Treatment for mitochondrial disorders
Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. The first review was carried out in 2003, and identified six clinical trials. This major update was carried out to identify new studies and grade the original studies for potential bias in accordance with revised Cochrane Collaboration guidelines. To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease. We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2, MEDLINE (1966 to July 2011), and EMBASE (January 1980 to July 2011), and contacted experts in the field. We included randomised controlled trials (including cross-over studies). Two of the authors independently selected abstracts for further detailed review. Further review was performed independently by all five authors to decide which trials fit the inclusion criteria and graded risk of bias. Participants included males and females of any age with a confirmed diagnosis of mitochondrial disease based upon muscle histochemistry, respiratory chain complex analysis of tissues or cell lines or DNA studies. Interventions included any pharmacological agent, dietary modification, nutritional supplement, exercise therapy or other treatment. The review authors excluded studies at high risk of bias in any category. The primary outcome measures included an change in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes. Two of the authors (GP and PFC) independently identified studies for further evaluation from all abstracts within the search period. For those studies identified for further review, all five authors then independently assessed which studies met the entry criteria. For the included studies, we extracted details of the number of randomised participants, treatment, study design, study category, allocation concealment and other risk of bias criteria, and participant characteristics. Analysis was based on intention-to-treat data. We planned to use meta-analysis, but this did not prove necessary. The authors reviewed 1335 abstracts, and from these identified 21 potentially eligible abstracts. Upon detailed review, 12 studies fulfilled the entry criteria. Of these, eight were new studies that had been published since the previous version of this review. Two studies which were included in the previous version of this review were excluded because of potential for bias. The comparability of the included studies is extremely low because of differences in the specific diseases studied, differences in the therapeutic agents used, dosage, study design, and outcomes. The methodological quality of included studies was generally high, although risk of bias was unclear in random sequence generation and allocation concealment for most studies. Otherwise, the risk of bias was low for most studies in the other categories. Serious adverse events were uncommon, except for peripheral nerve toxicity in a long-term trial of dichloroacetate (DCA) in adults.One trial studied high-dose coenzyme Q10 without clinically meaningful improvement (although there were multiple biochemical, physiologic, and neuroimaging outcomes, in 30 participants). Three trials used creatine monohydrate alone, with one reporting evidence of improved measures of muscle strength and post-exercise lactate, but the other two reported no benefit (total of 38 participants). One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid and reported a statistically significant improvement in biochemical markers and peak ankle dorsiflexion strength, but overall no clinical improvement in 16 participants. Five trials studied the effects of DCA: three trials in children showed a statistically significant improvement in secondary outcome measures of mitochondrial metabolism (venous lactate in three trials, and magnetic resonance spectroscopy (MRS) in one trial; total of 63 participants). One trial of short-term DCA in adults demonstrated no clinically relevant improvement (improved venous lactate but no change in physiologic, imaging, or questionnaire findings, in eight participants). One longer-term DCA trial in adults was terminated prematurely due to peripheral nerve toxicity without clinical benefit (assessments included the GATE score, venous lactate and MRS, in 30 participants). One trial using dimethylglycine showed no significant effect (measurements of venous lactate and oxygen consumption (VO(2)) in five participants). One trial using a whey-based supplement showed statistically significant improvement in markers of free radical reducing capacity but no clinical benefit (assessments included the Short Form 36 Health Survey (SF-36) questionnaire and UK Medical Research Council (MRC) muscle strength, in 13 participants). Despite identifying eight new trials there is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches. We suggest further research should identify novel agents to be tested in homogeneous study populations with clinically relevant primary endpoints.
Diagnosis and treatment of mitochondrial myopathies
& PATRICK F. CHINNERY
Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom, and
Clinician Investigator Program,
University of British Columbia, Vancouver, Canada
Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory
chain. Muscle tissue is highly metabolically active, and therefore myopathy is a common element of the clinical presenta-
tion of these disorders, although this may be overshadowed by central neurological features. This review is aimed at a
general medical and neurologist readership and provides a clinical approach to the recognition, investigation, and treatment
of mitochondrial myopathies. Emphasis is placed on practical management considerations while including some recent
updates in the ﬁ eld.
Key words: Diagnosis , mitochondrial disorders , mitochondrial myopathy , treatment
Mitochondrial myopathies (MM) comprise a large
heterogeneous group of disorders resulting from pri-
mary dysfunction of the mitochondrial respiratory
chain and causing muscle disease. These disorders
are characterized by dysfunction in multiple organ
systems, extensive variability in clinical presentation,
and generally poor genotype – phenotype correlation.
Several characteristics of mitochondria produce
features which differentiate mitochondrial disorders
from other genetic diseases and are relevant for clini-
cal practice. Mitochondria are intracellular organelles
which contain their own genetic material (mtDNA),
in the form of a 16.5-kb genome. However, most of
the mitochondrial proteins are encoded by the nuclear
genome (nDNA). Therefore, mitochondrial myopa-
thies can result from abnormalities of mtDNA or
nDNA. Abnormalities of mtDNA include point muta-
tions, single large-scale deletions, mtDNA depletion,
and multiple deletions. Point mutations of mtDNA
affect the protein-coding regions of the genome and
tRNA genes which alter intramitochondrial protein
synthesis. Single large-scale deletions are typically due
to sporadic events and are usually not inherited,
although inherited deletions have been described (1).
