Mitochondrial Cytopathies in Children and Adults

KEY POINT
A Mitochondria
are present in
MITOCHONDRIAL
every cell in the
human body, CYTOPATHIES IN
except red
blood cells.
In addition
CHILDREN AND ADULTS
to their main Mark A. Tarnopolsky
role providing
aerobically
derived ATP,
they are also ABSTRACT
involved in Mitochondrial cytopathies represent a heterogenous group of disorders with ab-
reactive normal mitochondrial structure or function as the defining entity and with clinical
oxygen species onset across all age groups. Given that the mitochondria provide the majority of
generation, cellular adenosine 50 -triphosphate (ATP), the clinical symptoms can manifest with a
apoptosis, and myriad of presentations. Cellular pathology includes a reduction in aerobic energy
calciumbuffering. transduction, an increase in anaerobic energy utilization (lactate production), and, in
some cases, higher oxidative stress. Diagnostic criteria include history (classic multi-
system involvement), blood test abnormalities (elevated lactate, alanine, and creatine
kinase activity), urine organic acids (3-methylglutaconic acid, ethylmalonic acid,
fumarate), muscle enzymology (reduction in activity), exercise testing (low maximum
oxygen consumption [V̇O2max], early lactate production) and other ancillary tests,
including MRI, MR spectroscopy, and near-infrared spectroscopy. Treatment is multi-
factorial and supportive, including optimization of nutrition and deficiency (folate and
vitamin B12) replacement, gastrostomy tube if necessary (failure to thrive), treatment
of secondary neurologic issues, vitamin and cofactor therapy (creatine monohydrate,
coenzyme Q10, -lipoic acid, etc), and exercise.
Continuum Lifelong Learning Neurol 2009;15(6):98–125.
INTRODUCTION onset mitochondrial cytopathies are

Mitochondria are essential to the func- surviving into adulthood, and intrafamil-
tional integrity and energy metabolism ial variability in age at onset and clinical
98 of all cells (except red blood cells) and manifestations of inherited mitochon-
can be directly implicated in human dis- drial conditions have implications for
ease (mitochondrial cytopathies) or as the care of all family members. This
contributors to health (mitochondrial chapter will provide an overview of mi-
proliferation in muscle cells of elite tochondrial biology and will discuss the
athletes) and disease (mitochondrial most common forms of mitochondrial
dysfunction in ischemic tissue, neuro- cytopathies in children and adults. Dis-
degenerative diseases, and critical ill- cussion of the contributions of second-
ness). Mitochondrial diseases manifest ary mitochondrial dysfunction in other
across the full spectrum from infancy to neurologic or systemic diseases is be-
old age. Children with severe early- yond the scope of this chapter.
Relationship Disclosure: Dr Tarnopolsky has received personal compensation for speaking engagements with
Transgenomic, Inc., has received personal compensation in an editorial capacity from Medicine & Science in
Sports & Exercise, and has received research support from ApoPharma, Inc., and Gilead.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Tarnopolsky has nothing to disclose.
Copyright # 2009, American Academy of Neurology. All rights reserved.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MITOCHONDRIAL BIOLOGY in the core series circuit of the electron
PRIMER transport chain (I, III, IV) and the adeno-
Mitochondria are the main ‘‘power- sine triphosphatase (ATPase) function
house’’ for all cells in the body except ( V ). There can be two to several dozens
red blood cells. The mitochondria are of mtDNA copies per mitochondria, and
considered an evolutionary parasite in certain cells, such as a multinucleate
evolved from purple photosynthetic bac- muscle cell, there may be many thou-
teria that invaded proto-eukaryotic cells sands of mitochondria.
approximately 11/2 billion years ago. This The purpose of the mitochondria is
symbiotic relationship is felt to confer to provide aerobically derived ATP for
selective advantage through enhanced a variety of cellular energy processes.
aerobic adenosine 50 -triphosphate (ATP) Fat, protein, and carbohydrate are all
delivery and oxygen detoxification given oxidized in the mitochondria through
a variety of different pathways that ul-
the steep oxygen gradient evolving in
timately converge on the electron trans-
the earth’s atmosphere. Over 11/2 billion
port chain. Nicotinamide adenine dinu-
years of evolution, all of the proteins
cleotide (reduced form) (NADH) + H+
involved in mitochondrial DNA (mtDNA)
( proton) derived from -oxidation or the
replication and maintenance were trans-
tricarboxylic acid (TCA) cycle provides
ferred to the nuclear genome, and the
reducing equivalents to complex I, where
bacterialike circular mitochondrial ge-
a proton is pumped from the mitochon-
nome retains only 16,569 base pairs en-
drial matrix to the intermembrane of
coding for 13 polypeptide subunits, 22
space, and electrons are passed onto
transfer RNAs (tRNAs), 2 ribosomal RNAs coenzyme Q10. Flavin adenine dinucleo-
(rRNAs), and a small noncoding region. tide (reduced)2 provides reducing equiv-
The circular genome is composed of alents to complex II from -oxidation
an outer heavy strand (predominately or the TCA cycle, and electrons are also
purines [adenine and guanine]) and an passed to coenzyme Q10. Electrons then
inner light strand (predominantly py- flow to complex III, where proton pump-
rimidines [cytosine and thymine]). ing occurs, and onto complex IV, which
Bacterialike polycistronic replication is the terminal oxygen acceptor, and a
of mitochondria is triggered by cellu- final proton is pumped. The potential
lar signals sensed through a variety of energy from the reducing equivalents is
mechanisms (reactive oxygen species, created by the relatively impermeable
protein kinase, energy charge) that in- inner mitochondrial membrane leading
crease gene expression of a variety to a buildup of a proton motive force and 99
of nuclear-encoded mitochondrial pro- the development of a membrane poten-
teins and mitochondrial transcription tial ($ M). The accumulated protons in
factor A (mtTFA) under coregulation the intermembrane space flow through
with peroxisome proliferator-activated a dynamic turbinelike system at com-
receptor -coactivator-1 ( Wu et al, plex V (ATPase synthase) toward the ma-
1999). mtTFA binds to regulatory ele- trix and generate ATP, analogous to the
ments in the mitochondrial genome, potential energy from a waterfall cap-
initiating replication of mtDNA. mtDNA tured by a turbine.
encodes for seven subunits of complex I, mtDNA is maternally inherited, and
one subunit of complex III, three sub- both male and female offspring will in-
units of complex IV, and two subunits herit mtDNA from their mother. A
of complex V. Consequently, mtDNA unique aspect of mtDNA is a concept
encodes for a component of each of termed heteroplasmy, referring to the
the major enzyme complexes involved relative proportion of mutant to wild
Continuum Lifelong Learning Neurol 2009;15(6)

" MITOCHONDRIAL CYTOPATHIES
KEY POINT
type mitochondrial genomes within a of large-scale mtDNA deletions as the
A It is estimated
cell. For example, a mother with a spe- cause of Kearns-Sayre syndrome, a tran-
that the
minimal cific transition mutation (A>G) at posi- sition mutation (3243 A>G) as a cause
prevalence of tion 3243 in the mtDNA that was 30% for mitochondrial myopathy, encepha-
mitochondrial mutant and 70% wild type would pass on lopathy, lactic acidosis, and strokelike
cytopathies the 3243 mutation in varying ratios to her episodes (MELAS), and a transition mu-
is 1:6000 offspring and each child would have tation (11778 G>A) as a cause of Leber
individuals and different ratios in each tissue. The latter hereditary optic neuropathy (Holt et al,
this is likely process is called replicative segregation, 1988; Singh et al, 1989). Since these
to increase in which the heteroplasmy in the oocyte original descriptions, and with the abil-
as new genes undergoes expansion, contraction, and ity to rapidly sequence mtDNA, the
are being
random expansion in different tissues identification of pathogenic point muta-
discovered for
within the developing embryo and fetus tions in mtDNA has exploded in recent
phenotypes
not previously
after going through an embryologic years, with 165 rRNA/tRNA mutations
considered bottleneck. Consequently, the propor- reported on Mitomap (www.mitomap.
to be tion of mutant:wild type heteroplasmy in org/cgi-bin/tbl9gen.pl) and 194 reported
mitochondrial different tissues can vary from 99:1 to mutations in coding and control regions
in origin. 1:99. Higher levels of mutant hetero- (www.mitomap.org/cgi-bin/tbl8gen.pl).
plasmy are generally associated with Many of the mitochondrial disorder
more severe mitochondrial dysfunction; names have followed in the tradition
however, the percent of heteroplasmy of an acronym describing the clinical
that results in mitochondrial dysfunction phenotype (eg, IOSCA = infantile on-
is highly variable and mutation specific, set spino cerebellar ataxia, MERRF =
and consequently a set level of mutant myoclonus epilepsy and ragged red fi-
heteroplasmy cannot be uniformly as- bers; MILS = maternally inherited Leigh
cribed as the threshold. disease).
Any somatic or mtDNA gene muta- An increasing number of nuclear-
tion that leads to a breakdown in the encoded mitochondrial function and
complex and carefully orchestrated elec- structural genes are clearly associated
tron transport chain energy circuit can with mitochondrial cytopathies (www.
lead to a reduction in energy transduc- mitomap.org/rimtab5.html). Although
tion and have tissue-specific deleterious once considered rare, the incidence
consequences. To some extent, the clini- and prevalence of mitochondrial cyto-
cal symptoms of mitochondrial dysfunc- pathies is increasing dramatically be-
tion can be predicted from the relative cause of increased recognition of these
100 reliance of different tissues on aerobic conditions and the discovery of genes
energy transduction. The latter fact pro- responsible for the disorders. It is es-
vides some rationale for the frequent timated that the minimal prevalence of
involvement of the CNS (strokes, seizures, mitochondrial cytopathies is 1:6000 in-
developmental delay, blindness, hypo- dividuals (Chinnery et al, 2000; Schaefer
acusis) and muscle (weakness, fatigue) et al, 2008), and again this is likely to
as common symptoms of mitochondrial increase as new genes are being discov-
cytopathies. ered for phenotypes not previously
considered to be mitochondrial in origin
MITOCHONDRIAL DNA (eg, mfn2 resulting in Charcot-Marie-
MUTATIONS AND DISEASE Tooth disease type 2) (Züchner et al,
The explosion of knowledge in the area 2004).
of mitochondrial cytopathies and the The largest representation of nu-
emergence of mitochondrial medicine clear mutations directly affecting the
began in 1988 to 1989 with a discovery electron transport chain subunits are

