2.1.1.2.3.1. Creatine-monohydrate. There is some anecdotal

evidence, which supports the use of creatine-monohydrate (20 g/d) in MIDs.31 A benecial effect concerning muscle strength was reported from a randomized cohort study with severely affected MID patients.86 In a patient with LS due to the mitochondrial 8344A > G mutation, creatine-monohydrate (0.2 g/kg/d, followed by 0.08 g/kg/d after two weeks) improved ne motor skills, respiratory functions, and cardiac functions.87 Creatine was also benecial in three children with KSS and MELAS syndrome.88 In a study on 16 patients with FA (6.75 g/d), however, no improvement of the outcome measures ATP production, as assessed by 31-phosphorus magnetic resonance spectroscopy (31P-MRS), neurological decits, as assessed by the international co-operative ataxia rating scale, or myocardial thickening could be observed.89 In a study on 15 patients with CPEO or KSS creatine-monohydrate (150 mg/kg/d) during six weeks did not improve the phospho-creatine/ATP ratio and there was no post-exercise PCr-recovery on 31P-MRS.90 Additionally, clinical scores and laboratory tests did not alter signicantly.90 No benecial effect was observed in another randomized trial.24
2.1.1.2.4. Cofactors (trophic nutrients). 2.1.1.2.4.1. L-arginine. Recent studies have shown that Larginine, a nitric oxide-precursor, may improve endothelial functions in patients with MELAS.91,92 L-arginine may be particularly benecial for SLEs in single patients with MELAS.64,91,92 L-arginine may be also helpful in patients with serial seizures or non-responsive status epilepticus [personal communication]. L-arginine may also reduce pulmonary artery hypertension in MELAS.93
L-carnitine is highly effective on primary carnitine-deciency and in primary carnitine-palmitoyl-transferase (CPT1) deciency 1. In single cases L-carnitine had also a benecial effect in secondary carnitine-deciency in patients with MILS due to the 8993T > C mtDNA mutation94 or mitochondrial fatty acid disorders.81 In a cross-over study on 16 patients with FA with L-carnitine (3 g/d) during four months, the phosphor-creatine recovery improved on 31PMRS.89 L-carnitine should be particularly given when valproic acid is unavoidable.24
2.1.1.2.5. Others. In MERRF patients with secondary cytochrome-c-oxidase deciency intravenous administration of copper was benecial.99 Copper was considered responsible to have reversed hypertrophic cardiomyopathy in a child with mutant SCO2, which died from respiratory insufciency at the age of 42 months.24 The trophic growth factors glycerophosphocholine and phosphatidylserine provide mitochondrial support and improve cognitive functions in neurodegenerative disease.72 In three patients with a hepatocerebral MDS due to a MPV17 mutation, continuous glucose infusions improved liver functions.100
2.1.1.2.4.2. L-carnitine.
agents. Substitution of growth hormone in a boy with KSS had no therapeutic effect.101 Topical brimonidine purite is unsuccessful to prevent involvement of the second eye in LHON.102 Also no benecial effect has been reported from the administration of selen,
2.1.1.2.5.1. Ineffective
37
carotin, biotin, calcium, phosphate, or uridine. Also ineffective is the current therapy of mitochondrial hepatopathy.103 Nitric oxide and epoprostenol were ineffective in resolving pulmonary artery hypertension in a child with MELAS.93