Depletion (loss of mtDNA) and multiple deletions
are typically secondary effects of faulty mtDNA
maintenance, from mutation of nDNA-encoded
Each cell contains several mitochondria, and
each mitochondrion contains numerous genomes.
In this setting, the phenomenon of genetic hetero-
plasmy arises, where a proportion of genomes con-
tain a mutation, and a proportion are wild-type
(normal). The degree of heteroplasmy affects the
likelihood and severity of the disease phenotype.
The major factor affecting the inherited level of
heteroplasmy of mutations occurs during oogenesis
and is referred to as the ‘ bottle-neck ’ effect, in
which the organism ’ s entire repertoire of mitochon-
dria is replicated from a small pool of genomes.
However, the transmission of mtDNA mutations is
complex and incompletely understood; women with
mtDNA mutations pass their mutations forward at
a level of heteroplasmy which is unpredictable, and
apparently random (2).
Correspondence: Professor Patrick F. Chinnery, Institute of Genetic Medicine, Central Parkway, Newcastle, NE13BZ, United Kingdom. E-mail: p.f.chinnery@
(Received 1 August 2011; accepted 15 August 2011)
Annals of Medicine, 2013; 45: 4–16
ISSN 0785-3890 print/ISSN 1365-2060 online © 2013 Informa UK, Ltd.
DOI: 10.3109/ 07853890.2011.605389
Mitochondrial myopathies 5
Although the focus of this article is on primary
mitochondrial disorders which feature myopathy, it
is important to mention that in many of these syn-
dromes the myopathy component is overshadowed
by other aspects of the clinical presentation. Disor-
ders which will not be considered in this review
include primary mitochondrial disorders which do
not have myopathy as a clinical feature (for example,
Leber optic neuropathy), and diseases due to sec-
ondary mitochondrial dysfunction, or which other-
wise involve the mitochondria in their pathogenesis
(several inherited and acquired muscle diseases, and
numerous common neurodegenerative and other
genetic diseases (3)). The reader should also be cau-
tioned that syndromes resembling primary mito-
chondrial disorders may be produced from secondary
mitochondrial dysfunction and acquired mitochon-
drial toxicity. Furthermore, acquired mitochondrial
toxicity and medication effects may also affect
the muscle biopsy or other test results to mimic
those seen in a primary mitochondrial disorder, as
may the effects of healthy ageing (4).
The prevalence of mitochondrial disorders as a
whole is approximately 1 in 10,000 (5), although the
carrier frequency of mtDNA mutations is about
1 in 200 (6). Onset can occur at any age, although
typically the more severe phenotypes present ear-
lier in life, and milder phenotypes present later in
life. As a prototype example of this, the so-called
deletion syndromes (caused by sporadic, large-scale
deletions of mtDNA) exist on a disease spectrum in
which the most severe syndrome presents in infancy
(Pearson syndrome), a more moderate syndrome in
early childhood or adolescence (Kearns – Sayre
syndrome (KSS)), and a milder syndrome in child-
hood up to late adulthood (progressive external
ophthalmoplegia (PEO)). MM are usually progressive
conditions which produce signiﬁ cant disability and, in
some instances, premature death, often due to non-
muscle involvement such as cardiac conduction
defects or seizures (7).
Because mitochondria are the main source of
energy production in mammalian cells, clinical fea-
tures typically involve tissues with the highest energy
requirements. Furthermore, the presence of mtDNA
in all human tissues means that dysfunction occurs
in multiple organ systems. The most commonly
affected organ systems are the nervous system (cen-
tral, peripheral, autonomic, as well as optic nerve
and retina), muscles (and in particular extra-ocular
muscle), cardiac, and endocrine systems. The clinical
presentation is highly variable with regard to onset
age, symptoms, signs, severity, and prognosis. The
clinician should consider a diagnosis of MM when
myopathy is accompanied by clinical features of
multi-organ dysfunction, which are summarized in
Figure 1. It is common for MM to present with con-
stellations of symptoms, which allow them to be cat-
egorized into one of several syndromes. Ocular
myopathy, which is manifested by ptosis and oph-
thalmoparesis, is an important feature in various
MM syndromes, which are summarized in Table I.
In this sense, PEO is both a syndrome on its own
but also a component of other syndromes when
certain combinations of other features are present.
Mitochondrial myopathies frequently pres- •
ent with multi-system dysfunction and have
a broad variety of phenotypes and genetic
Although no disease-modifying therapy •
exists, it is important to address disease
complications which are often treatable and
have an important impact on patient care.