KEY POINT
the complex I defects resulting in the optic atrophy and associated with
A A history
clinical picture of Leigh disease (Hoefs encephalopathy (Amati-Bonneau et al,
of fluctuating
et al, 2008; Lebon et al, 2007). Other 2008). Tafazzin gene mutations result in symptoms
autosomal recessively inherited muta- an X-linked condition associated with affecting
tions have been described in associa- cardiolipin defects causing Barth syn- multiple
tion with complex II subunit (SDHA) drome (noncompaction cardiomyopa- tissues or
and complex III subunit (UQCRB)- thy, 3-methylglutatonic aciduria, failure organs
associated Leigh disease. Autosomal to thrive), and mitofusin 2 (mfn2) gene should prompt
dominant mutations have been de- mutations result in an autosomal dom- consideration
scribed in the succinate dehydrogenase inant predominately axonal myopathy of a
(SDHB, C, D) gene, usually resulting called Charcot-Marie-Tooth disease type mitochondrial
cytopathy in
in paraganglionoma and pheochromo- 2 ( Verhoeven et al, 2006).
any age group.
cytoma (Astuti et al, 2001). A large num- It is likely that the number of nuclear
ber of mutations characterized to date genes responsible for mitochondrial dis-
affecting nonstructural nuclear genomes orders will increase dramatically in the
implicated mitochondrial disease. For years to come. A significant advantage
example, a number of genes have been derived from the discovery of nuclear
implicated in Leigh disease (SURF-1, gene mutations is the ability to provide
LRPPRC, COX15, and BCS1L) or cardio- accurate prenatal diagnosis and genetic
encephalomyopathy and hypertrophic counseling, as the transmission follows
cardiomyopathy (SCO2) and hypertro- mendelian genetics. Although prenatal
phic cardiomyopathy (COX10, COX15) counseling can be given for some of the
(Antonicka et al, 2003a; Antonicka et al, mtDNA mutations, such as maternally in-
2003b; Horvath et al, 2006; Jaksch et al, herited Leigh disease (MILS, 8993 T>C/G)
2001a). Mitochondrial genes implicated (Dahl et al, 2000; White et al, 1999), hetero-
in mtDNA stability represent the largest plasmic transmission from mother to child
group of nuclear mutations involved always leads to uncertainty regarding the
in mitochondrial cytopathy. The largest relative risk to the fetus of inheriting a
subgroup is the polymerase gamma (POLG) high proportion of mutated to wild type
mutations responsible for a variety of mitochondria. Some of the more com-
syndromes including Alpers syndrome mon mitochondrial disorders are sum-
(hepatic encephalomyopathy), chronic marized in Table 6-1.
progressive external ophthalmoplegia
(CPEO), spinocerebellar ataxia, and sen- MITOCHONDRIAL MYOPATHY
sory ataxic neuropathy with dysarthria
and ophthalmoplegia (SANDO). Other
DIAGNOSIS 101
stability factors including ANT1 and History
C10ORF2 (Twinkle) are associated with Given that the mitochondria are very im-
CPEO, and mutations in the ECGF1 (thy- portant in terminally differentiated tissues,
midine phosphorylase) gene result in a including brain, heart, and muscle, mito-
severe disorder called myoneurogastro- chondrial cytopathies commonly involve
intestinal encephalomyopathy (MNGIE). these tissues. Mitochondrial dysfunction in
Two genes implicated in maintenance of brain can result in developmental delay,
the deoxynucleotide triphosphate pool hypotonia, seizures, strokelike episodes,
include DGUOK and TK2, which result in visual loss, and hypoacusis. Involvement
hepatocerebral and myopathic mtDNA in skeletal muscle can lead to hypoto-
depletion syndrome, respectively. Genes nia in younger children with gross
affecting mitochondrial integrity include motor delay, while manifestations in
OPA1, which is a dynamin-related pro- older children, adolescents, and adults
tein resulting in autosomal dominant tend to include muscle weakness and

TABLE 6-1 Examples of Common Types of Mitochondrial Disorders in Children

and Adults
Disease Genetics Clinical Presentation/Features
MELAS 3423 A>G Infancy: rare (less than 1% of cases)

3271 T>C Childhood and adult: (variable pattern and age of onset)
encephalopathy, strokelike episodes, lactic acidosis, myopathy,
3260 A>G
cognitive decline, hypoacusis, type 2 diabetes, ataxia,
(Maternal) optic atrophy
MERRF 8344 A>G Childhood and adult: (variable pattern and age of onset)
generalized epilepsy (myoclonic and tonic-clonic),
8356 T>C
myoclonus, cognitive decline, hypoacusis, ataxia, optic
8363 G>A atrophy, head and neck lipomas, muscle
weakness/atrophy, neuropathy, psychiatric disorders
(Maternal)
Kearns-Sayre Deletion (1.3 kb–8.8 kb) Childhood and adult: progressive external ophthalmoplegia,
syndrome of mtDNA pigmentary retinopathy, and cardiac conduction block; can
also have early-onset cognitive decline, hypoacusis, ataxia,
(Often sporadic)
proximal muscle weakness, and multiple endocrinopathies
CPEO Deletions of mtDNA Adult: slowly progressive weakness of muscles involved in

horizontal eye movements and eyelid opening, resulting in
(AD and AR; polymerase
a progressive and symmetric external ophthalmoplegia with
gamma, Twinkle and ANT
bilateral ptosis
mutations; sporadic)
Leigh Complex I, II, IV, pyruvate Infancy and childhood: (often fatal at less than 5 years
disease dehydrogenase deficiency, of age) hypotonia failure to thrive due to poor feeding
8993 mutations and suck reflex, and recurrent vomiting; also noted are
psychomotor retardation, ophthalmoplegia, optic atrophy,
muscle weakness, spasticity, abnormal movements
(dystonia, chorea), and ataxia
MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF = myoclonic epilepsy
and ragged red fibers; CPEO = chronic progressive external ophthalmoplegia; mtDNA = mitochondrial DNA; AR = autosomal
recessive; AD = autosomal dominant.
102 exercise intolerance. Cardiac involve- testinal symptoms can be mild and
ment can manifest in infancy with nonspecific, including irritable bowel-
cyanosis and cardiac failure (SCO2 gene like symptoms and constipation in
mutations), contribute to exercise intol- MELAS syndrome and other mito-
erance at any age, and manifest as chondrial cytopathies, or can be more
cardiomyopathy later in life. Cardiomy- severe, including intestinal pseudo-
opathy is usually hypertrophic, but obstruction (MELAS syndrome) or severe
dilated forms or left ventricular non- gastrointestinal dysfunction (MNGIE
compaction can also occur (Scaglia et al, syndrome). Symptoms of peripheral
2004). Liver involvement is most com- neuropathy (numbness, tingling, dis-
monly seen with Alpers syndrome tal weakness) are seen frequently in
(POLG mutations) and mtDNA deple- MNGIE syndrome and may be misdiag-
tion due to dGUOK gene mutations nosed as Charcot-Marie-Tooth disease.
(Mandel et al, 2001; Naviaux et al, 1999; Numbness, tingling, and sensory ataxia
Naviaux and Nguyen, 2004). Gastroin- are common in SANDO syndrome seen

KEY POINT
with POLG and Twinkle gene muta- disease and do not mention them in
A Mitochondrial
tions (Gago et al, 2006; Hudson et al, the context of an ill child. Neurologic
dysfunction
2005). Psychiatric symptoms of demen- examination of both parents and all in the brain
tia (MELAS), depression (Twinkle), and siblings is always an important aspect of can result in
pervasive developmental symptoms, the family investigation. developmental
including autism, have been described. delay,
We have seen a number of patients with Blood and Urine Testing hypotonia,
adolescent-onset or later-onset psycho- An elevated serum lactate level raises seizures,
sis as part of the clinical manifestations the suspicion of mitochondrial cyto- strokelike
of mitochondrial disease (MELAS 3271, pathy; however, the sensitivity is only episodes,
MERRF 8363, Twinkle). approximately 60% (Tarnopolsky et al, visual loss, and
hypoacusis.
Ataxia is a common symptom in chil- 2003). Thus, a normal lactate level can-
Involvement
dren with Leigh disease and is particu- not be used to exclude mitochondrial
of skeletal
larly prominent in a syndrome termed cytopathy. An elevated lactate level is muscle can
infantile-onset spinocerebellar ataxia also not specific for mitochondrial dis- lead to
(IOSCA), and in mitochondrial reces- ease and can be seen in adults with type hypotonia/
sive ataxia syndrome (MIRAS). IOSCA 2 diabetes or if the individual has not motor delay
has been associated with mutations in been fasting. Lactate elevation in blood in children
Twinkle (Hakonen et al, 2007; Nikali is also very common in upset or and weakness/
et al, 2005), and MIRAS is usually as- struggling children who not only may exercise
sociated with mutations in the POLG have their arm held firmly (tourniquet intolerance in
gene (Hakonen et al, 2008). Both of effect), but who use excessive isomet- adolescents
these conditions lead to mtDNA deple- ric muscle contraction, leading to an and adults.
Cardiac
tion in the brain and liver with complex I increase in the generation of lactate
involvement
deficiency seen only in large neurons through anaerobic pathways. Finally,
can manifest
(Hakonen et al, 2008). accurate determination of lactate re- in infancy
The family history is also helpful in quires proper sample handling: samples with cyanosis
diagnosing mitochondrial myopathy. A must be collected and placed imme- and cardiac
strong maternal inheritance pattern is diately on ice (as red blood cells are failure (SCO2
suggestive of mtDNA mutation. Absence obligate anaerobes and thus will gen- mutations)
of maternal inheritance does not rule erate lactate unless their metabolism and as
out mitochondrial cytopathy. Nuclear is inhibited by cooling) followed by cardiomyopathy
inheritance patterns are represented prompt centrifugation. The lactate/ anytime later
in all types of mitochondrial cytopathy, pyruvate ratio can also be obtained in in life.
including autosomal recessive (NDUF-and CSF or in culture medium from tis-
SURF-1-associated Leigh disease, SCO2 sue culture where the absolute lactate 103
mutations, mtDNA depletion, MNGIE syn- level and the lactate/pyruvate ratio may
drome), autosomal dominant (OPA-1, be helpful in differentiating pyruvate
CMT2A2 [mfn2 gene], POLG- and ANT1- dehydrogenase deficiency from primary
associated CPEO, Twinkle-associated mitochondrial cytopathies.
SANDO and CPEO), and X-linked (PDHA1- Plasma amino acid profiles are help-
associated Leigh disease, Barth syndrome, ful in ruling out primary aminoacidopa-
and DDP gene mutations causing deafness thies and may show elevated alanine in
and dystonia). It is extremely important mitochondrial cytopathies. Serum crea-
to specifically ask for a history of deafness, tine kinase activity may be elevated in
short stature, early cardiac death, muscle some mitochondrial cytopathies, espe-
discomfort or exercise intolerance, or cially those with a myopathic presenta-
early-onset diabetes. Many families do tion; however, they cannot be used for
not appreciate these conditions as man- ruling in or ruling out mitochondrial
ifestations of inherited mitochondrial cytopathies. A very high level of creatine

