treatment of mitovondrial

7/31/2019 Treatment of Mitovondrial

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Review article

Treatment of mitochondrial disorders

Josef Finsterer*

Krankenanstalt Rudolfstiftung, Vienna, Austria

a r t i c l e i n f o

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

a b s t r a c t

Treatment of mitochondrial disorders (MIDs) is a challenge since there is only symp-

tomatic 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 physio-

therapy. Drug treatment may be classified as specific (treatment of epilepsy, headache,

dementia, dystonia, extrapyramidal symptoms, Parkinson syndrome, stroke-like

episodes, or non-neurological manifestations), non-specific (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, fibrates, neuroleptics, and anti-retroviral agents. Invasive measures include

implantation of a pacemaker, biventricular pacemaker, or implantable cardioverterdefibrillator, or stent therapy. Dietary measures can be offered for diabetes, hyperlipid-

emia, 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, centralnervous 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 weightedimaging; EEG, electroencephalogram; FA, Friedreich ataxia; GRACILE, growth retardation, Fanconi type aminoaciduria, cholestasis,iron overload (liver hemosiderosis, hyperferritinemia, hypotransferrinemia, increased transferrin iron saturation, and free plasmairon), profound lactic acidosis, and early death; HAART, highly active anti-retroviral therapy; HTX, heart transplantation; ICD,implantable cardioverter defibrillator; INR, international normalized ratio; KSS, Kearns Sayre syndrome; LHON, Lebers hereditary

optic neuropathy; LTX, liver transplantation; LS, Leigh syndrome; MDS, mitochondrial depletion syndrome; MELAS, mitochondrialencephalomyopathy, lactacidosis, stroke-like episodes; MERRF, myoclonic epilepsy and ragged red fibers; MID, mitochondrialdisorder; MILS, maternally inherited Leigh syndrome; MLASA, autosomal recessive sideroblastic anemia with mitochondrialmyopathy and lactic acidosis; MNGIE, mitochondrial neuro-gastrointestinal encephalomyopathy; MRI, magnetic resonanceimaging; 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 pig-mentosa; 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, polymerasegamma; PS, Pearson syndrome; RARS, refractory anemia with ring sideroblasts; RC, respiratory chain; ROS, reactive oxygenspecies; SANDO, sensory ataxic neuropathy, dysarthria, ophthalmoplegia; SCAE, juvenile-onset spino-cerebellar ataxia andepilepsy; 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: [email protected]

Official Journal of the European Paediatric Neurology Society

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

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 4 ( 2 0 1 0 ) 2 9 4 4
mailto:[email protected]:[email protected]


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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 significant

impact on the course and outcome.

2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .301.1. Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .301.2. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

1.2.1. Mitochondrial DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .311.2.2. mtDNA mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .311.2.3. Nuclear DNA mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .311.2.4. Mitochondrial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32

1.3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .322. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

2.1. Symptomatic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

2.1.1. Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .332.1.2. Prophylactic avoidance of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .372.1.3. Substitution of cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .372.1.4. Hemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .372.1.5. Inasive measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .372.1.6. Surgical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .372.1.7. Diatary measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382.1.8. Physiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382.1.9. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38

2.2. Causal therapy (experimental) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382.2.1. Somatic stem cell therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382.2.2. Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382.2.3. Germline therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39

2.3. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .393. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

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 centralnervous system (CNS), the endocrine

glands, and the heart.5 Various combinations of organ affec-

tions 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 beencarried

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 multi-

system 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

definition of various mitochondrial syndromes, for which well



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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 fit into one

of these syndromes (non-syndromic MIDs (nsMIDs)).