Further study is required to assess the efﬁ - •
cacy of various treatments, but a trial of
is reasonable as it may be use-
ful for the rare patients with coenzyme Q
ANS ataxia-neuropathy syndromes
, also known as ubiquinone
COX cytochrome c oxidase
EM electron microscopy
KSS Kearns–Sayre syndrome
MELAS myopathy, encephalopathy, lactic acidosis
and stroke-like episodes
MEMSA myoclonic epilepsy myopathy sensory ataxia
MERRF myoclonus, epilepsy, and ragged red ﬁ bres
MIRAS mitochondrial recessive ataxia syndrome
MM mitochondrial myopathy
MNGIE myopathy, neurogastrointestinal
mtDNA mitochondrial DNA
NADH nicotinamide adenine dinucleotide
nDNA nuclear (or chromosomal) DNA
PEO progressive external ophthalmoplegia
POLG polymerase gamma
RCE respiratory chain enzyme
RRF ragged red ﬁ bres
SANDO sensory ataxic neuropathy, dysarthria,
SCAE spinocerebellar ataxia and epilepsy
SDH succinate dehydrogenase
TP thymidine phosphorylase
tRNA transfer RNA
6 G. Pfeffer & P. F. Chinnery
The ocular muscle weakness develops gradually, and
presentation may be delayed by years or decades
until the signs are noticed by family members. Iso-
lated PEO, which is the mildest syndrome, may still
carry signiﬁ cant visual and other disability (8) and
often presents with multiple features of mitochon-
drial disease (9). PEO deserves special mention
because of its extensive genetic heterogeneity, which
has implications for the risk to other family members
of inheriting the disease. PEO may be sporadic
(due to single deletions), maternally inherited (due
to mtDNA mutation), autosomal dominant, or
recessive (due to nDNA mutations). These are often
clinically indistinguishable, emphasizing the impor-
tance of obtaining a molecular diagnosis. The
phenotypic variability should also be emphasized,
since this condition may present at any age, the
ophthalmoparesis may be anywhere along a spec-
trum of subtle to complete, and associated features
of the condition may appear in any combination.
For the ataxia-neuropathy syndromes (ANS),
this includes an overlapping group of disorders,
about half of which have PEO as part of their clini-
cal presentation. These syndromes are variably
referred to as spinocerebellar ataxia with epilepsy
(SCAE), myoclonic epilepsy myopathy sensory ataxia
(MEMSA), sensory ataxia, neuropathy, dysarthria,
ophthalmoplegia (SANDO), or mitochondrial reces-
sive ataxia syndrome (MIRAS). These syndromes
have in common the presence of an axonal sensory
Neurologic - central
• Movement disorder
• Stroke-like episodes
• Cognitive impairment
• Myopathy: ophthalmoplegia
• Optic atrophy
• Pigmentary retinopathy
• Conduction abnormalities
• Cardiomyopathy: hypertrophic>
Skeletal muscle: ocular >
axial/proximal > bulbar > distal
Smooth muscle: dysphagia
• Axonal polyneuropathy
• Sensory ataxia
• Sensorineural hearing loss
• Autonomic dysfunction
• Short stature
• Spontaneous abortion
• Dysmotility: gastroparesis,
diarrhoea, constipation, and/or
• Hepatic failure
• Renal tubular defects
• Diabetes mellitus
• Gonadal failure
• Growth hormone
Figure 1. Clinical features of mitochondrial myopathies, by organ system.
Mitochondrial myopathies 7
neuropathy, affecting proprioceptive function in
combination with variable degrees of cerebellar
ataxia, making them part of a disease spectrum
which is caused by nDNA mutations affecting
Other syndromes present with multi-organ dys-
function, without ocular myopathy, and these are
summarized in Table II. In myoclonus, epilepsy,
and ragged red ﬁ bres (MERRF), myopathy, enceph-
alopathy, lactic acidosis, and stroke-like episodes
(MELAS), and some of ANS, central nervous sys-
tem dysfunction predominates on a background of
dysfunction in other organ systems. For these syn-
dromes, genotype – phenotype correlations are some-
what better, where the majority of MELAS and
MERRF patients have common tRNA mutations
(respectively, m.3243A ⬎ G and m.8344A ⬎ G, and
ANS are most often caused by mutations in the gene
encoding the mtDNA polymerase gamma, POLG ).
Isolated MM typically presents with axial and
proximal weakness, variable age of onset or severity,
and variable co-occurrence of other features of
mitochondrial dysfunction. As in PEO, genotype –
phenotype correlation is poor, and as it stands this
condition is already difﬁ cult to distinguish from
other types of acquired or genetic myopathy, due to
its fairly non-speciﬁ c presentation.
The infant-onset mitochondrial myopathies have
a severe clinical presentation, although it is impor-
tant to be aware of a subset of patients with infantile
cytochrome c oxidase (COX)-deﬁ ciency myopathy
with reversible disease, whose molecular defect has
recently been described (10,11).