KEY POINT
kinase in the absence of rhabdomyolysis drial cytopathy. A muscle biopsy can be
A A muscle biopsy
would, however, point one more toward obtained with a modified needle tech-
for suspected
mitochondrial primary dystrophy evaluation. Elevation nique or an open technique (Bourgeois
disease must of liver aminotransferase (alanine amino- and Tarnopolsky, 2004). Modifications
include transferase and aspartate aminotransfer- to needle biopsy tools have aided in the
microscopic ase) bilirubin, and glutamyl transferase ability to obtain adequate sample sizes
analysis (light can be seen in Alpers syndrome and for light and electron microscopic eval-
and electron) hepatic mtDNA depletion (dGUOK muta- uation as well as DNA and enzyme stud-
with two other tions). An early sign of Alpers syndrome ies. A needle biopsy can be obtained
pieces collected may be the elevation of -fetoprotein in less than 20 minutes in the clinic
into liquid (Robert Naviaux, MD, PhD; oral commu- from most people aged 12 or older; in
nitrogen or dry
nication, 2008), but high levels should younger children or young adults who
ice and stored
also prompt consideration of ataxia tel- are very anxious, a short propofol in-
at 808C for
enzyme and
angiectasia in children and/or an un- fusion (children) or lorazepam (young
molecular derlying tumor in children or adults. adults) is often required. Irrespective
or protein Specific testing for thymidine levels of whether an open or needle biopsy
analysis. showing massive elevations is character- technique is used, it is imperative that
istic of MNGIE syndrome. the sample be handled appropriately.
Urine analysis for organic acids can Muscle biopsies for suspected mito-
also be quite helpful with a pattern chondrial disease should be performed
showing 3-methylglutaconic acid and in a facility with a metabolic laboratory,
various TCA cycle intermediates (fuma- or at least with well-trained staff familiar
rate, malate) (Barshop, 2004). High levels with proper technique. In addition to
of isolated ethylmalonic acid should preparing a frozen section with an op-
prompt investigation into the ETHE1 timal cutting temperature embedding
gene responsible for encephalopathy. medium and placing a piece of tissue
High 3-methylglutaconic acid levels into chilled glutaraldehyde, another
should prompt investigation into tafazzin piece must be placed in liquid nitrogen
mutations responsible for Barth syn- or immediately on dry ice and trans-
drome. Cerebral folate deficiency has ported to the laboratory for enzyme as-
also been seen as a nonspecific con- sessment. A detailed description of all
sequence of mitochondrial cytopathy of the pathologic consequences of mi-
(Garcia-Cazorla et al, 2008; Pineda et al, tochondrial cytopathies is beyond the
2006). CSF studies are also helpful in scope of this chapter, and readers may
ruling out mitochondrial mimics such as refer to specific reviews (Bourgeois and
104 CSF neurotransmitter defects or disor- Tarnopolsky, 2004; DiMauro, 2006;
ders of CSF folate metabolism. In my ex- Moraes et al, 1992).
perience, approximately 10% to 13% of In general, alterations apparent on
the patients with mitochondrial cytopathy light microscopy are less prevalent in
have a coincidental deficiency of vitamin children than in adults. Specifically,
B12, red blood cell folate, or vitamin E in ragged red fibers (RRFs) tend to accu-
serum. Given that deficiencies in each of mulate with age. While the presence
these vitamins can cause neuropathy of RRFs is one of the classic patterns
and ataxia, it is prudent to check levels of mitochondrial disease (visualized on
in patients, particularly in teenagers in routine muscle histochemistry by the
whom diet may not be optimal. modified Gomori trichrome stain), RRFs
can be present in otherwise healthy
Muscle Biopsy older adults. RRFs often indicate a tRNA
A muscle biopsy is important in the defect in mtDNA. A uniform reduction
investigation of suspected mitochon- in cytochrome c oxidase (COX) staining

KEY POINT
can be seen in SCO2 deficiency (cardio- tions, and large mitochondria with
A A skin biopsy
myopathy, spinal muscular atrophy–like homogenous matrix staining with pau-
taken at the
syndrome) or SURF1 mutations (Leigh city of cristae can be seen in the mtDNA time of the
disease). COX-negative fibers are seen depletion syndrome (Bourgeois and muscle biopsy
in aging (older than 65 years), CPEO, Tarnopolsky, 2004). can be used for
MELAS, and MERFF syndrome and high- The electron transport chain enzyme fibroblast
light as ‘‘ragged blue’’ fibers when com- analysis is an essential component of analysis if
bined with succinate dehydrogenase the workup for suspected mitochon- muscle samples
(SDH) staining (see later discussion). drial disease. Skeletal muscle is an ideal are limited.
COX-negative RRFs are characteristic of tissue for sampling, given that histologic
MERFF, Kearns-Sayre syndrome, and analysis, heteroplasmy determinations
CPEO, while in MELAS the RRFs are for specific mutations and deletion/
COX positive. Other stains, including depletion analysis can also be done on
SDH and NADH, usually parallel the the sample. Some laboratories have
changes with Gomori trichrome, al- found that fibroblast analysis is helpful;
though the SDH stain is useful in high- however, the diagnostic yield in skeletal
lighting mitochondrial proliferation in muscle is usually higher. In spite of the
blood vessels, and strongly SDH-positive ongoing debate about fresh isolated
blood vessels are seen predominately mitochondrial preparations and frozen
in MELAS syndrome. muscle, the most important issue is
Electron microscopy is imperative that the enzyme analysis is done in an
in the evaluation of pediatric mito- experienced laboratory and that normal
chondrial cytopathies. Significant ab- reference ranges are available for that
normalities may not be apparent with specific laboratory. For frozen sample
any histologic stains, and changes such analysis, it is important that the tissue
as paracrystalline inclusions, pleomor- is frozen rapidly on dry ice or liquid
phism, and alterations of mitochondrial nitrogen and stored in either liquid
cristae structure may be very evident nitrogen or at less than 808C before
on electron microscopy without any analysis. Dr David Thorburn has exten-
histopathologic correlate. Although pa- sive experience with frozen tissue analy-
racrystalline inclusion is one of the hall- sis and has presented data showing long-
marks of mitochondrial dysfunction, it term (greater than 5 years) stability of
is more likely in older patients and may electron transport chain enzyme activ-
be absent in the pediatric age group. ity in a single large muscle sample kept
Paracrystalline inclusions represent up- at less than 808C (David Thorburn,
regulation of mitochondrial creatine ki- PhD; oral communication, 2006). The 105
nase for dimeric crystalline structures in complex V assay is the only one that
the presence of peroxynitrite (oxidative must be done on fresh mitochondria;
stress). These crystalline structures ac- however, this aspect of the analysis can
cumulate in the intermembrane space be performed from fibroblasts (it is
and disrupt the three-dimensional rela- suggested that one obtain a small skin
tionship between the inner and outer biopsy from the muscle biopsy site, place
mitochondrial membrane and alter con- the skin in sterile fibroblast culture
tact sites important for energy transduc- medium, and then grow the fibroblasts
tion. Paracrystalline inclusions can also for analysis). Furthermore, many of the
be seen in nonmitochondrial cytopa- conditions affecting complex V have
thies due to secondary mitochondrial characteristic features, and clinical suspi-
dysfunction (HIV medications, type 2 cion would lead to mutation analysis
diabetes). Markedly pleomorphic mi- of ATPase 6 and 8 genes in such cases
tochondria are seen in POLG muta- (eg, maternally inherited Leigh disease,

KEY POINT
neurogenic muscle weakness, ataxia, and (MRS) may be useful in the diagnosis of
A Exercise testing
retinitis pigmentosa). mitochondrial cytopathies. The princi-
may reveal a
low maximal An isolated complex I deficiency is ple of exercise testing is that a primary
oxygen the most common abnormality in pedi- mitochondrial disorder will generally
consumption atric enzyme assessment. In most cases reduce the maximal oxygen consump-
(V̇O2max) of isolated complex I deficiency, a tion per unit time ( V̇O2) of a person and
and/or a high definitive pathogenic mutation is often lower the V̇O2max during exercise and/or
respiratory not found. The exception is in a Leigh- increase the rate of lactate/CO2 produc-
exchange ratio. like presentation in which enzymatic tion ( high peak respiratory ratio during
Laboratories evidence of complex I deficiency is as- exercise). A variety of testing protocols
must establish sociated with an increasing number of available have been developed and vali-
their own
nuclear mutations (NDUF nuclear- dated in adults, and extensive details
normative data.
encoded complex I subunits). regarding principles and practice of ex-
Muscle biopsy results often guide ercise testing have been described else-
genetic investigations. A severe COX de- where (Taivassalo and Haller, 2005;
ficiency in a child with cardiomyopa- Tarnopolsky, 2004; Tarnopolsky and
thy or spinal muscular atrophy pattern Raha, 2005). Near-infrared spectroscopy
would be consistent with a SCO-2, SCO-1, evaluates the oxygenation/deoxygenation
or COX-15 mutation; and an isolated status of hemoglobin and myoglobin.
COX deficiency in a child with a Leigh- Consequently, the peripheral extraction
like presentation would be most consis- of oxygen by the mitochondria during
tent with a SURF-1 mutation. Global re- exercise normally leads to deoxygenation
ductions in many enzymes can be seen in but fails to do so in patients with
the mtDNA depletion syndromes, while mitochondrial disease (Taivassalo and
complex I and IV deficiencies are seen in Haller, 2005). A downside to the use of
the mtDNA-encoded tRNA mutations. exercise testing in children with mito-
Deletions in mtDNA can be seen in chondrial disease is that most children
a variety of conditions and be de- under 6 years of age cannot comply with
tected using long-range PCR or Southern testing or the equipment is not suitable
blotting. Large single deletions can be for them. Furthermore, children with cog-
seen in Kearns-Sayre syndrome or cases nitive issues and major neurologic impair-
of later-onset CPEO with and without ments, such as ataxia or spasticity, often
other neurologic features (CPEO plus). cannot complete exercise protocols.
Multiple deletions are often seen in The MRI evaluation of the brain is
POLG, Twinkle, ANT1, thymidine phos- extremely helpful in the diagnostic eval-
106 phorylase (ECGF1), or OPA1 mutations. uation of a child with suspected mito-
For most neurologists, the key to chondrial disease. The patterns of Leigh
diagnosis of a patient with suspected disease on MRI are fairly characteristic
mitochondrial disease rests on direct with high T2 signal in the basal ganglia
communication with the pathology de- ( primarily the putamen) and the brain-
partment staff member obtaining the stem as the more common findings
specimen, with the medical director of (Saneto et al, 2008; Savoiardo et al,
the mitochondrial laboratory, and with 2002), with progression to bilateral stria-
a metabolic genetics team. tal necrosis sometimes seen. A pattern of
strokelike lesions crossing vascular terri-
tories with a propensity for the occipital
Miscellaneous Tests cortex should prompt investigations for
A variety of other ancillary tests, includ- MELAS syndromes. Most patients with
ing exercise testing, near-infrared spec- mitochondrial encephalopathy, however,
troscopy, MRI, and MR spectroscopy have nonspecific periventricular white