1.2. Etiology

MIDs may have a genetic etiology or may be acquired. The

actualreviewmainlydeals 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

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) Mito-

chondria 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 (homo-

plasmy). 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, genera-

tions 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 pheno-

type may change accordingly) and polyploidy phenotypic

expression is dependent on a threshold effect (usually6090%),8 such that theloadof 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 trans-

lation factors with mitochondrial tRNAs and rRNAs. (9)

Phenotypic variability is additionally dependent on the path-

ogenicity 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 classified 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 influence

of nuclear modifier genes, environmental factors, or thepresence 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

1.2.3. Nuclear DNA mutations

nDNA mutations are classified 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 expres-

sion of mtDNA leading to faulty intergenomic communication

Table 1 Classification of mitochondrial disordersaccording to the genetic background.

mtDNA genes

1. Point mutations (maternally inherited, homoplasmic or

heteroplasmic)

a. Genes encoding for tRNAs or rRNAs

MELAS

MERRFb. Genes encoding for RC subunits

LHON

NARP

MILS2. Single deletions/duplications (sporadic, heteroplasmic)

mtCPEO

PS

KSSnDNA genes

1. RC subunits

LS, nsMID

2. Assembly factors of RC subunits

LS, GRACILE

3. Intergenomic signaling

a. Breakage syndromesAD-CPEO, AR-CPEO

SANDO

SCAE

AHS

MNGIE

b. Depletion syndromes

nsMID

AHS

c. Translation defects

MLASA4. Lipid milieu

Barth syndrome

5. CoQ production

LS, nsMID

6. Mitochondrial transport machineryDDS (MTS) (X-linked)

XLSA (X-linked)

7. Mitochondrial biogenesis

CMT2A (mitofusin)

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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) Muta-

tions in genes involved in the coenzyme-Q (CoQ) metabolism

(LS). (6) Mutations in genes resulting in defective mitochon-

drial trafficking or transport machinery (DDS/MTS, XLASA). (7)Mutations in genes encoding proteins involved in the mito-

chondrialbiogenesis, such as fusion or fissionof mitochondria

(OPA, CMT2A) (Table 2).13

The genotypephenotype-correlation in MIDs is generally

poor.7 Whethermutated 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

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 ofhydrogen ions,which flow into thematrix 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-palmitoyl-

transferase I and II. Inside the mitochondrion FFA undergo

beta-oxidation, with acetyl-CoA as the end-product. Hydrogen

ions from the Krebs cycle or beta-oxidation are transferred to

either NAD, generating NADH or to flavin adenine dinucle-

otide (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 find 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, gastro-

enterologic, nephrologic, hematologic, or dermatologic

investigation. Instrumental investigations should be addi-tionally applied to detect subclinical phenotypic manifesta-

tions 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 MILSis 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 syn-

dromic MID due to a nDNA gene mutation (GRACILE, AD-

CPEO, 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 forenzymes of the coenzyme-Q biosynthesis should be under-

taken. If the single biochemical defect is maternally inherited,

one should proceed with mtDNA sequencing. If multiple auto-

somally 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 MPV17is recommended. If Southernblottingdetects

no mtDNA depletion sequencing of mutated genes involved in

the mitochondrial protein synthesis machinery is necessary.

Table 2 Therapeutic concepts for MIDs.A. Symptomatic therapy

Drugs

Specific drug therapy (antiepileptics, antispastics, analgetics,

bone marrow stimulating factors, iron substitution, etc.)

Non-specific 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 (riboflavin, 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-carbo-

hydrate, 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 symp-

tomatic 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 indi-

vidualized, integrated, multi-disciplinary approach needs tobe adopted. This includes specialist nurses, speech, occupa-

tional, 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 forthe effectiveness of remedies forMIDs

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 specific or non-specific manifestations,

invasive interventions, surgery, dietary measures, or physio-therapy. Care should be taken with local anesthetics and

elective generalized anesthesia. Causal therapy in the form of

gene therapyis not availablein the clinical routine, but various

promising attempts in cell or animal models have been

undertaken or are ongoing.

2.1. Symptomatic therapy

Symptomatic measures for MIDs are important since patients

often need specific treatment for various manifestations of

the disease and since symptomatic measures are often the

only help, which can be provided to these patients. Symp-

tomatic measures may be divided into specific and non-specific drug therapy, hemodialysis, invasive measures,

surgical therapy, dietary measures, and physiotherapy. A

classification of non-specific 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 riboflavin, vitamin C, vitamin E, or quinones.