Another rare but important subgroup of patients
with MM are due to defects in coenzyme Q
) biosynthesis. These disorders are important
to recognize because of their partial responsiveness
supplementation. The infantile-onset form
deﬁ ciency is a multi-systemic disorder with
encephalopathy and nephropathy. Typically this is
steroid-resistant and may progress to renal failure
(12,13). In adults, CoQ
deﬁ ciency manifests as
adult-onset myopathy or ataxia with variable myopathy,
peripheral neuropathy, and/or seizures (14 – 16).
Numerous patients with MM do not ﬁ t into the
described syndromes. Many features of MM are
uncommon, or recently described (such as distal
myopathy from certain POLG mutations (17)).
These ill-deﬁ ned syndromes may have a novel or
unique molecular basis, or they may be due to muta-
tions previously described to cause speciﬁ c syn-
dromes. For example, the m.3243A ⬎ G mutation
has been implicated in a broad variety of atypical
clinical presentations (18).
For patients with suspected MM, diagnostic tests fall
into two broad categories. The ﬁ rst category of test-
ing conﬁ rms the presence of dysfunction in various
organ systems (summarized in Table III) and does
not as such conﬁ rm a diagnosis of MM. These tests
Table I. Mitochondrial myopathy syndromes presenting with ocular myopathy.
Syndrome Clinical symptoms/signs Onset age Genetics
Proximal myopathy often
present. Various other
clinical features variably
Any age of onset.
Typically more severe
mtDNA single deletions; mtDNA
point mutations (including
m.3243A ⬎ G, m.8344A ⬎ G);
nDNA mutations ( POLG, ANT,
PEO1, OPA1 )
Kearns – Sayre syndrome (KSS) PEO, ptosis, pigmentary
ataxia, CSF elevated
protein, diabetes mellitus,
sensorineural hearing loss,
⬍ 20 years
mtDNA single deletions
Ataxia neuropathy syndromes
(ANS): Including MIRAS,
SCAE, SANDO, MEMSA
SANDO: PEO, dysarthria,
Other ANS: variable presence
of PEO and/or myopathy
Teen or adult nDNA mutations ( POLG , PEO1 )
PEO, ptosis, GI dysmotility,
proximal myopathy, axonal
Childhood to early
nDNA mutations in (TP )
MEMSA⫽myoclonic epilepsy myopathy sensory ataxia; MIRAS⫽mitochondrial recessive ataxia syndrome; SANDO⫽ sensory ataxia
neuropathy dysarthria ophthalmoplegia; SCAE⫽spinocerebellar ataxia with epilepsy.
8 G. Pfeffer & P. F. Chinnery
are nonetheless important to deﬁ ne the extent of
the phenotype, to exclude other disorders, and to
increase or decrease the clinical suspicion of a MM
diagnosis. The tests selected are guided by the pat-
tern of organ involvement in each individual patient.
Some of these tests deserve special mention, because
of their potential to alter patient management. Car-
diac investigations are of particular importance
because cardiac conduction defects can be fatal if
not identiﬁ ed and are treatable with cardiac pace-
makers. Endocrine investigations may identify dia-
betes mellitus, hypothyroidism, or growth hormone
deﬁ ciency, all of which are treatable. Patients with
hearing or visual symptoms should be investigated
in order to obtain appropriate aids if required. Dys-
phagia is common in some mitochondrial syndromes
and can be managed with dietary modiﬁ cation.
The second category of tests deﬁ nitively addresses
whether the patient is affected by a MM, and these
mainly include muscle biopsy and molecular genetic
studies. These studies are performed in combination,
since the assessment of mtDNA should ideally be
done from DNA extracted from muscle (the high
replication rate of blood cells selects against patho-
genic mtDNA abnormalities, therefore many mtDNA
abnormalities are not detectable in blood).
Muscle biopsy is typically performed from a limb
muscle, such as quadriceps femoris or deltoid, and
examples of characteristic abnormalities are pro-
vided in Figure 2. The testing should include a
variety of histochemical functional assays and be
performed in a centre with experience in mitochon-
drial disease diagnosis. The major diagnostic feature
is the presence of ﬁ bres deﬁ cient for COX activity,
Table II. Mitochondrial myopathy typically presenting without PEO.
Syndrome Clinical symptoms/signs Onset age Genetics
Childhood or adult onset
lactic acidosis, stroke like
Stroke-like episodes with
seizures. Variable presence
A minority of patients have
Typically ⬍ 40 years of age but
childhood more common
mtDNA point mutations
(m.3243A ⬎ G in 80%)
Myoclonus, epilepsy, and
ragged red ﬁ bres
generalized seizures, ataxia,
cardiomyopathy. A minority
of patients have PEO
Childhood mtDNA point mutations
(m.8344A ⬎ G most
Sensory axonal neuropathy
with variable degrees of
sensory and cerebellar
ataxia. PEO in 50%.