2.1.1.2.5.2. Drug therapy of SLEs. Currently there is no consensus and no standardization of the treatment of SLEs.104 Most of the therapeutic strategies have been adopted as a result of case reports or limited clinical studies with a group of heterogeneous MIDs (class C evidence).104 Current concepts are based on the application of antioxidants, or cofactors in the form of vitamins.104 In a growing number of patients the intravenous application of L-arginine in a dosage of 0.5 g/kg has been shown to be benecial.92,105112 Interictal oral administration of L-arginine (0.150.30 g/kg) diminished the frequency and severity of SLEs.92 Since no side effects were reported from the administration of L-arginine for SLEs, it appears a veritable option in this indication but well-designed studies are lacking. Benecial effects were occasionally also reported from corticosteroids together with L-arginine, glycerol and edaravone,64 DCA,77 or edaravone (60 mg/d) alone.48 Whether patients with SLEs may also prot from an antiepileptic therapy according to the epilepsy hypothesis of SLEs is currently a subject of debate.113,114 In addition to drugs, physiotherapy, occupational, respiratory, swallow, and speech therapy are of great value in accelerating recovery from SLEs.24 2.1.1.2.5.3. Cocktails lipophilic tri-phenyl-phosphonium cation. Most frequently cofactors, ROS-scavengers, and alternative energy sources are administered in the form of cocktails with varying composition.115 In a study on 15 pediatric patients with biochemically or genetically conrmed MIDs a cocktail of thiamine, riboavin, CoQ, vitamin C (10 mg/kg/d) and a high-fat diet were administered; nine improved, of whom four attained further developmental skills, these being temporary in six of them.115 Patients carrying the 3243A > G mutation experienced a reduction in the frequency of migraine attacks, one patient experienced a signicant reduction in the severity of seizures, and in a single patient seizures completely resolved.115 In a patient with MELAS and pulmonary artery hypertension, a mixture of biotin, riboavin, L-carnitine, and CoQ was ineffective.93 A cocktail of megadoses of idebenone, vitamin C, and riboavin during one year did not improve vision of the affected eye and did not prevent affection of the second eye in two patients with LHON.54 In a study on 14 LHON patients the combined administration of idebenone, vitamin B2, and vitamin C during at least one year resulted in the recovery of impaired vision in these patients.51 In a study on 12 MID patients with CoQ, L-carnitine, vitamin B complex, vitamin C, and vitamin K1 over one year, resulted in increased ATP production but no clinical improvement.116 The cocktail preferred by DiMauro and co-workers is composed of L-carnitine (1000 mg three times a day) in addition to CoQ (at least 400 mg/d).17
carboplatin),117,118 inhibit mtDNA replication and cause mtDNA depletion or reduce RCCI/RCCIV activity (nucleoside analogues (zidovudine)),24,119,120 impair mtDNA transcription (interferon), block RCCI (carvedilol, bupivacain or articain, phenothiazines),121123 inhibit non-competitively the ATPase and thus stage-3-respiration (beta-blockers),124 inhibit the RC electron transport (acetyl-salicylic-acid, sevourane),125,126 reduce endogenous CoQ (statines), reduce the transmembrane mitochondrial potential (corticosteroids), inhibit beta-oxidation (tetracyclines, amiodarone), reduce mitochondrial protein synthesis and the number and size of mitochondria (barbiturates, chloramphenicol),127 sequester carnitine and generally reduce RC/OXPHOS activity (doxorubicin, valproic acid),24,128,129 or cause lactacidosis (biguanides). Valproic acid must be particularly avoided in MIDs with involvement of the liver, such as AHD or other mitochondrial depletion syndromes (MDSs) with hepatopathy. Generally, care should be taken with general anesthesia. MID patients also should avoid exposure to ozone.
2.1.3. Substiution of cells. Blood transfusions may be helpful in the case of XLASA or Pearson syndrome or any other syndromic or nsMID, which goes along with anemia resistant to iron substitution or the stimulation of precursor cells to erythropoietin. Transfusion of thrombocytes may be necessary in case of severe pancytopenia with Pearson syndrome. 2.1.4. Hemodialysis. Hemodialysis may be indicated in MID patients with severe renal failure in whom NTX is not yet available. Hemodialysis has been also applied to two patients with MNGIE to remove increased serum levels of thymidine and deoxyuridine.130 Unfortunately, the obvious benecial effect of hemodialysis was too eeting in these patients.130 Temporary hemodialysis may be also necessary in patients with severe rhabdomyolysis due to primary CoQ-deciency.24 2.1.5. Invasive measures. Impaired impulse propagation in