2.1.1. Drugs

2.1.1.1. Specific drug therapy. Specific symptomatic drug

therapy comprises antiepileptics for seizures (avoid valproic

acid for its inhibition of the carnitine uptake17), cholines-

terase-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 lamo-

trigine 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

Open-angle glaucoma requires adequate therapy with beta-

blockers.22 Many MID patients with endocrine disturbances

may profit from substitution of hormones for hypopituitarism,

hypothyroidism, hypoparathyroidism, hypoinsulinism, hypo-

corticism, or hypogonadism. Hyperthyroidism requires

adequate drug therapy or evenradiotherapy.If there is adrenal

insufficiency patients may profit from hydrocortisone, in

addition to coenzyme Q (CoQ) or L-carnitine.23 Recombinanthumangrowth hormone therapy improved growth and muscle

strength in a MERRF patient24 but the increased metabolic

demand mayoverburden the alreadychallengedmetabolism.24

Cardiac drug therapy is indicated in case of rhythm abnor-

malities or heartfailure.Oral anticoagulation may be inevitable

in case of atrial fibrillation, 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 insufficiency (PS) requires

replacement therapy with digestive enzymes.24 Patients may

also profit from thesubstitution of potassiumor sodiumin case

of hypokalemia or hyponatremia from renal failure or hypo-

aldosteronism. In case of anemia or pancytopenia iron, trans-fusions, or hematopoetic cell stimulators may be beneficial.

2.1.1.2. Non-specific drug therapy. Non-specific 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 bysuperoxide dismutase by generating H2O2.

24 In thepresence of

metal ions H2O2 can be further reducedto the hydroxyl radical

(OH). H2O2 itself can be detoxified by glutathione peroxidase

or by catalase.24 Reduction of increased oxidative stress in

MIDs can be enhanced by the administration of ROS-scaven-

gers. Particularly beneficial in MIDs are quinones, vitamin E,

lipoic acid, corticosteroids, vitamin C, melatonin, or gluta-

thion.25,26 ROS-scavengers may not only be beneficial in

primary MIDs (RC/OXPHOS defects) but also in neurodegen-

erative diseases due to other mitochondrial defects.24,27

Antioxidative therapymay be particularlyeffective in FA since

deficiency of frataxin is associated with mitochondrial iron

accumulation, increased sensitivity to stress, deficit RCactivity, or impaired tissue energy metabolism.28

2.1.1.2.1.1.1. Quinones. Quinones (CoQ, idebenone, decyl-

ubiquinone, 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 anti-

oxidativeeffect 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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ubiquitous compound, vital to a number of activitiesrelated 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 pre-

venting lipid peroxidation, and is an indirect stabilizer of

calcium-channels.34 Potential side effects of CoQ include

gastrointestinal discomfort, arterial hypotension, or hypo-

glycemia.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 chain-

breaking 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-deficiency

(COQ2, PDSS2 mutations) presenting as exercise intolerance,

lactacidosis, or cerebellar manifestations.24,3540 CoQ has been

also reported beneficial in RCCII and RCCIII defects, clinically

presenting as MILS.41,42 CoQ substitution is also effective in FA

associated with primary CoQ-deficiency, presenting as exer-

cise intolerance, lactacidosis, or cerebellar manifesta-

tions.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 showedalso a beneficialeffecton

the symptoms and signs in patients with MELAS, MERRF, andKSS.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 effec-

tive in patients with MELAS but also in patients with nsMID. 48

CoQ is less effective in patients with renal failure and primary

CoQ-deficiency.24 UbiQGel, a special type of CoQ was granted

US FDA orphan drug status for the treatment of MIDs.34

2.1.1.2.1.1.1.2. Idebenone. Only limitedexperiences exist with

substances like idebenone29,30 and the results on the effec-

tiveness of idebenone are conflicting. In FA idebenoneappeared to be particularly effective for hypertrophic cardio-

myopathy.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 confirmed 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 thesecond eye in LHON patients from being alsoaffected.54

2.1.1.2.1.1.2. Vitamin E (alpha-tocopherol). There are con-

flicting 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 significantly 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

Table 3 Drug effects on mitochondrial functions.