Epilepsy and dysarthria are
present in some
Adult onset nDNA mutations ( POLG ,
TWINKLE , OPA1 )
Axial/proximal myopathy. May
have other features of
Any age of onset mtDNA point mutations
Congenital or infant-onset
Diffuse myopathy or
Congenital or infantile
weakness, and death within
few years of life. Infantile
COX-deﬁ ciency myopathy
occasionally reverses after
ﬁ rst year of life
Infantile myopathy with
Diffuse myopathy, lactic
Fatal in ﬁ rst year, or
reversible after ﬁ rst year in
(m.14674T ⬎ C) in the
MEMSA⫽myoclonic epilepsy myopathy sensory ataxia; MIRAS⫽mitochondrial recessive ataxia syndrome; SANDO⫽ sensory ataxia
neuropathy dysarthria ophthalmoplegia; SCAE⫽spinocerebellar ataxia with epilepsy.
Mitochondrial myopathies 9
which represents poor activity of complex IV of the
respiratory chain (and is encoded by both mtDNA
and nDNA genes). However, a low frequency of
COX-deﬁ cient ﬁ bres is a normal ﬁ nding in healthy
aged individuals. In general, the detection of any
COX-deﬁ cient ﬁ bres in individuals ⬍ 50 years of age,
or a higher frequency of COX-deﬁ cient ﬁ bres at any
age ( ⬎ 5%), is strongly suggestive of a mitochondrial
disorder. The identiﬁ cation of COX-deﬁ cient ﬁ bres
is greatly helped by serially staining muscle for COX
followed by succinate dehydrogenase (SDH), which
stains for complex II (and is encoded entirely by
nuclear genes). The demonstration of COX- deﬁ cient,
SDH-positive muscle ﬁ bres is thought to have the
best sensitivity and speciﬁ city for MM (19). The
sub-sarcolemmal accumulation of mitochondria is a
classic feature of MM, and can be demonstrated by
SDH histochemistry (so-called ‘ raggedblue ﬁ bres ’ ),
or the Gomori trichrome stain (so-called ‘ ragged red
ﬁ bres ’ or RRF). Again, a low frequency of RRFs
( ⬍ 5%) can be seen in healthy aged individuals.
However, the detection of RRFs in individuals ⬍ 50
years of age, or ⬎ 5% RRF at any age, is highly sug-
gestive of MM, although even high levels can be sec-
ondary to other pathologies, such as inclusion body
Electron microscopy (EM) may also be performed
on muscle specimens and demonstrate a variety of
abnormalities associated with MM, although these
are rarely speciﬁ c for mitochondrial diseases. These
Table III. Conﬁ rmatory tests for organ dysfunction in mitochondrial myopathy.
Symptom/sign/disorder Tests Possible abnormalities Examples of treatments
EEG Epileptiform abnormality,
Stroke-like episodes MRI brain High-signal T2 abnormality not
conforming to vascular
L-arginine a possible therapy
Sensory neuropathy Nerve conduction studies Axonal sensory or sensorimotor
Myopathy CK Normal or slightly elevated.
May be very high in CoQ
EMG Myopathic changes or normal
Respiratory failure PFTs, sleep studies Decreased FVC. Apnoeic
episodes during sleep
CPAP or BiPAP
Cardiac Electrocardiogram Conduction abnormalities Antiarrhythmics, pacemaker
Echocardiogram Cardiomyopathy ACE inhibitors
Endocrinopathy Fasting glucose, glucose
tolerance test, HgBA1c,
TSH, calcium, PTH,
cortisol, synacthen test
Abnormalities consistent with
type 2 diabetes mellitus, and/
or hypothyroidism, and/or
agents and/or insulin;
Cognitive dysfunction Mental status testing May indicate cognitive
Hearing loss Audiography Sensorineural-type hearing loss Auditory aids, cochlear
Ocular symptoms/signs Ophthalmology referral Oculomotor abnormalities,
optic atrophy, pigmentary
Corrective lenses, surgery for
strabismus or ptosis
Dysphagia Swallowing studies (video
ﬂ uoroscopy or manometry)
Cricopharyngeal achalasia or
Dietary modiﬁ cation
Other general tests Serum lactate Normal, or elevated
CSF lactate Normal, or elevated
CSF analysis Normal, or elevated protein
CT brain Normal, or basal ganglia
calciﬁ cations ⫾ atrophy
MRI brain Basal ganglia signal
abnormalities, non-speciﬁ c
white matter abnormalities,
stroke-like lesions, cerebellar
or brain-stem atrophy, or
normal. MR spectroscopy
may demonstrate elevated
10 G. Pfeffer & P. F. Chinnery
include enlarged pleiomorphic mitochondria and
paracrystalline inclusions. At present EM is thought
to provide minor criteria for the diagnosis of MM
(20). However, EM may provide minor diagnostic
criteria for mitochondrial disease in some patients
with normal histochemistry (9), therefore EM may
contribute additional information in selected cases.
Some caveats to diagnosis with muscle biopsy
should be discussed. Muscle histochemistry and/or
EM may be normal even in the context of genetically
proven mitochondrial syndromes (21), particularly
early in the disease course or when the biochemical
defect does not involve complex IV (COX). Further-
more, for certain MM syndromes (mainly PEO),
unconventional muscle biopsy sites have been stud-
ied for their utility in providing a diagnosis of MM.