KEY POINT
matter high signal on T2 and fluid- have clinical features that mimic mito-
A Leigh disease
attenuated inversion recovery imaging. chondrial disease (Rett syndrome, leuko-
often presents
MRS using proton (1H) spectroscopy can dystrophies [eg, metachromatic, Krabbe], before age 2
show elevated lactate in brain parenchy- chromosomal anomalies, etc), and we with
ma, particularly if the MRS voxel is placed have seen many children who have had psychomotor
in an area of involvement (basal ganglia abnormal mitochondrial electron trans- regression,
or abnormal white matter) (Sijens et al, port chain enzyme tests (especially com- optic atrophy,
2008). Importantly, a normal scan does plex I deficiency) in whom subsequent ophthalmoplegia,
not rule out mitochondrial disease, and testing confirmed an alternative diagnosis dystonia,
children with a previously normal scan (eg, Rett syndrome, Prader-Willi syn- spasticity, ataxia,
may demonstrate abnormalities only dur- drome, chromosomal deletion, congeni- and respiratory
changes. Most
ing acute decompensation. Phosphorus- tal muscular dystrophy).
children with
31 MRS ( 31P-MRS) can show a reduced
Leigh disease
brain phosphocreatine and/or a low SPECIFIC PEDIATRIC do not survive
phosphocreatine/inorganic phosphate MITOCHONDRIAL DISORDERS beyond age 5.
ratio. Comprehensive analyses of the
MRI and MRS findings associated with Leigh Disease
mitochondrial cytopathies have been Leigh disease was first described by
published (Farina et al, 2002; Muñoz Dennis Leigh in 1951 based on neuro-
et al, 1999; Saneto et al, 2008; Sijens et al, pathologic findings of cystic cavitation,
2008; Valanne et al, 1998). demyelination, vascular proliferation,
The diagnosis of mitochondrial dis- and neuronal loss predominately in the
orders is ultimately based on a compos- thalamus, brainstem, and posterior col-
ite of several tests, and sole reliance on a umns of the spinal cord in a child with
single test, such as electron transport a neurodegenerative disease (Morava
chain enzyme activities, can be mislead- et al, 2006; Vilarinho et al, 1997; Zhang
ing. Consequently, individuals have pro- et al, 2007). Leigh disease is a rapidly
posed several diagnostic criteria for progressive encephalopathy occurring
mitochondrial disease (Bernier et al, in infancy or childhood with a mean age
2002; Thorburn et al, 2004). It is clear of onset of approximately 2 years. Mani-
that the diagnostic criteria for each of festations include developmental delay
the aforementioned templates is influ- or psychomotor regression, optic atro-
enced by the strengths of the clinic/ phy, ophthalmoplegia, dystonia, tremor,
laboratory making the proposal; conse- spasticity, ataxia, and/or respiratory ab-
quently, it is important for a given normalities (apnea/hypopnea). The neu-
center to adopt the criteria that best fit rologic deterioration is often more 107
with the available testing methods. For apparent during periods of concurrent
example, if the local laboratory uses illness and other metabolic stressors.
frozen muscle for electron transport The progression of neurologic dysfunc-
chain assessment, it would not be useful tion can be rapid, with compromised
to use criteria based on isolated mito- respiratory status being the main in-
chondria from a fresh biopsy. Given the dication for intensive care admission.
treatment and counseling implications, Leigh disease is associated with com-
we have found it useful to use the labels plex I (approximately 35%), complex II
possible, probable, and definite mito- (approximately 5%), complex III (ap-
chondrial disease for these patients. It proximately 5%), complex IV (approxi-
is very important to entertain the pos- mately 20%), or pyruvate dehydrogenase
sibility of alternative diagnoses until arriv- (approximately 15%) deficiencies, and
ing at a definitive diagnosis. For example, mtDNA mutations (approximately 20%)
many pediatric neurologic disorders can (Berger et al, 2008; Kirby et al, 2003;

Schiff et al, 2006; Zhang et al, 2007; Zhu Cardiomyopathies

et al, 1998).
A muscle biopsy with electron trans- Cardiomyopathy is a common finding
port chain enzyme activity analysis is in pediatric and adult mitochondrial
helpful to target definitive mutational cytopathy, with a recent study showing
analysis (complex I = NDUF mutations, that 40% of children with mitochon-
mtDNA (10158 T>C, 10191 T>C, 11777 drial cytopathies had cardiomyopathy
C>A, 14459 G>A); complex IV = SURF-1, (Scaglia et al, 2004). Most patients had
LRPPRC). If the electron transport chain hypertrophic cardiomyopathy (58%),
enzyme activity for complexes I through 29% had dilated cardiomyopathy, and
IV are normal, pyruvate dehydrogenase 13% showed echocardiographic evi-
analysis should be considered, as should dence of left ventricular noncompac-
point mutation analysis for ATPase mutation. The diagnosis of cardiomyopathy
tions associated with Leigh disease in a child with mitochondrial cytopathy
(9176 T>G/C, 9185 T>C, 8993 T>C/G). implies a poor prognosis, with a survival
Specific mutation analysis is also very rate of only 18% by age 16. In contrast,
helpful from a genetic counseling and pre- children with mitochondrial cytopa-
natal diagnostic perspective (Case 6-1). thy manifesting solely with skeletal
Case 6-1
A 13-month-old boy presented with a 2-month history of decreased eating and falling off the
growth curve for weight, height, and head circumference. Developmental history indicated
that he started to cruise on furniture at 12 months but appeared weak, never attained the ability
to ambulate, and subsequently lost his ability to stand. Impaired swallowing necessitated a
percutaneous gastrostomy tube, which was associated with rapid weight gain and improved
neurologic function and alertness.
On neurologic examination, he was alert and demonstrated age-appropriate stranger anxiety.
He would look at his mother and father to command but did so by moving his head to gain visual
fixation. He was unable to initiate voluntary eye movements to an object of interest, consistent
with ocular motor apraxia. Motor examination demonstrated mild hypotonia and thin muscle
bulk. Muscle stretch reflexes were normal with no clonus, and the plantar response was flexor.
Serum lactate levels were mildly elevated on two of three blood draws (3.2 mmol/L and 2.8 mmol/L,
normal is less than 2.2 mmol/L). Cranial MRI demonstrated symmetric hyperintensity and increased
108 fluid-attenuated inversion recovery signal bilaterally in the brainstem, particularly in the ventral
aspect of the medulla. MRS demonstrated a lactate peak in the basal ganglia. Muscle biopsy
demonstrated COX enzyme activity less than 5% of normal. A diagnosis of complex IV deficiency
Leigh disease was confirmed by the finding of a homozygous SURF1 mutation 845-846 delCT
(Ser272cys). Parents were devastated by the diagnosis and then revealed that the mother was
10 weeks pregnant with their second child.
Comment. This case demonstrates the often ominous outcome in children presenting with
developmental regression. The nonspecificity of the weight loss and the absence of neurologic
symptoms until several months into the disease course diverted diagnostic attention initially
toward more of a gastrointestinal-focused investigation. The marked changes on MRI showing
much more extensive changes than are revealed by the clinical examination are a common feature
in patients with Leigh disease. Prenatal counseling for the family was offered. Optimism was very
high for prenatal diagnosis given that the SURF1 mutation is nuclear. At our institution we
have provided prenatal testing for previously documented Leigh disease–associated mutations in
three separate families and have had successful outcomes (not affected) in all three cases.