Substance Effect on mitochondrial function

Corticosteroids Increase mitochondrial membrane

potential, generate ROS, reduce

antioxidants, induce apoptosis

Antiepileptics

Valproic acid Inhibits OXPHOS, induces apoptosis ofmicroglia, sequesters carnitine, reduces RC

activity

Phenytoin Inhibits mitochondrial ATPase

Anesthetics

Intravenous

Barbiturates Inhibit RCCI, reduce mitochondrial protein

synthesis and function

Volatile

Halothane Inhibi ts RCCI

Isoflurane Inhibi ts RCCI

Sevoflurane Inhibits the RC electron transport

Local anesthetics

Bupivacain Inhibits RCCI

Articain Inhibits RCCI

Lipid lowering drugsFibrates Inhibit RCCI

Statines Reduce coenzyme Q10, inhibit RCCI

Antidiabetics

Biguanides Inhibit RCCI, cause lactacidosis

Thiazolidinediones Inhibit RCCI

Antiarrhythmics

Amiodarone Inhibits b-oxidation

b-blockers Inhibit ATPase and stage-3-respiration,

inhibit RCCI

Neuroleptics

Haloperidol Inhibits RCCI

Chlorpromazine Inhibits RCCI

Quetiapine Inhibits RCCI

Risperidone Inhibits RCCI

AntibioticsChloramphenicol 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-salicylic-

acid

Inhibits RC electron transport

ROS: reactive oxygen species, RC: respiratory chain.



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

compound functioning as an essential cofactor for mito-

chondrial 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 freeradicals, 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 poly-

neuropathy, although no well-designed studies have been

carried out to support single observations.

2.1.1.2.1.1.4. Corticosteroids. Corticosteroids may have bene-

ficial 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), cortico-

steroids resulted in a significant improvement of these mani-festations, but could not prevent death from the intractable

epileptic state one year after initiation of therapy.60 Cortico-

steroids were also effective in a female with MELAS, CPEO, and

secondary carnitine-deficiency61 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 L-

arginine, glycerol and edaravone were highly effective in a 16

year old girl with MELAS.64 Corticosteroids have been reported

beneficial to prevent visual loss in a 7 year old LHON patient.65

Corticosteroids have been also proven useful to treat eosino-

philia in MID.66 Another patient with nsMID developed respi-

ratory failure six months after the initiation of corticosteroidsfor initially suspected granulomatous myositis.67

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 significantly

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 beneficial effect. On the contrary, vitamin C has been shown

to be effective in a mouse model of oxidative stress.69 Also inmice vitamin C had a beneficial effect on zidovudine-induced

oxidative damage of cardiac mitochondria.56

2.1.1.2.1.1.6. Glutathione. Glutathione is an endogenous ROS-

scavenger 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 deficiency

due to isolated or combined RCC defects exogenous gluta-

thione may supplement the endogenous deficiency.71

2.1.1.2.1.1.7. Other antioxidants. Anecdotal reports also

showed a beneficial effect of other antioxidants, such as

NADH,72 edaravone, or angiotensin-II-inhibitors. Edaravone

(30 mg/twice a day) intravenously for twoweeks maydecrease

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 beneficial since they enhance mitochondrial

energy production and protect mitochondrial structures by

the inhibition of ROS.73 As a precursor of an antioxidant N-

acetyl 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

2.1.1.2.1.2. 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 manifesta-

tions in 3243A>G mutants. DCA acts by inhibiting the PDC

complex, keeping pyruvate-dehydrogenase in the dehydro-

genated(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 elec-

trophysiological abnormalities.76 In a single patient cyto-chrome-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 dysfunc-

tion 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 poly-

neuropathy 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 beneficial effect in PDC-

deficiency.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 riboflavin and succinate.