These include levator palpebrae superioris (22) and
orbicularis oculi (23,24), which are easily accessible
muscles during corrective ocular surgery for ptosis
in PEO. For patients requiring ocular surgery,
biopsy of ocular muscle may be able to provide a
diagnosis and avoid a separate procedure for limb
muscle biopsy — however, limited information from
healthy controls can limit interpretation from these
Another test available from muscle tissue is
respiratory chain enzyme (RCE) analysis. This test-
ing must be done either on fresh or snap-frozen
muscle samples. RCE is technically difﬁ cult to per-
form, even in specialist laboratories (19,25,26),
and the results should be interpreted in the context
of the other investigations. Demonstrating a RCE
defect is a crucial diagnostic step in patients with
normal or near-normal muscle histochemistry,
The genetic tests should be guided based on the
muscle biopsy ﬁ ndings, the MM syndrome which is
suspected, and, if present, the inheritance pattern.
Figure 2. Abnormalities on skeletal muscle biopsy in mitochondrial myopathy. Serial sections through vastus lateralis in a patient with
mitochondrial myopathy showing: (A) haematoxylin and eosin, (B) cytochrome c oxidase histochemistry (COX) (note the COX deﬁ cient
ﬁ bres), (C) succinate dehydrogenase histochemistry (SDH) (note the sub-sarcolemmal accumulation of mitochondria analogous to a
ragged red ﬁ bre), and (D) sequential COX-SDH histochemistry showing a mosaic COX defect as seen in patients with mtDNA
Mitochondrial myopathies 11
As a general rule, mosaic appearance of COX-
negative ﬁ bres suggests a mtDNA mutation (due to
the variable degrees of heteroplasmy between muscle
cells), whereas uniformly decreased COX activity
suggests a nDNA mutation (which would be equally
present in all muscle cells). If only a single respira-
tory chain complex has decreased activity, this sug-
gests a mutation in a structural gene for the relevant
complex, which may be in mtDNA or nDNA, or a
speciﬁ c complex assembly factor in nDNA. How-
ever, these general principles are not invariably true,
because patients with mtDNA depletion may have
isolated complex deﬁ ciencies early in the disease
course. Other characteristic features include the
presence of strongly succinate dehydrogenase-
positive blood vessels (SSVs) seen in patients with
MELAS harbouring m.3243A ⬎ G (27). If the
patient ﬁ ts into a particular clinical syndrome, this
can be helpful in deciding testing, and common
mutations for different phenotypes are listed in
Tables I and II. Cases in which genetic testing may
precede muscle biopsy include syndromes and/or
inheritance history that implicate nDNA mutations,
which may be tested in blood. Characteristic exam-
ples include syndromes caused by POLG mutations
(autosomal dominant or recessive PEO, the ANS,
and hepatocerebral syndromes such as Alpers syn-
drome) (28). The m.3243A ⬎ G mutation is easily
detected in urine, may cause a variety of mitochon-
drial syndromes (MELAS, maternally inherited dia-
betes and deafness, PEO, isolated MM, and
cardiomyopathy), and its mutation load may even
provide prognostic information (29). Elevations of
plasma and urine thymidine are seen in myopathy,
neuropathy, gastro intestinal encephalopathy
(MNGIE) syndrome due to mutations in TP .
If a genetic diagnosis is not reached after elimi-
nating common molecular defects, more extensive
testing should be carried out. This may involve
sequencing the mitochondrial genome and/or known
nuclear disease genes. In the case of mtDNA genome
sequencing, previously described mutations may
be identiﬁ ed in this manner, or novel mutations,
although distinguishing mutations from the high
level of variability in the mtDNA sequence in the
general population is a challenging exercise (30).
Tissues aside from muscle may be biopsied to sup-
port a diagnosis of MM. Skin biopsy is a non-invasive
procedure which is used to obtain ﬁ broblasts for RCE
and DNA for genetic studies. However, the RCE defect
or molecular genetic defect may not be present in ﬁ bro-
blasts in all patients, and as a result this method has
lower sensitivity than muscle biopsy (31). Liver biopsy
is appropriate in selected situations with an important
component of hepatic failure, providing there is no
coagulopathy. In these situations the biopsy is helpful
to exclude other disorders and is a tissue source for
histological, EM, RCE, and DNA analysis.
Diagnosis of MM due to CoQ
defects are made by the demonstration of CoQ
deﬁ ciency in muscle tissue and may be supported by
decreased levels in other tissues such as ﬁ broblasts
and white blood cells (12,26). Plasma levels have a
broad reference range and may be normal in this
condition (26). RCE analysis may demonstrate the
combination of either complex I ⫹ III deﬁ ciency or
complex II ⫹ III deﬁ ciency, since these complexes are
Another category of diagnostic tests for MM
includes exercise testing. There are numerous des-
cribed protocols for testing using cycle ergometry or
treadmill exercise (32). The diagnostic usefulness of
these investigations is controversial, given reports
revealing low speciﬁ city (33,34) and sensitivity (35).