KSS or other MIDs often requires the implantation of a pacemaker, already at the early stages of the disease. In case of a propensity to ventricular tachycardias implantation of an implantable cardioverter debrillator (ICD) is indicated. An ICD is also indicated in case of hypertrophic cardiomyopathy and signicant reduction of arterial blood pressure during the cycle exercise test [personal communication]. Patients with coronary artery disease or peripheral artery stenosis may require OAC, implantation of a stent or reconstruction therapy. In case of heart failure from asynchronous contraction of both ventricles implantation of a biventricular pacing device may prevent heart transplantation (HTX).
2.1.2. Prophylactic avoidance of drugs. More important than the administration of certain drugs is the avoidance of certain remedies in MIDs (Table 3). Particularly avoided should be drugs, which cause mtDNA mutations (ifosamide,
2.1.6. Surgical therapy. Ptosis often requires surgical reconstruction and can be temporarily effective.131 In most patients however, a second or third operation is necessary to achieve a long-standing benecial effect. Cataract from MID can be best treated by implantation of an articial lens. Dysphagia due to crico-laryngeal achalasia in KSS may be resolved by myectomy.24 Patients with severe kyphoscoliosis may prot from stabilization of the spinal column, such as in FA.132 Cochlear implants may be helpful to overcome hypoacusis if single or binaural amplication aids become ineffective.133
38
Thyroid resection may be indicated in case of thyroid adenoma. Pseudoobstruction in MNGIE or MELAS may require emergency resection of some parts of the intestines. If dysphagia, frequent vomiting, malabsorption, or recurrent diarrhea leads to prominent kachexia (LS), a percutaneous endoscopic gastroenterostomy (PEG) should be considered. Pituitary adenoma requires resection if it becomes symptomatic. In case of intractable heart failure, HTX is an ultimate option in single cases, particularly when the heart is the predominantly affected organ. Liver transplantation (LTX) has been tried in patients with hepatic MDS from mutations in the POLG1, PEO1, DGUOK, or MPV17 genes.104,134 However, the role of LTX in patients with liver failure due to mitochondrial hepatopathy, or of HTX in patients with heart failure is poorly dened because of the multi-system nature of MIDs and the toxicity of life-long immunosuppression after surgery.104 NTX is a veritable option in patients with renal failure but is also limited by the life-long intake of immunosuppresants.
doxorubicin-induced MID, manifesting as cardiomyopathy, could be prevented under endurance training by improving cell defense systems and reducing oxidative stress.128 Endurance training particularly limited doxorubicin-triggered apoptosis, the decrease in aconitase activity, decrease in state-3-respiration, the respiratory control ratio, uncoupled respiration, the protein-sulfhydril content, and oxidative damage.128 Training also prevented the increased sensitivity to calcium, inhibited the increase in mitochondrial protein carbonyl groups, malon-dialdehyde, Bax, and tissue-caspase3-activity. Training also increased the expression of mitochondrial HSP-60, of tissue HSP-70, and the activity of mitochondrial and cytosolic superoxide dismutase (SOD).128 In addition to drug therapy, occupational, respiratory, swallow, and speech therapy are of great value in aiding MID patients with ataxia, dysarthria, dysphagia, spasticity, or weakness.24
2.1.9. Miscellaneous. MID patients should generally avoid