KEY POINT
myopathy experienced a survival rate by alomyopathic form and a hepato-
A Cardiomyopathy
age 16 of 95% (Scaglia et al, 2004). encephalopathic form. mtDNA deple-
may be a
Hypertrophic cardiomyopathy may tion is characterized by a reduction in subclinical
be the predominant and/or exclusive mtDNA copy number, and mutations comorbidity
feature in children with defects in COX have been demonstrated in the deoxy- in some
assembly, including SCO2, COX10, and guanosine kinase (dGUOK) gene in mitochondrial
COX15 mutations (Antonicka et al, patients with the hepato-encephalopathic disorders
2003a; Jaksch et al, 2001b). Most chil- form (Mandel et al, 2001), and thymi- (ie, MELAS)
dren with SCO2 deficiency also show dine kinase (TK2) in children with the or can be the
significant hypotonia owing to alpha encephalomyopathic form of mitochon- defining
drial depletion syndrome (Saada et al, feature (ie,
motor neuron involvement. These chil-
1555 A>G,
dren can be indistinguishable at onset 2001). These mutations interrupt the
3260 A>G,
from those with Werdnig-Hoffman dis- deoxyribose nucleotide pathway and
SCO2). Most
ease (spinal muscular atrophy type I). A inhibit incorporation of the deoxynu- cases of
major distinguishing feature between cleotide triphosphates into the mtDNA, cardiomyopathy
spinal muscular atrophy type 1 and resulting in mtDNA depletion. Muta- in mitochondrial
SCO2 mutations is presence of high tions in dGUOK are found in approxi- diseases are
lactate concentration in serum/plasma mately 10% to 15% of all patients with hypertrophic,
seen in SCO2. Most children with SCO2 the hepato-encephalopathic form of but dilated and
deficiency die before 2 years of age, and mtDNA depletion, and approximately noncompacted
20% of patients with the encephalo- forms of
many succumb in the first few months
myopathic form have TK2 mutations cardiomyopathy
of life ( Jaksch et al, 2001b). Cardiomy-
(Carrozzo et al, 2003; Mandel et al, 2001; may also occur.
opathy can be a part of the phenotype
in MELAS 3243 A>G or the predomi- Saada et al, 2001). More recently, mu-
nant symptom in other mtDNA muta- tations in POLG, Twinkle, and OPA1
tions (1555 A>G, 3260 A>G, 4295 and (Amati-Bonneau et al, 2008; Hakonen
4269 A>G, 4320 C>T, 4330 A>G, 8296 et al, 2007; Hudson et al, 2005; Hudson
A>G, 8363 G>A, 9997 T>C, and 15243 et al, 2008) have also been associated
G>A) (Case 6-2). Although conduc- with mtDNA depletion, and the clinical
tion disturbances can be seen in the features can overlap with TK2-associated
cardiomyopathies, patients rarely re- mtDNA depletion. The discovery of
quire pacemakers, although those with these specific mutations is helpful in
Kearns-Sayre syndrome often show pro- understanding pathogenesis of the syn-
gressive conduction block requiring pac- drome and for accurate genetic and pre-
natal counseling.
ing in the absence of cardiomyopathy.
The mtDNA depletion syndromes 109
A cardiomyopathy is often asymp-
tomatic and usually picked up as part often present in the first few months
of the workup in a child with sus- of life and frequently have a rapidly pro-
pected mitochondrial disease. Every gressive and fatal outcome. Significant
child with mitochondrial cytopathy clinical heterogeneity occurs for any
should be screened for cardiomy- given mutation. For example, mutations
opathy using echocardiography given in TK2 can present with encephalopathy
the opportunity for therapeutic inter- and hypotonia, and some can present
vention (ie, afterload reduction) and with a spinal muscular atrophy (lower
prognostication. motor neuron disease) picture (Mancuso
et al, 2002; Saada et al, 2001). The
dGUOK mutations usually present with
Mitochondrial DNA Depletion progressive hepatic failure, and POLG
mtDNA depletion syndromes are cat- mutations manifest with Alpers syn-
egorized into two groups: an enceph- drome (Mandel et al, 2001). In addition,

Case 6-2
An 8-year-old girl presented with shortness of breath on exertion and
cyanosis. Cardiovascular workup revealed a hypertrophic cardiomyopathy
with very low ejection fraction. In spite of afterload reduction, heart
failure worsened rapidly and she received a cardiac transplant. In the
postoperative period she was encephalopathic. Serum lactate levels rose to
over 20 mmol/L (normal is less than 2 mmol/L).
Pathologic examination of the native heart demonstrated mitochondrial
proliferation of pleomorphic mitochondria with paracrystalline inclusions.
Genetic analysis revealed a 3260 A>G transition mutation with high
heteroplasmy in heart tissue and skeletal muscle (mutant 90%).
Evaluation of family members revealed two siblings with lactic acidemia
(6 mmol/L to 8 mmol/L) and moderate to severe exercise intolerance.
The mother experienced exercise-induced deafness, had resting lactic
acidemia, and had suffered a severe strokelike episode at age 42. The
maternal grandmother died at age 42 with ‘‘encephalitis.’’ One maternal
uncle had severe migraines and exercise-induced rhabdomyolysis, a
maternal aunt also had migraines and had experienced a single strokelike
episode at age 38, and another aunt also had migraines. All children
born to the maternal aunts had lactic acidemia and exercise intolerance,
while the two children of the maternal uncle were asymptomatic and
had normal resting lactate levels.
The proband went on to develop multiple strokelike episodes with
incomplete neurologic recovery, seizures, and progressive emaciation.
She had a percutaneous gastrostomy tube placed and over the ensuing
year had marked improvement in neurologic function, gained 1.8 kg of
weight, had less abdominal pain, and increased exercise capacity with
activities of daily living.
Comment. The comprehensive family pedigree highlights the extreme
clinical heterogeneity that can arise from a single point mutation
(cardiomyopathy, strokelike episodes, seizures, hypoacusis, migraines,
exercise-induced rhabdomyolysis, and intestinal pseudo-obstruction).
Of particular relevance is the fact that it was not until the proband
presented with cardiac failure that the true nature of the familial disorder
was revealed. Migraines are a common neurologic disorder, and the
early onset of strokes was thought to be related to cholesterol or
110 blood pressure, although no family members were hypertensive or
hypercholesterolemic. Exercise-induced deafness was reported by the
mother to her family physician, who found her hearing to be normal at
rest and dismissed the symptom as odd, without further investigation.
This case also illustrates the clinical improvement that is often seen in
patients with mitochondrial cytopathy when adequate nutrition and
hydration are provided. In addition, such treatment ensures timely and
complete delivery of prescribed medications. Seizures were managed
with carbamazepine, as valproic acid is contraindicated in patients with
mitochondrial disease (valproic acid impairs mitochondrial carnitine
transport).
children can present with a renal Fanconi plegia. Occasionally, the disease can
syndrome, seizures, congestive heart fail- present with psychomotor regression
ure, and progressive external ophthalmo- and/or progressive weakness in childhood.

KEY POINT
mtDNA depletion is measured using onset can range from childhood to mid-
real time PCR for the copy number of
A mtDNA disorders
dle age (forties) and usually a progres-
are maternally
mtDNA relative to a nuclear DNA house- sive decline in function occurs. inherited and
keeping gene (eg, 18S). mtDNA deple- Leber hereditary optic neuropathy arise from
tion is very often tissue specific with (LHON) usually results in painless, ra- specific point
liver being the criterion standard for pidly progressive, visual loss with cen- mutations in
the hepato-encephalopathic form, and trocecal scotoma in teenagers or young either tRNA or
skeletal muscle showing depletion in adults. A marked sex difference is found, specific subunit
the encephalomyopathic form. with more men carrying the mutation regions of
developing symptoms (40% to 70%) as the mtDNA.
compared with women (20% to 30%). Mutations exist
Mitochondrial DNA Disorders The three common mutations (11778 in essentially
every region
mtDNA disorders are maternally in- G>A = 69%; 3460 G>A = 13%; and
of the mtDNA
herited and arise from specific point 14484 T>C = 13%) account for the with over 100
mutations in either tRNA or specific majority of cases. Some of the LHON specific point
subunit regions of the mtDNA. Muta- mutations can present with a multiple mutations now
tions exist in essentially every region of sclerosis–like syndrome, including the considered
the mtDNA with over 100 specific point most common 11778 G>A mutation pathogenic
mutations now considered pathogenic (Vanopdenbosch et al, 2000). Other and over 200
and over 200 more reported and await- LHON mutations have been associated more reported
ing confirmation. An updated list of all with dystonia, especially the 14459 G>A and awaiting
reported pathogenic and polymorphic mutation (Tarnopolsky et al, 2004). confirmation.
mtDNA sequence variants can be found Several other mtDNA mutations that
on Mitomap (www.mitomap.org/). In can present in the pediatric age group
general, more adults than children are include lethal infantile mitochondrial
identified with mtDNA point mutations. disorder (15923 A>G, 15924 A>G),
MELAS syndrome is the most com- complex I deficiency Leigh disease
mon of the mtDNA point mutations and (10191 T>C, 10158 T>C, 12706 T>C,
can show an extremely wide range of 13513 G>A, 14459 G>A), isolated
phenotypic manifestations, including myopathy (618 T>CC, 3250 T>C,
hypoacusis, ataxia, dementia, ophthal- 3302 A>G, 5521 G>A, 12320 A>G,
moplegia, encephalopathy, strokelike 15990 C>T), and exercise intolerance
episodes, exercise intolerance, proxi- (predominately cytochrome b muta-
mal myopathy, and type 2 diabetes. The tions such as 14846 G>A, 15059 G>A,
progression of MELAS can resemble 15084 G>A, and 15615 G>A) (www.
multiple sclerosis and be chronically mitomap.org/cgi-bin/tbl8gen.pl). 111
progressive or relapsing and remitting. Point mutations in the tRNA regions
The age at onset of symptoms is as of mtDNA often result in variable com-
variable as the clinical phenotypes with binations of electron transport chain
presentations starting in infancy and up enzyme activity reduction, whereas iso-
to adult age groups (Case 6-2). lated enzyme activity reductions can
MERRF can present as isolated myo- point to specific protein subunit DNA
clonic epilepsy with and without ataxia, regions (eg, complex I = ND subunits,
myopathy, peripheral neuropathy, and complex III = cytochrome b). Targeted
multiple lipomas ( particularly in the head PCR-restriction fragment length polymor-
and neck). In our experience, neuropsy- phism is the most common method used
chiatric manifestations, including severe to screen for the ‘‘common’’ mutations,
obsessive-compulsive disorder, depres- whereas exploratory analysis for new
sion, and psychotic features, as well as mutations can be done with DNA se-
type 2 diabetes, are common. The age of quencing, denaturing high-performance