2.1.1.2.2.1. Riboflavin. Most frequently riboflavin is adminis-

tered together with other cofactors or antioxidants why its

therapeutic effect cannot be sufficiently assessed. However,

there is anecdotal evidence for riboflavin to be effective in

MIDs,31,55 particularly in secondary riboflavin deficiency in

mitochondrial fatty acid disorders.81 Riboflavin also has



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electron donor/acceptor properties and may thus directly

interfere with the RC.82 Riboflavinwas highly effective in three

children with rare isolated RCCII defect. In two of them

neurological abnormalities remained stable under riboflavin;

in the third growth retardation and lactacidosis markedly

improved.83 Riboflavin has been also tried in patients with

ethylmalonic encephalopathy with some effect.84

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 question-

able. Succinate also proved useful in a MELAS patient in whom

dementia, myoclonus and hemiparesis resolved duringa follow-

up 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 beneficial effect concerning musclestrength 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-mono-

hydrate (0.2 g/kg/d, followed by 0.08 g/kg/d after two weeks)

improved fine motor skills, respiratory functions, and cardiac

functions.87 Creatine was also beneficial 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

deficits, 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-mono-hydrate (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 significantly.90 No beneficial

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 L-

arginine, a nitric oxide-precursor, may improve endothelial

functions in patients with MELAS.91,92 L-arginine may be

particularly beneficial 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 [personalcommunication]. L-arginine may also reduce pulmonary

artery hypertension in MELAS.93

2.1.1.2.4.2. L-carnitine. L-carnitine is highly effective on

primary carnitine-deficiency and in primary carnitine-palmi-

toyl-transferase (CPT1) deficiency 1. In single cases L-carnitine

had also a beneficial effect in secondary carnitine-deficiency

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 31P-

MRS.89 L-carnitine should be particularly given when valproic

acid is unavoidable.24

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)-deficiency 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 conflicting. Some reports describe thiamine

treatment to be beneficial in single cases with sideroblastic

anemia,55 PDC-deficiency, and single patients carrying the

3243A>G mtDNAmutation.95 In twosiblings andtheirmother,

carrying the mitochondrial 3243A>G mutation, manifesting

clinically as myopathy, lactic acidosis, cardiomyopathy, and

thiamine deficiency, thiamine treatment resulted in the

lowering of serum lactate and pyruvate in one of the three.95

Thiamine deficiency was attributed to malabsorption of thia-

mine in these patients.95 Thiamine was also effective in

a patient with RCCI defect due to a mutation in the megalo-

blastic anemia gene SLC19A2.96Otherstudies,however, did notconfirm this effect [personal communication].

2.1.1.2.4.5. Folic acid. Folic acid has been shown to be bene-

ficial 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 riboflavin, vitamin C, or vitamin E, has been discussed

already above. Concerning the effect of niacin, pyridox-

alphosphat, or vitamin K in MIDs, there are only few reportsavailable. There is anecdotal evidence forniacinto be effective

in MIDs.31,55 Only in single cases of XLASA it has been shown

that pyridoxine has a beneficial effect.97 There is also anec-

dotal 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 rote-

none in cultured cardiomyocytes.98

2.1.1.2.5. Others. In MERRF patients with secondary cyto-

chrome-c-oxidase deficiency intravenous administration of

copper was beneficial.99 Copper was considered responsible to

have reversed hypertrophic cardiomyopathy in a child withmutant SCO2, which died from respiratory insufficiency at the

age of 42 months.24 The trophic growth factors glycer-

ophosphocholine and phosphatidylserine provide mitochon-

drial support and improve cognitive functions in

neurodegenerative disease.72 In three patients with a hep-

atocerebral MDS due to a MPV17 mutation, continuous

glucose infusions improved liver functions.100

2.1.1.2.5.1. Ineffective 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 beneficial

effect has been reported from the administration of selen,



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carotin, biotin, calcium, phosphate, or uridine. Also ineffec-

tive 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 asa 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 beneficial.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. Beneficial effects were occasionally also

reported from corticosteroids together with L-arginine, glyc-

erol and edaravone,64 DCA,77 or edaravone (60 mg/d) alone.48

Whether patients with SLEs may also profit from an antiepi-

leptic 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 alter-

native energy sources are administered in the form of cock-

tails with varying composition.115 In a study on 15 pediatric

patients with biochemically or genetically confirmed MIDs

a cocktail of thiamine, riboflavin, CoQ, vitamin C (10 mg/kg/d)and a high-fatdiet wereadministered;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 reductionin the frequency of migraine