psychic stress, exercise stress, extreme cold, extreme heat, alcohol, nicotine, drugs, and infectious diseases. Additionally, MID patients should have sufcient sleep and should perform regular physical activity below the maximum limit. Patients with MID may also need aggressive warming to maintain normothermia during surgery since heat production can be impaired in these patients.140 Orthopedic shoes improve gait, stability, speed of walking, and step length in patients with FA. MID patients frequently develop uni- or bilateral hypoacusis and may prot from amplication aids.24 Patients with respiratory insufciency may require nocturnal or continuous non-invasive positive pressure ventilation.24
2.1.7. Dietary measures. Though dietary measures are mostly

ineffective, some patients with PDC-deciency may prot from a ketogenic diet (keton bodies provided by a high-fat and low-carbohydrate diet)135 or an anaplerotic diet (3035% triheptanoin).136 In children with refractory epilepsy due to PDCdeciency the ketogenic diet may even match the effect of most anticonvulsants.135 Patients with primary CPT1 deciency or other mitochondrial fatty acid disorders81 may prot from a diet high in carbohydrates or a diet with medium-chain triglycerides, and reduced amount of long-chain fatty acids (class C evidence).81 Single patients with MELAS or nsMID may also prot from a high-fat diet in addition to thiamine, riboavin, CoQ, and vitamin C.115
2.2. Causal therapy (experimental) 2.2.1. Somatic stem cell therapy

Allogeneic stem cell transplantation had been rst carried out in 2006 in patients with MNGIE.141 MNGIE is caused by thymidine phosphorylase deciency, which leads to toxic accumulation of thymidine and deoxyuridine. In these patients infusion of platelets from healthy donors transiently restored circulating thymidine phosphorylase and produced a nearly full biochemical correction of thymidine and deoxyuridine imbalances in blood.142 Allogeneic stem cell therapy has been also tried in patients with refractory anemia with ring sideroblasts (RARS).24
2.1.8. Physiotherapy. MID patients frequently suffer from

exercise intolerance due to impaired oxidative capacity and physical deconditioning.137 However, there is little doubt that inactivity should be avoided because of its deconditioning effects.24 The effect of exercise training for MIDs is currently unsettled.138 Only few trials have been carried out to study the effect of exercise training on muscle performance in MID patients. In a study on 20 MID patients undergoing combined cycle exercise at 70% of their peak work rate and three upperbody weight-lifting exercises at 50% of the maximum capacity during three months, however, increased maximum oxygen uptake by 29%, work-output by 16%, minute ventilation by 40%, endurance performance by 62%, walking distance, and peripheral muscle strength by 3262%.137 However, heteroplasmy may increase during exercise training. The discrepancy between functional improvement and molecular worsening could be explained by a threshold level not yet exceeded.24 Recommendation for or against exercise training is actually difcult, but in clinical routine it is individual experience with physical exercise that will help to make this decision. Exercise physiologists and sport medicine practitioners may help to nd out if exercise training can be helpful at all and under which conditions. In endurance athletes, in whom fatigue, myalgia, dyspnea, or muscle cramping leads to diagnostic work-up for MID, controlled exercise training has been recommended if the suspected diagnosis of a MID was conrmed.139 In a study on 40 Wistar rats it turned out that
2.2.2. Gene therapy

Gene therapy in MIDs due to mtDNA mutations is a challenge because of polyplasmy and heteroplasmy.24 Gene therapeutic approaches can be divided into three groups: (1) rescue of a defect by expression of an engineered gene from the nucleus (allotopic or xenotopic expression), (2) import of normal mtDNA copies or relevant sections into the mitochondrion, and (3) manipulation of the mtDNA heteroplasmy (gene shifting).8 An excellent review on this eld has been recently published.8
2.2.2.1. Allotopic and xenotopic expression. Allotopic expression is based on the introduction of engineered mitochondrial genes into the nucleus. The appropriate gene product is translated within the cytosol and then imported into the mitochondrion.143 Though importation of the gene product
39
has been demonstrated, integration of the protein into a RCC was not convincing so far. One disadvantage of allotropic expression is that due to the high hydrophobicity of mitochondrial proteins their import into mitochondria is limited.143 This disadvantage can be overcome by associating gene products to cis-acting elements of SOD2 or COX10, with which they can be effectively translocated within the mitochondrial matrix (mRNA sorting to the mitochondrial surface).143 Xenotopic expression relies on the expression of cognate genes from other species encoding for RCC subunits, which are synthesized in the cytosol, successfully targeted to the inner mitochondrial membrane, and then replace mutant RCC subunits. Examples for this strategy are the expression of cyanide-insensitive alternative oxidase from Ciona intestinalis or the Nid1 oxidase from Saccharomyces cerevisiae.8
zygote with wild-type mtDNA needs to be enucleated to form a cytoplast. Then an egg from the patient would be fertilized in vitro with the sperm of the healthy partner. Pronuclei from the fertilized patients oocyte will then be removed and fused with the cytoplast.8 This approach may bring hope to patients with mtDNA disorders who wish to have a child but in whom oocyte donation is not feasible or desired.
2.2.4. Future perspectives