KEY POINT
liquid chromatography, and sequencing be variably symptomatic or even asymp-
A Most POLG
microarrays. tomatic (Hirano et al, 1994). The age
mutations are
associated with of onset is usually in the early to late
Polymerase Gamma Mutations teenage years with progression of the
progressive
and Alpers Syndrome gastrointestinal problems leading to a
external
ophthalmoplegia The explosion of information regarding feeding tube and eventually total paren-
in adults, Alpers polymerase gamma mutations began tal nutritional requirement. The leuko-
syndrome, when Naviaux discovered low POLG dystrophy may become apparent during
myocerebro- activity in a child with fatal seizures, periods of concurrent illness in which
hepatopathy, hepatopathy, coma, and lactic acidosis a delirium/encephalopathic picture can
and other (Alpers syndrome) (Naviaux et al, 1999). appear. The evaluation of these patients
infantile
POLG is the sole polymerase for mtDNA will show variably elevated serum lac-
hepatocerebral
replication. The POLG protein has a tate levels and a demyelinating peripheral
syndromes
associated
polymerase domain, a linker region, and neuropathy, leukodystrophic changes on
with mtDNA an exonuclease domain. Close to 100 MRI, and often multiple mtDNA deletions
depletion in mutations have been reported in each of or depletion in skeletal muscle. The gene
children. the three main regions and have been responsible for this disorder is ECGF1,
listed in the Human DNA Polymerase which encodes thymidine phosphorylase
Gamma Database (http://tools.niehs. involved in the degradation pathway of
nih.gov/polg/). Most of the reported thymidine (Nishino et al, 1999). Patients
mutations have been associated with will show very elevated levels of plasma
progressive external ophthalmoplegia in thymidine, and white blood cell prepara-
adults, Alpers syndrome, myocerebro- tions can be used to demonstrate the
hepatopathy, and other infantile hep- reduced thymidine phosphorylase activ-
atocerebral syndromes associated with ity (Marti et al, 2004) (Case 6-4).
mtDNA depletion in children. Muta-
tions in the POLG gene have also been Miscellaneous Conditions
seen in children with Leigh disease, Kearns-Sayre syndrome is a multisystem
Charcot-Marie-Tooth neuropathy, MIRAS, mitochondrial disorder characterized
SANDO, and other ataxia-neuropathy by progressive external ophthalmople-
syndromes resembling Friedreich ataxia. gia, retinitis pigmentosa, hypoacusis,
A teenage-onset disorder with seizures, ataxia, myopathy, heart block, elevated
ataxia, headache, neuropathy, myoclo- CSF protein, and onset before the age
nus, and ophthalmoplegia with the of 25. These patients usually have high
A467T and W748S POLG mutations has lactate levels in plasma, and muscle
112 also been described (Tzoulis et al, 2006) biopsy shows RRFs, a variable reduction
(Case 6-3). Mutations in POLG result in in electron transport chain enzyme ac-
mtDNA depletion and sometimes dele- tivity, and a single large-scale deletion
tions (especially in adult-onset cases), (4,977 bp) in muscle (not white blood
but the ETC enzyme activity in skeletal cells) detected by long-range PCR or
muscle may be normal. Southern blot. The specific nuclear
gene responsible for this condition has
Myoneurogastrointestinal not yet been identified, and the diagno-
Encephalomyopathy Syndrome sis is based on the clinical and muscle
MNGIE is an autosomal recessive condi- biopsy features.
tion associated with severe abdominal Coenzyme Q10 (CoQ10) deficiency has
pain, malabsorption, and weight loss. been reported in a variety of clinical synd-
The associated peripheral neuropathy romes, including childhood-onset ataxia
may be the presenting feature, but the with cerebellar atrophy, encephalopa-
associated leukoencephalopathy may thy and seizures, encephalomyopathy,

Case 6-3
A 56-year-old man presented with a several-year history of feeling a bit off balance. He first noticed
this while playing soccer when he had difficulty turning suddenly and would bump into people.
He also had a difficult time suddenly trying to get out of the way of the ball when it was coming
at him. In the preceding 2 months he had noted some slurring of his words. He was fine otherwise
with a negative functional inquiry; his past history was positive for a three-vessel bypass in 1995
for atherosclerotic heart disease secondary to hypercholesterolemia. He had been on statin
medications for 14 years prior to presentation. He had no allergies, did not smoke, rarely consumed
ethanol, and worked in a university employee relations office. Family history revealed that his
mother had balance problems for as long as he could remember. One brother died from cancer at
age 65 and had no reported problems. Two other brothers were reportedly without symptoms.
His 29-year-old son and 31-year-old daughter had no neurologic symptoms. Examination showed
normal mental status, horizontal nystagmus, and scanning speech; cranial nerves were otherwise
normal. Motor examination showed normal bulk, power, and tone proximally and distally in
the upper and lower extremities. Muscle stretch reflexes were normal, and pathologic reflexes were
absent. Sensory examination was normal. Dysmetria was noted in both arms and legs. He could
not perform tandem gait. EMG and nerve conduction studies were normal. Amino acids, C-reactive
protein, autoimmune workup, antigliadin antibodies, aprataxin and SCA 1, 2, 3, 6, 7, 8, 17 gene
mutations, vitamin B12, red blood cell, folate, vitamin E, thyrotropin, and complete blood count
values were normal. Serum lactate was elevated at 3.0 mmol/L (normal is less than 2.2 mmol/L). Urine
organic acid showed a large elevation of 3-methylglutaconic acid and the moderate elevation of
ethylmalonic acid. Cranial MRI showed nonspecific high signal and periventricular white matter with
no cerebellar atrophy. Vastus lateralis muscle biopsy showed borderline type II fiber atrophy and
prominent lipid droplets on electron microscopy. Electron transport chain enzyme activities showed
a slight reduction in complex I + III relative to citrate synthase (8% ratio) with complex II + III, IV
normal and citrate synthase slightly high, indicative of mitochondrial proliferation. Point mutation
analysis from muscle-derived DNA was normal for MELAS 3243, 3271, NARPP 8993 and LHON 11778.
During the course of the workup, his brother reported similar symptoms when asked specifically
and was evaluated by a neurologist at another center who found similar clinical findings. Mutation
analysis revealed a 2243 G>C heterozygous mutation in POLG1 gene causing a Trp748Ser mutation
(W748S +/). The sequence variant was not found in either of the two asymptomatic children, and
his symptomatic brother was being screened for the mutation.
Comment. This case describes the value of muscle biopsy with enzyme workup as well as full
mitochondrial screening, including lactate and urine organic acids in atypical cases of ataxia.
Diagnosis can be elusive as highlighted by the relatively normal MRI and the absence of any
classic mitochondrial changes on muscle biopsy with histology and electron microscopy. Of
interest also is the fact that subsequent lactates have been normal (hence the value of three
lactates taken at different times in suspected cases of mitochondrial cytopathy). This also shows
113
that having a single allele mutation for the W748S mutation can lead to later-onset neurologic
symptoms, and previous reports have demonstrated ataxia and epilepsy in an adult (age 55)
positive for the W748S +/ mutation (Tzoulis et al, 2006). Several reports have documented
pediatric-onset seizures in ataxia with W748S homozygous state (Engelsen et al, 2008). This
also shows the value of ongoing follow-up in patients, for initially his brother was reported
to have no symptoms but after 1 year he clearly had identical symptoms.
cardiomyopathy and renal failure, and have been found in association with
isolated myopathy (Horvath et al, 2006; CoQ10 deficiency, including mitochondrial
Lamperti et al, 2003) CoQ10 is the electron parahydroxybenzoid-polyprenyltransferase
acceptor for complexes I and II and (CoQ2), APTX, CABC1, and prenyl (deca-
transfers electrons to complex III of the prenyl) diphosphate synthase subunit
electron transport chain. Several genes 2 gene (PDSS2) or PDSS1 (DiMauro et al,

Case 6-4
A 12-year-old boy presented with a several-month history of weakness and clumsiness. In
the preceding few months he had increasing problems tripping, stubbing his toe, and feeling
off balance. He also described some nausea and had lost approximately 0.91 kg over the same
time period. Examination revealed a thin boy with normal mental status and cranial nerve
examination. His muscles were generally thin with mild distal atrophy in the intrinsic foot
muscles and 4/5 weakness of dorsiflexion and eversion. He was areflexic in the upper and
lower extremities. Vibration sensation was reduced in the lower extremities, and pain and
temperature sensation were reduced in a stocking distribution.
Nerve conduction study confirmed a motor and sensory axonal neuropathy. Family history
was negative for confirmed mitochondrial disease, although his mother had absent ankle
reflexes, mild pes cavus, and borderline slowing of nerve conduction studies in the peroneal
nerve. Genetic testing for CMT1A and CMTX was negative.
Over the following 6 weeks, the patient continued to lose weight and developed persistent
abdominal pain, and his teachers noted that he had difficulty in maintaining concentration.
An MRI revealed confluent white matter high signal on T2-weighted images. Investigations
for common forms of leukodystrophy were negative, as were lactate, vitamin B12, and very
long-chain free fatty acids. A muscle biopsy of the vastus lateralis showed normal histology and
ultrastructure and no mtDNA deletions.
Plasma thymidine levels were markedly elevated (5.7, normal range less than 0.05 mol/L),
and thymidine phosphorylase activity in white blood cells was very low (50, normal range =
634 +/ 237 ng/h/mg protein). A diagnosis of MNGIE was confirmed with mutation analysis
showing homozygosity for the c.770 A>C, p.254 T>P mutation in the ECGF1 gene.
Over the ensuing 3 years he developed severe abdominal pain and gastroparesis requiring total
parenteral nutrition. His parents requested transfer of care to the pediatric facility, where he
received all care until he reached the age of 18. At age 18, he weighed 34 kg, was profoundly
weak in all four limbs, and was dependent for all aspects of care. He developed increasing
respiratory distress, confirmed to be pneumonia at his local emergency department. The pediatric
facility on-call physician, who was not familiar with the family, stated that the patient should
be admitted to the adult care hospital. The attending adult care physician told the family that
he had never even heard of MNGIE. The parents and the patient were frantic and called their
neurologist at home. He arranged compassionate admission to the pediatric care facility, where
the patient died from sepsis following a prolonged stay in the intensive care unit.
Comment. This case discussion highlights the characteristic picture of MNGIE syndrome, as well
as the diagnostic challenges. Of particular relevance are the issues faced in caring for a young
terminally ill adult with a rare pediatric-onset disease. Many pediatric facilities will extend their
114 age of care for patients with such disorders, but this care plan must be discussed prior to age
18 years, and letters documenting approval for admission as an adult must be in the medical
record as well as in the family’s possession. If admission for young adults is not permissible at
the pediatric facility, then transition of care should occur well before the 18th birthday to ensure
that the adult facility will have a comprehensive medical record that includes detailed plans of
care. The case also highlights the challenges in making a diagnosis of mitochondrial disorder,
because common tests such as lactate and muscle structure were normal.
2007; Lopez-Martin et al, 2007). This tration in skeletal muscle to below

condition is suspected when linked 50% of healthy controls. The impor-
muscle enzyme assays (I and III, and tance of making the diagnosis comes
II and III) show low activity, yet from the fact that some of the children
the individual components do not have shown a clinical response to very
show reductions and are confirmed high doses of CoQ10 (Lamperti et al,
by showing reduced CoQ10 concen- 2003).