attacks, one patient experienced a significant reduction in the

severity of seizures, andin a single patient seizures completely

resolved.115 In a patient with MELAS and pulmonary artery

hypertension, a mixture of biotin, riboflavin, L-carnitine, and

CoQ was ineffective.93 A cocktail of megadoses of idebenone,

vitaminC,andriboflavinduringoneyeardidnotimprovevision

of the affected eye and did not prevent affection of the second

eyeintwopatientswithLHON.54 Inastudyon14LHONpatients

the combined administration of idebenone, vitamin B2, andvitamin 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 ofL-carni-

tine (1000 mg three times a day) in addition to CoQ (at least

400 mg/d).17

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,

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, sevoflurane),125,126

reduce endogenous CoQ (statines), reduce the trans-membrane mitochondrial potential (corticosteroids), inhibit

beta-oxidation (tetracyclines, amiodarone), reduce mito-

chondrial protein synthesis and the number and size of

mitochondria (barbiturates, chloramphenicol),127 sequester

carnitine and generally reduce RC/OXPHOS activity (doxoru-

bicin, 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 helpfulin the case of XLASA or Pearson syndrome or any other syn-

dromic or nsMID, which goes along with anemia resistant to

iron substitution or the stimulation of precursor cells to

erythropoietin. Transfusion of thrombocytes may be neces-

sary 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 beneficial

effect of hemodialysis was too fleeting in these patients.130

Temporary hemodialysis may be also necessary in patientswith severe rhabdomyolysis due to primary CoQ-deficiency.24

2.1.5. Invasive measures. Impaired impulse propagation in

KSS or other MIDs often requires the implantation of a pace-

maker, already at the early stages of the disease. In case of

a propensity to ventricular tachycardias implantation of an

implantable cardioverter defibrillator (ICD) is indicated. An

ICD is also indicated in case of hypertrophic cardiomyopathy

and significant 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 contrac-tion of both ventricles implantation of a biventricular pacing

device may prevent heart transplantation (HTX).

2.1.6. Surgical therapy. Ptosis often requires surgical recon-

struction and can be temporarily effective.131 In most patients

however, a second or third operation is necessary to achieve

a long-standing beneficial effect. Cataract from MID can be

best treated by implantation of an artificial lens. Dysphagia

due to crico-laryngeal achalasia in KSS may be resolved by

myectomy.24 Patients with severe kyphoscoliosis may profit

from stabilization of the spinal column, such as in FA. 132

Cochlear implants may be helpful to overcome hypoacusis if

single or binaural amplification aids become ineffective.133



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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 symp-

tomatic. In case of intractable heart failure, HTX is an ultimateoption 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

defined 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.

2.1.7. Dietary measures. Though dietary measures are mostly

ineffective, some patients with PDC-deficiency may profitfrom a ketogenic diet (keton bodies provided by a high-fat and

low-carbohydrate diet)135 or an anaplerotic diet (3035% tri-

heptanoin).136 In children with refractory epilepsy due to PDC-

deficiency the ketogenic diet may even match the effect of

most anticonvulsants.135 Patients with primary CPT1 defi-

ciency or other mitochondrial fatty acid disorders81 may profit

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 profit from a high-fat diet in addition to thiamine, ribo-

flavin, CoQ, and vitamin C.115

2.1.8. Physiotherapy. MID patients frequently suffer fromexercise 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 upper-

body 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, hetero-plasmy may increase during exercise training. The discrep-

ancy 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 difficult, but in clinical routine it is individual

experience with physical exercise that will help to make this

decision. Exercise physiologists and sport medicine practi-

tioners may help to find 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

confirmed.139 In a study on 40 Wistar rats it turned out that

doxorubicin-induced MID, manifesting as cardiomyopathy,

could be prevented under endurance training by improving

cell defense systems and reducing oxidative stress.128 Endur-

ance 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 sensitivityto calcium, inhibited the increase in mitochondrial protein