In addition to somatic stem cell therapy, gene therapy, and germline therapy future therapeutic options may include a number of various approaches, which have shown promising effects at least in cell cultures or animal models. In cell culture studies lithium and valproate enhanced mitochondrial functions and protected against mitochondrially-mediated toxicity.146 MitoE2 and MitoQ not only have an antioxidative effect but also increase matrix Ca concentrations in HeLa cells.147 A novel class of mitochondria-targeted aromaticcationic peptides has demonstrated efcacy in animal models of Parkinsonism by promoting mitochondrial functions, reducing mitochondrial ROS generation, inhibition of mitochondrial permeability transition, and by preventing apoptosis.148 Only limited experiences exist with lipophilic cations, to which bioactive molecules can be conjugated to enter mitochondria.145,149 For example, the effect of the antioxidants tocopherol and ubiquinones can be enhanced by attaching these compounds to the lipophilic cation tri-phenylphosphonium.150 An ethanol extract of Ganoderma lucidum has been shown to increase the activity of PDH, alpha-KGDH, SDH, and RCCI in aged Wistar rats.151 Also in rats near-infra-red light prevented the neurotoxic effect of the RCCI-inhibitor rotenone.152 Recent cell studies have shown that humanin, an endogenous peptide that suppresses apoptosis and increases cellular ATP without inducing mtDNA replication, appears as a promising therapeutic agent for 3243A > G mutants.153 Another promising drug seems to be the antioxidant melatonin,154 which directly scavenges toxic oxygen or nitrogenbased reactants, stimulates antioxidative enzymes, increases RC efcacy by limiting electron leakage and free radical generation, and promotes ATP synthesis.154 Melatonin prevents apoptosis and protects liver cells from oxidative stress in mice.155 Melatonin also protects against the common deletion of mtDNA-augmented mitochondrial oxidative stress and apoptosis.25 In a mouse model of Parkinsonism melatonin prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation, without inuencing weight loss or hypokinesia.156
2.2.2.2. Rescue of mtDNA mutations through mitochondrial transfection. This approach is based on the re-introduction of
normal copies of the mutated gene into mtDNA. The approach faces obstacles such that transfection is difcult as there are three membrane barriers to surmount and that DNA expression in the case of successful importation may be transient.8
2.2.2.3. Manipulation of heteroplasmy levels (gene shifting).