KEY POINTS
Recently CPEO plus ataxia pheno- Cornstarch, however, is difficult to add
types and multiple sclerosis–like phe-
A Nutritional
to formula but can be mixed into baby
support for all
notypes have been described in adults foods. Care must be taken not to clog patients with
with mutations in OPA1 (Hudson et al, percutaneous endoscopic and gastro- mitochondrial
2008; Verny et al, 2008). OPA1 is a stomy tubes when using cornstarch, disease is
dynamin-related GTPase that is involved Polycose, or creatine monohydrate. A critical.
in mitochondrial maintenance (fission, high-fat diet may be of benefit in com- Gastrostomy
cristae organization). Although tradi- plex I deficiency, especially when severe tube placement
tionally associated with isolated optic seizures are a feature, given the poten- should be
atrophy (Alavi et al, 2007), several tial benefit from the ketosis. Since many considered
groups have described hypoacusis, ax- infants and children have limited exer- early in any
onal motor-sensory neuropathy, optic child or adult
cise capacity, energy expenditure can be
with weight
atrophy, progressive external ophthal- quite low and care must be taken to not
loss, as
moplegia, ataxia, and myopathy start- overfeed children and induce obesity, persistently
ing in childhood or young adulthood which can further impair mobility and inadequate
(Amati-Bonneau et al, 2008). The myop- lead to other chronic health care issues. caloric intake
athy is characterized by RRFs and COX- From an anesthetic perspective, one directly
ve fibers and multiple mtDNA deletions of the most important issues is to avoid compromises
(Amati-Bonneau et al, 2008). prolonged periods of fasting. The pro- residual
Several disorders have been asso- vision from 10% aqueous dextrose solu- mitochondrial
ciated with mutations in the BCS1L tion (D10W) and/or total parenteral function and
gene involved in complex III assembly nutrition is important to prevent a exacerbates
(Blazquez et al, 2009; Fellman et al, fasting-induced metabolic stress. It is neurologic and
2008; Hinson et al, 2007). In addition to multiorgan
also important to postpone any surgical
failure.
Leigh disease described earlier in this procedure during a period of even mi-
chapter, cases of growth retardation, nor concurrent illness. With respect to A In patients with
mitochondrial
amino aciduria, cholestasis, iron over- specific anesthetic agents, there does
disease, it is
load, lactic acidosis, early death (GRACILE not appear to be a particular predis- important to
syndrome), and Bjornstad syndrome position toward true malignant hyper- postpone any
(sensorineural hearing loss and pili torti) thermia in patients with mitochondrial surgical
have been reported (Hinson et al, 2007). cytopathy; however, malignant hyper- procedure
These conditions are all associated with thermia-like situations can arise with a during a
a reduced complex III activity and mu- metabolic crisis induced by additional period of
tations in the BCS1L gene. metabolic stress that then can mimic even minor
some aspects of malignant hyperther- concurrent
mia. It is important to maintain nor- illness. 115
TREATMENT OF mothermia throughout the anesthetic
MITOCHONDRIAL DISORDERS period to avoid an increase in shivering-
induced thermogenesis. For brief proce-
General Care Issues dures such as a needle muscle biopsy,
From a nutritional perspective, most EMG, or lumbar puncture we have found
children do not tolerate prolonged pe- that propofol and local anesthesia have
riods of fasting, and, in general, more been well tolerated without a single
frequent meals throughout the day are adverse reaction in several hundred pro-
preferable. In some cases, the addition cedures. Given that propofol only induces
of complex carbohydrates such as Poly- conscious sedation, we always use local
cose or cornstarch may be required. anesthesia, often with preapplication of a
Polycose is generally much easier to topical anaesthetic such as a eutectic
blend into food but does not have as mixture of local anesthetics (EMLA) cream
long a duration of action as cornstarch. 60 minutes before the procedure.

Peripheral neuropathy and other pain, cramps, and diarrhea predominate.

types of neurogenic pain can be a fea- These symptoms may be improved
ture of mitochondrial cytopathy, espe- with elemental diets or total parenteral
cially in MNGIE syndrome and SANDO. nutrition if necessary. Buscopcan may
Gabapentin is often well tolerated and be helpful in alleviating abdominal
one of the first-line therapies for neu- cramps and pain, and if excess gas pro-
ropathic pain; however, it is best to start duction is present, simethicone can be
gabapentin in the evening and gradually introduced. In a variety of other con-
titrate the dose to avoid somnolence. ditions ( particularly MELAS), severe
More recently, we have had success with constipation, in some cases leading to
pregabalin in patients who cannot tol- intestinal pseudo-obstruction, can be
erate gabapentin. We have also found seen. High-fluid and high-fiber intake is
that a combination of capsaicin cream the first-line therapy, followed by stool
and EMLA (50/50 mix) is often effective softeners, lactulose, glycerin supposito-
for mild to moderate dysesthesias from ries if no bowel movement occurs in
peripheral neuropathy and has the ad- 3 days. Mineral oil–based laxatives
vantage of being nonsystemic. should not be used because reflux, with
For severe spasticity, occupational the potential for aspiration, is quite
therapy and physiotherapy may help to common and can lead to serious chem-
prevent and treat contractures. Baclofen ical pneumonitis.
is a good first-line medication for spas- Psychological support is important
ticity, and in children with a seizure for patients with mitochondrial cytop-
disorder, benzodiazepines are quite help- athy and their families. A high degree
ful. Some patients may benefit from of anxiety and marital strife may occur
tizanidine with varying levels of suc- in families affected by maternally in-
cess. The use of dantrolene should be herited disorders, with individuals blam-
avoided in patients with mitochondrial ing themselves or their spouse for the
disorders because it can result in muscle condition. A high degree of stress in the
weakness and fatigue. In children with families of children with severe mito-
severe spasticity limiting hygiene or ac- chondrial cytopathy is also posed by the
tivities of daily living, botulinum toxin need for medical appointments, multi-
injections can be of benefit. ple hospitalizations, and the complexi-
Seizures are common in children with ties and intensity of care. Psychological
mitochondrial cytopathy. In general, and emotional support for the care-
standard anticonvulsants for the given givers is very important, and often peo-
116 seizure types should be employed albeit ple find comfort and support through a
with a few caveats. Valproic acid should group such as the United Mitochondrial
not be used except as a last resort be- Disease Foundation, which has a great
cause it may trigger Reye syndrome– deal of educational information (eg,
like hepatic dysfunction in children MITO 101: A Primer for Physicians
with mitochondrial cytopathy, most no- and Patients) and conducts a yearly
tably in children with POLG mutations conference for scientists, patients, and
(McFarland et al, 2008; Uusimaa et al, their families. As children get older and
2008). Topiramate is particularly sedat- gain insight into their disorder, depres-
ing in children with mitochondrial cy- sion and despair may develop, particu-
topathy but still can be used in selective larly in those who experienced the death
cases. from mitochondrial cytopathy of an
A number of patients experience gas- older sibling or other family members.
trointestinal problems particularly, with Early intervention with counseling and
MNGIE syndrome in which abdominal possibly antidepressant medications may

be of benefit. Some general suggestions
TABLE 6-2 General Principles of Treatment
for care are found in Table 6-2.
" Treat Underlying Neurologic Issues

Cofactors, Antioxidants, Seizures (antiepileptic drugs, avoid valproic acid).
and Drugs
Spasticity (baclofen, botulinum toxin [focal]; avoid
The rationale for treatment of mito- dantrolene if liver is involved).
chondrial disorders is derived from the
Dystonia (diazepam, botulinum toxin [focal],
pathologic consequences of the disease
trihexyphenidyl).
as described earlier in this chapter: (1)
Increase antioxidant capacity (vitamin Headache (acute: nonsteroidal anti-inflammatory
drugs and acetaminophen; avoid aspirin and triptans
E, vitamin C, CoQ10, -lipoic acid). (2)
in mitochondrial myopathy, encephalopathy, lactic
Enhance electron transport chain flux acidosis, and strokelike episodes [MELAS]; chronic:
and/or bypass a specific defect (succi- amitriptyline, calcium blockers, riboflavin, coenzyme
nate, CoQ10, riboflavin, and thiamine). Q10, -lipoic acid).
(3) Alternative energy sources such as " Identify and Treat Nutritional Deficiencies
creatine monohydrate increase intracel-
Growth curves are imperative to identify suboptimal
lular phosphocreatine stores with some
nutrition.
evidence of success in vivo and in vitro
(Hultman et al, 1996; Tarnopolsky et al, Identify and treat deficiencies in vitamins (vitamins A,
B12, E, D, folate for red blood cells), minerals (iron,
1997). (4) A high-fat diet may increase
zinc, selenium, calcium, magnesium), and protein
the flux through complex II in patients calorie (albumin, prealbumin).
with a complex I defect (Roef et al,
If children fall off growth curves and show signs or
2002), and a high-fat diet may also be
symptoms of undernutrition and do not respond
of some benefit in pyruvate dehydro- to a nutritionist’s suggestions, consider a feeding
genase mutations, particularly with tube (also helpful for medications and mitochondrial
difficult-to-control seizures, in which cocktail).
ketogenesis may be secondarily useful " Avoid Metabolic Stressors
as an antiseizure intervention. (5) Lev-
Extremes of heat and cold are not well tolerated.
ocarnitine is sometimes used because a
Fever should be treated with acetaminophen
secondary carnitine deficiency can oc- (10 mg/kg every 4 hours to 15 mg/kg every 4 hours).
cur in the absence of primary carnitine Shivering is metabolically expensive and should
deficiency. In general, most clinicians be avoided.
recommend a combination of several of Patients should avoid unaccustomed strenuous
the above-mentioned compounds as a exercise. They should not exercise in the fasted state
‘‘mitochondrial cocktail,’’ with the ra- or with a concomitant illness.
117
tionale of providing compounds that Avoid prolonged (greater than 12 hours) fasting.
target the final common pathways of
cellular dysfunction in mitochondrial
cytopathies (Tarnopolsky and Beal,
2001). A list of some of the treat-
ments and their doses is presented in c.dnJEKLNqFoG/b.4585961/k.C6AC/MITO_
Table 6-3. A more complete discussion 101.htm).
of each of these compounds can be Dichloroacetate has been proposed as
found in review papers (Murphy et al, a treatment for mitochondrial cytopa-
2008; Tarnopolsky, 2008; Tarnopolsky thies since it reduces serum lactate
and Raha, 2005) and in MITO-101: A concentrations by activating the pyruvate
Primer for Physicians and Patients dehydrogenase complex. Several trials
links from the United Mitochondrial Di- have been completed; however, the
sease Foundation (www.umdf.org/site/ overall efficacy has not been dramatic,

TABLE 6-3 Examples of Commonly Used Vitamins, Cofactors, and

Other Nutraceuticals
Medication Mechanism of Action Dose Range
Coenzyme Q10 Bypass complexes I and II 5 mg/kg/d to 10 mg/kg/d