Protocols for measuring venous pO
testing have demonstrated excellent speciﬁ city, and
for practical purposes these work well as non- invasive
screening tests for MM (36,37).
There is currently no available disease-modifying
therapy for MM. Several agents (mostly nutritional
supplements) have been investigated with double-blind,
placebo-controlled studies. These include carnitine
(38), creatine (39 – 41), CoQ
(42,43), cysteine (44),
dichloroacetate (42,45 – 48), dimethylglycine (49), and
the combination of creatine, CoQ
, and lipoic acid
(50). None has demonstrated efﬁ cacy in clinical disease
end-points, although numerous non-blinded studies
and case reports have suggested efﬁ cacy. Examples of
treatments with reported beneﬁ t in MM that have not
yet been evaluated in placebo-controlled trials are
summarized in Table IV. Further study is required to
identify whether any of these agents have therapeutic
Although extremely rare, MM caused by CoQ
deﬁ ciency will sometimes respond to CoQ
mentation (51,52), therefore a trial on this agent is
appropriate for patients who have a possible pheno-
type of these conditions. Anecdotal and open-labelled
case series report improvements with the CoQ
logue idebenone in mitochondrial myopathy (53 – 55).
Otherwise, due to the lack of available treatments,
numerous experimental treatments are in develop-
ment, and these were reviewed recently (56). These
include the PPAR/PGC-1 α activator bezaﬁ brate,
which increased mitochondrial biogenesis and
delayed the onset of myopathy in transgenic mice
with a COX defect (57), and the mitochondrially
targeted antioxidant MitoQ which has been used
safely in several common human diseases (58).
12 G. Pfeffer & P. F. Chinnery
There has been great interest in exercise pro-
grammes and their beneﬁ t on both biochemical
and clinical end-points in MM. Aerobic (59,60),
endurance (61,62), and resistance (63) training pro-
grammes have been studied. It is currently not clear
whether the beneﬁ ts of exercise in MM are simply
reversing the de-conditioning, which is a common
feature of many muscle diseases, or whether the
exercise affects the underlying pathology. In any
event, evidence is mounting that exercise programmes
are safe and beneﬁ cial for numerous end-points,
including strength, fatigue, and quality of life.
Treatment of MM concentrates on the manage-
ment of disease complication. A diseasecomplica-
tion which is particular to MM is the stroke-like
episodes of MELAS. A non-blinded study of 24
MELAS patients compared L-arginine with placebo
as acute treatment for stroke-like episodes (64).
Symptoms improved 30 minutes and 24 hours after
administration. A portion of the study also followed
six patients on daily treatment with L-arginine for
18 months. The frequency and severity of stroke-like
episodes were signiﬁ cantly decreased. However,
these ﬁ ndings have not been replicated, and the non-
blinded nature of the study may have biased the
results. Recently, a small study suggested a beneﬁ t
of L-arginine in cardiomyopathy due to MM (65),
and so further study of this agent would be of
interest. Finally, status epilepticus was successfully
treated with intravenous magnesium in two teenage
girls with juvenile-onset Alpers syndrome due to POLG
mutations (66). One died 2 weeks after treatment from
pneumonia. The other remained seizure-free 8 months
Other disease complications of MM are due to
dysfunction of various organ systems, which are
important to recognize and treat because they are
potentially preventable causes of death and disability
in MM patients (67). Table III provides a summary
of these as well as examples of possible treatments.
Cardiac dysfunction will be discussed in further
detail because it is common, frequently asymptom-
atic, and potentially fatal. Cardiac dysfunction can
take many forms, namely cardiac conduction defects
and cardiomyopathy. Abnormalities of cardiac con-
duction are common, even among asymptomatic
patients (68), and although they are a central feature
of KSS they may occur in any MM. Cardiomyopathy
may be hypertrophic or dilated and is most com-
monly present in MELAS, MERRF, and KSS (69).
Figures are not available for adults, although one
study in children demonstrated hypertrophic cardio-
myopathy to be present in 17%, often asymptomatic,
and associated with higher mortality than MM
patients without cardiomyopathy (70). Patients with
MM should therefore be screened with 12-lead ECG
and transthoracic echocardiogram irrespective of
whether they are symptomatic for cardiac disease.
Guidelines do not exist as to whether investigations
should be repeated in the event that they are normal,
although repeating investigations every 1 – 3 years may
be reasonable. Other cardiac investigations which
may be considered include Holter monitoring in
patients with symptoms suggestive of arrhythmia.