Shifting of the level of heteroplasmy towards wild-type mtDNA has become the goal of a variety of invasive and noninvasive methods.8,17,144 Levels of heteroplasmy may be changed to more wild-type mtDNA by induction of muscle regeneration, importation of polypeptides into mitochondria, selective inhibition of replication of mutant mtDNA, or selective methylation of mtDNA.24 The easiest approach is exercise or endurance training with the activation of satellite cells, which have much lower heteroplasmy rates than mature muscle cells.17 Particularly in patients with mtDNA deletions resistance training may increase muscle strength, increase the proportion of satellite cells, improve the muscle oxidative capacity, and may cause muscle ber damage and regeneration.145 However, there are indications that despite the benecial clinical effect, heteroplasmy rates may further increase. The second approach targets engineered endonucleases to mitochondria, where the mutation generates a specic restriction site. Endonucleases selectively degrade mutant mtDNA and thus decrease the heteroplasmy rate. The third approach relies on the importation of cell membrane crossing oligomers (CMCOs), which selectively bind to the mutant mtDNA and potentially inhibit their replication. The fourth mechanism relies on the selective methylation of mtDNA by the introduction of zinc-ngerbinding proteins with sequence binding specicity. Methylation is carried out by a DNA methylase, which fuses with zincnger-binding chimaera.8 A friendlier way of reducing the mtDNA mutation load is exposure to keton bodies instead of glucose as the carbon source.24
3. Conclusions
Though there is no causal therapy of MIDs yet available, there are a number of promising therapeutic concepts under development and investigation, which might reach clinical applicability. These include up-regulation of endogenous ROS-scavengers, such as superoxide dismutase or glutathione, stem cell therapy, or gene therapy. Among the strategies of gene therapy reduction of the heteroplasmy rate appears, at the moment, the most promising approach. A
2.2.3. Germline therapy

Germline therapy is being considered for preventing maternal transmission of mtDNA mutations, but raises ethical problems.24 Germline therapy tries to generate a zygote from the parents gametes by standard in vitro fertilization techniques without the mtDNA defect. For this purpose a single cell
40
further important approach is the detection of drugs, which are effective for specic symptomatic drug therapy, without having mitochondrion-toxic side effects. Thus, it is a major task for the future to nd out, which drugs are actually mitochondrion-toxic and why. To import bioactive molecules into mitochondria they can be conjugated to lipophilic cations.157 Though treatment of MID is actually limited to symptomatic measures,158 a therapeutic nihilism is not justied, since many patients do well for years with symptomatic measures alone. Symptomatic measures may markedly improve the quality of life and prognosis of affected individuals since there are a number of agents available, which preserve the integrity of mitochondria and thus help to maintain cell functions and cell survival.
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Treatment of Mitovondrial

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european journal of paediatric neurology 14 (2010) 2944

Ofcial Journal of the European Paediatric Neurology Society

Treatment of mitochondrial disorders

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

Table 1 Classication of mitochondrial disorders according to the genetic background.

1.2.2. mtDNA mutations

1.2.1. Mitochondrial DNA

1.2.3. Nuclear DNA mutations

european journal of paediatric neurology 14 (2010) 2944

1.2.4. Mitochondrial function

Table 2 Therapeutic concepts for MIDs.

european journal of paediatric neurology 14 (2010) 2944

2.1. Symptomatic therapy

european journal of paediatric neurology 14 (2010) 2944

Table 3 Drug effects on mitochondrial functions. Substance

Effect on mitochondrial function

Antiepileptics Valproic acid

ROS: reactive oxygen species, RC: respiratory chain.

european journal of paediatric neurology 14 (2010) 2944

2.1.1.2.1.1.3. Lipoic acid. Alpha-lipoic acid is a dithiol

european journal of paediatric neurology 14 (2010) 2944

2.1.1.2.2.2. Succinate. In a patient with RCCI defect due to

2.1.1.2.3. Alternative energy sources. 2.1.1.2.3.1. Creatine-monohydrate. There is some anecdotal

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

2.1.9. Miscellaneous. MID patients should generally avoid

2.1.7. Dietary measures. Though dietary measures are mostly

2.2. Causal therapy (experimental) 2.2.1. Somatic stem cell therapy

2.1.8. Physiotherapy. MID patients frequently suffer from

2.2.2. Gene therapy

european journal of paediatric neurology 14 (2010) 2944

2.2.4. Future perspectives

2.2.2.3. Manipulation of heteroplasmy levels (gene shifting).

2.2.3. Germline therapy

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

european journal of paediatric neurology 14 (2010) 2944

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