carbonyl groups, malon-dialdehyde, Bax, and tissue-caspase-

3-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 sufficient sleep and should performregular 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 profit from amplification aids.24 Patients with

respiratory insufficiency may require nocturnal or continuous

non-invasive positive pressure ventilation.24

2.2. Causal therapy (experimental)

2.2.1. Somatic stem cell therapyAllogeneic stem cell transplantation had been first carried out

in 2006 in patients with MNGIE.141 MNGIE is caused by

thymidine phosphorylase deficiency, 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 deoxy-

uridine imbalances in blood.142 Allogeneic stem cell therapy

has been also tried in patients with refractory anemia with

ring sideroblasts (RARS).24

2.2.2. Gene therapy

Gene therapy in MIDs due to mtDNA mutations is a challengebecause 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 xenotopicexpression),(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 field has been recently published.8

2.2.2.1. Allotopic and xenotopic expression. Allotopic expres-

sion 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



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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 mito-

chondrial 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 mito-

chondrial matrix (mRNA sorting to the mitochondrialsurface).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

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 difficult as there are

three membrane barriers to surmount and that DNA expres-sion 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 non-

invasive 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 inpatients with mtDNA deletions resistance training may

increase muscle strength, increase the proportion of satellite

cells, improve the muscle oxidative capacity, and may cause

muscle fiber damage and regeneration.145 However, there are

indications that despite the beneficial clinical effect, hetero-

plasmy rates may further increase. The second approach

targets engineered endonucleases to mitochondria, where the

mutation generates a specific restriction site. Endonucleases

selectively degrade mutant mtDNA and thus decrease the

heteroplasmy rate. The third approach relies on the impor-

tation of cell membrane crossing oligomers (CMCOs), which

selectively bind to the mutant mtDNA and potentially inhibit

their replication. The fourth mechanism relies on the selectivemethylation of mtDNA by the introduction of zinc-finger-

binding proteins with sequence binding specificity. Methyla-

tion is carried out by a DNA methylase, which fuses with zinc-

finger-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

2.2.3. Germline therapy

Germline therapy is being considered for preventing maternal

transmission of mtDNA mutations, but raises ethical prob-

lems.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

zygote with wild-type mtDNA needs to be enucleated to form

a cytoplast. Then an egg from thepatient 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 numberof various approaches, which have shown promising

effects at least in cell cultures or animalmodels. In cell culture

studies lithium and valproate enhanced mitochondrial func-

tions 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 aromatic-

cationic peptides has demonstrated efficacy in animal models

of Parkinsonism by promoting mitochondrial functions,reducing mitochondrial ROS generation, inhibition of mito-

chondrial 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 anti-

oxidants tocopherol and ubiquinones can be enhanced by

attaching these compounds to the lipophilic cation tri-phenyl-

phosphonium.150 An ethanol extract ofGanoderma lucidum has

been shown to increase the activity of PDH, alpha-KGDH, SDH,

andRCCI in aged Wistarrats.151Alsoin ratsnear-infra-redlight

prevented the neurotoxic effect of the RCCI-inhibitor rote-

none.152 Recent cell studies have shown that humanin, an

endogenous peptide that suppresses apoptosis and increasescellular ATP without inducing mtDNA replication, appears as

a promising therapeutic agent for 3243A>G mutants.153

Another promising drug seems to be the antioxidant mela-

tonin,154 which directly scavenges toxic oxygen or nitrogen-

based reactants, stimulates antioxidative enzymes, increases

RC efficacy 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-synu-

clein aggregation, without influencing weight loss orhypokinesia.156

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 gluta-

thione, stem cell therapy, or gene therapy. Among the strat-

egies of gene therapy reduction of the heteroplasmy rate

appears, at the moment, the most promising approach. A



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further important approach is the detection of drugs, which

are effective for specific symptomatic drug therapy, without

having mitochondrion-toxic side effects. Thus, it is a major

task for the future to find 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 notjustified, since many patients do well for years with symp-

tomatic measures alone. Symptomatic measures may mark-

edly 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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