Cardiac MRI is a new imaging modality, but from
case reports the ﬁ ndings in MM may be characteristic
Endocrinopathy is another common ﬁ nding in
MM patients and is treatable. The classic endocrine
manifestation is diabetes mellitus, which is particu-
larly associated with KSS and MELAS (73). Hypo-
thyroidism may also be a common endocrinopathy
Table IV. Treatments with reported beneﬁ t in mitochondrial myopathy which may beneﬁ t from further study in blinded placebo-controlled
Agent Reported beneﬁ t Evidence
PNMR and symptomatic Single case reports in complex III deﬁ ciency
High-fat diet with
vitamins and CoQ
Short-term improvement in neurodevelopment,
seizure control, level of consciousness
Open-label study of 15 paediatric patients (94)
Idebenone Biochemical improvements; delayed disease
progression; improvement of respiratory
Single case reports (53 – 55)
L-arginine Reduction in acute symptoms of stroke-like
episodes, reduction of incidence of stroke-like
episodes in MELAS; improvement of TCA
metabolic rate on C11-PET in cardiomyopathy.
Non-blinded, placebo-controlled study of 24
MELAS patients (64); C11-PET study in
6 patients with MELAS (65)
Magnesium Resolution of refractory status epilepticus in
Two patients (66)
Nicotinamide Biochemical improvements. Reduced
encephalopathy and stroke-like episodes in
Six-month open label trial of seven MELAS
patients (95), and single case reports (96,97)
Succinate Improvement of respiratory muscle weakness
decrease in stroke-like episodes
Single case reports (98,99)
Mitochondrial myopathies 13
in milder syndromes (9), and the clinician should be
aware that any type of endocrine abnormality is pos-
sible, particularly growth hormone deﬁ ciency, which
Respiratory dysfunction can have serious rami-
ﬁ cations (74), although it has received limited study
in MM. Recent clinical series have queried the pres-
ence of respiratory symptoms but found them to
be similar to controls in a large series of MELAS
patients (73), and present in only 1 patient in a
series of 40 PEO patients (9). The only major study
on this subject investigated respiratory parameters
during sleep in eight patients with PEO (75).
Although all had no respiratory symptoms, during
the sleep studies four of the patients had central
apnoeic episodes and/or poor responsivity to CO
This was postulated to be due to the chronic adap-
tation to respiratory and laryngeal muscle weakness,
or due to a central mechanism. While it is unclear
what effect these asymptomatic respiratory distur-
bances had on these patients, clinicians should have
a low threshold to investigate respiratory- and sleep-
related symptoms in MM patients. Another series
reporting more severe respiratory disturbances sug-
gested a central mechanism that could be episodic
and exacerbated by metabolic stressors, such as
infection or anaesthesia (76).
Other management considerations in MM
include the avoidance of agents which may worsen
the patient ’ s condition. While the list of medications
with theoretical toxicity is massive (77), a few agents
of clinical importance will be discussed here. Statin
medications are thought to cause toxic effects on
skeletal muscle through a disturbance of mitochon-
drial function (78), although the precise mechanisms
remain unclear. Statins appear to cause muscle
symptoms in 10% of patients who receive the drugs
(79), have been reported to unmask symptoms of
metabolic myopathies in patients who were previ-
ously asymptomatic (80), and occasionally these
agents are associated with syndromes resembling
PEO (81,82). They should therefore be used cau-
tiously in MM, with careful monitoring of symptoms
and the serum creatine kinase. Antiretroviral agents
are known to cause reversible and dose-dependent
mitochondrial toxicity (83). If necessary for the
treatment of HIV, it appears that certain agents have
less mitochondrial toxicity (84) and should be used
preferentially. Small series have documented the
development of PEO-like syndromes in patients on
antiretrovirals (85 – 87), although whether this is due
to an unmasking effect or whether the disease is
caused by cumulative mitochondrial toxicity is
unknown. This is especially the case for nucleotide
reverse transcriptase inhibitors. Valproic acid is
known to interfere with mitochondrial function and
in clinical practice can aggravate symptoms in
patients with MM (88), and valproate-induced hepa-
totoxicity may be more common in MM patients
(89,90). Genetic variation in POLG is strongly asso-
ciated with increased risk of hepatotoxicity due to
valproic acid (91).
In summary, the identiﬁ cation of patients with
possible MM depends upon the investigation of
multiple organ dysfunction in the clinical history,
examination, and clinical tests. Although there is no
disease-modifying therapy for MM, there are numer-
ous points of clinical relevance that can reduce mor-
bidity and improve quality of life for patients with
G.P. is the recipient of funding from the Clinician
Investigator Program from the University of British
Columbia, and from a Bisby Fellowship from the
Canadian Institutes of Health Research.
P.F.C. is an Honorary Consultant Neurologist at
Newcastle upon Tyne Foundation Hospitals NHS
Trust. He is a Wellcome Trust Senior Fellow in Clin-
ical Science and a UK NIHR Senior Investigator
who also receives funding from the Medical Research
Council (UK), the Association Fran ç aise contre les
Myopathies, and the UK NIHR Biomedical Research
Centre for Ageing and Age-related disease award to
the Newcastle upon Tyne Foundation Hospitals
Declaration of interest: No competing interests
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