Coenzyme Q10 (Coenzyme Q10 deficiency) 75 mg/kg/d to 150 mg/kg/d
Creatine Energy source, neuroprotection 100 mg/kg/d
monohydrate
Thiamine Pyruvate dehydrogenase 3 mg/kg/d to 9 mg/kg/d
cofactor
Riboflavin Bypass complex I defects 3 mg/kg/d to 5 mg/kg/d
Vitamin E Antioxidant 5 mg/kg/d to 10 mg/kg/d
Vitamin C Antioxidant 7 mg/kg/d to 15 mg/kg/d
Levocarnitine Treating secondary deficiencies 30 mg/kg/d to 50 mg/kg/d
Succinate Bypass complex I defects 30 mg/kg/d to 70 mg/kg/d
-Lipoic acid Antioxidant 5 mg/kg/d to 7 mg/kg/d
It is important to start with a single compound at the lower end of the dosing range for
a few days and to add in a new compound one at a time, titrating the dose to the
desired effect as tolerated. The main side effect with all of the above medications is
gastrointestinal upset, which can often be treated by dividing the dose into a 2-times-per-
day or 3-times-per-day dosing regimen and taking the medication with meals. Liquid or
hydrosoluble forms of coenzyme Q10 appear to be better absorbed than powdered cap-
sule forms.
and one of the side effects is the de- a complete mitochondrial cocktail strate-
velopment of peripheral neuropathy gy capable of targeting multiple final
(Kaufmann et al, 2006). Our approach common pathways of cellular dysfunction
has been to use dichloroacetate in cases induced by mitochondrial disorders. The
of acute metabolic crisis for short periods difficulty, however, will be to evaluate the
of time, only when serum lactate concen- infinite possible combinations in a het-
trations are elevated above 10 mmol/L. erogeneous group of individuals, using
118 In summary, most of the constituents a prospective randomized double-blind
of the mitochondrial cocktail are based methodology. The development of ani-
on biological rationale (Tarnopolsky and mal models of mitochondrial disease will
Beal, 2001), and many of the components certainly be useful in identifying combi-
have been well tolerated (Haas, 2007; nation therapies for mitochondrial cyto-
Mahoney et al, 2002; Matthews et al, 1993; pathies to advance the development of
Rodriguez et al, 2007). As single agents, clinical studies (Torraco et al, 2009; Wenz
CoQ10 and creatine monohydrate proba- et al, 2009).
bly have been most extensively investi-
gated (Haas, 2007; Klopstock et al, 2000; Other Therapies
Tarnopolsky et al, 1997), and, on balance, No genetic therapies for mitochon-
there does appear to be some degree of drial cytopathies are currently available,
efficacy when the two are combined with although in vitro approaches using
-lipoic acid (Rodriguez et al, 2007). mutation-specific peptide nucleic acids
Further studies are required to develop for mtDNA mutations and deletions have

KEY POINT
shown some promise (Taylor et al, 1997). progressive increases in activity, the
A Exercise has been
With an increasing recognition of nuclear threshold for the onset of these symp-
demonstrated
DNA mutations, the potential for viral toms is increased, and most people are to be of
vector and other DNA-based strategies as better able to tolerate activities of daily benefit in
well as possible short interfering RNA living without adverse affects. We usu- mitochondrial
strategies may be greater in the future. ally advise that they do not perform any cytopathies,
Both endurance and resistance exer- vigorous physical activity if they are with endurance
cise has also been demonstrated to be experiencing a migraine headache or and resistance
of benefit in mitochondrial cytopath- have a concurrent illness such as an types of
ies in adults (Taivassalo et al, 2006; upper respiratory tract infection. Activi- exercise
Taivassalo and Haller, 2005). At the ties such as tai chi, karate, and ballet are showing
evidence of
genetic level, the sporadic mitochon- particularly helpful in children with
efficacy.
drial mutation may be more amenable dyscoordination and/or ataxia.
to therapy for exercise-induced muscle In summary, the diagnosis, treatment,
damage and can activate satellite cells and long-term care of patients with
that often show no or very low levels mitochondrial cytopathies is extremely
of mutational burden. The activation complicated and requires a dedicated
of the satellite cells results in mtDNA team of specialists, including physi-
‘‘shifting,’’ which can reduce the per- cians (geneticists, neurologists, pulmo-
centage of mutant heteroplasmy in the nologists, cardiologists, physiatrists, gas-
skeletal muscle (Murphy et al, 2008; troenterologists, psychiatrists), nurses,
Taivassalo et al, 1999). The difficulty social workers, occupational and physi-
with exercise in the pediatric popula- cal therapists, genetic counselors, and
tion is that compliance and accessibility specifically trained nutritionists, in order
to appropriate exercise methods are to deal with all of the complexities of
challenging. In general, we recommend mitochondrial cytopathies. The age of
that children be as active as possible in onset of the mitochondrial cytopathies
school-based and play-based activities, can range from infancy to adults older
provided that they work within their than 65 years, with considerable clinical
limit and not push to the point where and genetic heterogeneity. A patient
they get nausea, vomiting, or encepha- who presents with neurologic symp-
lopathic features. We have had several toms commonly seen in mitochondrial
patients who have experienced vertigo, cytopathies (eg, ptosis, ophthalmople-
nausea, vomiting, and even exercise- gia, hypoacusis, optic atrophy, muscle
induced deafness with overexertion. fatigue) or shows evidence of both
For these reasons, we advise people to neurologic and other systemic involve- 119
‘‘listen to their body’’ and progress ment should be investigated for the
slowly and cautiously. With careful and possibility of a mitochondrial cytopathy.
REFERENCES
Alavi MV, Bette S, Schimpf S, et al. A splice site mutation in the murine Opa1 gene
features pathology of autosomal dominant optic atrophy. Brain 2007;130(pt 4):
1029–1042.
Amati-Bonneau P, Valentino ML, Reynier P, et al. OPA1 mutations induce mitochondrial

DNA instability and optic atrophy ‘plus’ phenotypes. Brain 2008;131(pt 2):338–351.

Antonicka H, Leary SC, Guercin GH, et al. Mutations in COX10 result in a defect in
mitochondrial heme A biosynthesis and account for multiple, early-onset clinical
phenotypes associated with isolated COX deficiency. Hum Mol Genet 2003a;12(20):
2693–2702.
Antonicka H, Mattman A, Carlson CG, et al. Mutations in COX15 produce a defect in

the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic
cardiomyopathy. Am J Hum Genet 2003b;72(1):101–114.
Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase

subunit SDHB cause susceptibility to familial pheochromocytoma and to familial
paraganglioma. Am J Hum Genet 2001;69(1):49–54.
Barshop BA. Metabolomic approaches to mitochondrial disease: correlation of urine

organic acids. Mitochondrion 2004;4(5–6):521–527.
Berger I, Hershkovitz E, Shaag A, et al. Mitochondrial complex I deficiency caused by

a deleterious NDUFA11 mutation. Ann Neurol 2008;63(3):405–408.
Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders
in adults and children. Neurology 2002;59(9):1406–1411.
Blazquez A, Gil-Borlado MC, Morán M, et al. Infantile mitochondrial encephalomyopathy

with unusual phenotype caused by a novel BCS1L mutation in an isolated
complex III-deficient patient. Neuromuscul Disord 2009;19(2):143–146.
Bourgeois JM, Tarnopolsky MA. Pathology of skeletal muscle in mitochondrial disorders.

Mitochondrion 2004;4(5–6):441–452.
Carrozzo R, Bornstein B, Lucioli S, et al. Mutation analysis in 16 patients with mtDNA

depletion. Hum Mutat 2003;21(4):453–454.
Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic
mitochondrial DNA mutations. Ann Neurol 2000;48(2):188–193.
Dahl HH, Thorburn DR, White SL. Towards reliable prenatal diagnosis of mtDNA point
mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults.
Hum Reprod 2000;15(suppl 2):246–255.
DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol 2006;18(6):636–641.
120 DiMauro S, Quinzii CM, Hirano M. Mutations in coenzyme Q10 biosynthetic genes.
J Clin Invest 2007;117(3):587–589.
Engelsen BA, Tzoulis C, Karlsen B, et al. POLG1 mutations cause a syndromic epilepsy
with occipital lobe predilection. Brain 2008;131(pt 3):818–828.
Farina L, Chiapparini L, Uziel G, et al. MR findings in Leigh syndrome with COX

deficiency and SURF-1 mutations. AJNR Am J Neuroradiol 2002;23(7):1095–1100.
Fellman V, Lemmelä S, Sajantila A, et al. Screening of BCS1L mutations in severe neonatal

disorders suspicious for mitochondrial cause. J Hum Genet 2008;53(6):554–558.
Gago MF, Rosas MJ, Guimarães J, et al. SANDO: two novel mutations in POLG1 gene.
Neuromuscul Disord 2006;16(8):507–509.

Garcia-Cazorla A, Quadros EV, Nascimento A, et al. Mitochondrial diseases associated
with cerebral folate deficiency. Neurology 2008;70(16):1360–1362.
Haas RH. The evidence basis for coenzyme Q therapy in oxidative phosphorylation
disease. Mitochondrion 2007;(suppl 7):136–145.
Hakonen AH, Goffart S, Marjavaara S, et al. Infantile-onset spinocerebellar ataxia and

mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect
and mtDNA depletion. Hum Mol Genet 2008;17(23):3822–3835.
Hakonen AH, Isohanni P, Paetau A, et al. Recessive Twinkle mutations in early onset
encephalopathy with mtDNA depletion. Brain 2007;130(pt 11):3032–3040.
Hinson JT, Fantin VR, Schönberger J, et al. Missense mutations in the BCS1L gene
as a cause of the Bjornstad syndrome. N Engl J Med 2007;356(8):809–819.
Hirano M, Silvestri G, Blake DM, et al. Mitochondrial neurogastrointestinal

encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an
autosomal recessive mitochondrial disorder. Neurology 1994;44(4):721–727.
Hoefs SJ, Dieteren CE, Distelmaier F, et al. NDUFA2 complex I mutation leads to Leigh
disease. Am J Hum Genet 2008;82(6):1306–1315.
Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in
patients with mitochondrial myopathies. Nature 1988;331(6158):717–719.
Horvath R, Schneiderat P, Schoser BG, et al. Coenzyme Q10 deficiency and isolated
myopathy. Neurology 2006;66(2):253–255.
Hudson G, Amati-Bonneau P, Blakely EL, et al. Mutation of OPA1 causes dominant optic
atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial
DNA deletions: a novel disorder of mtDNA maintenance. Brain 2008;131(pt 2):329–337.
Hudson G, Deschauer M, Busse K, et al. Sensory ataxic neuropathy due to a novel C10Orf2
mutation with probable germline mosaicism. Neurology 2005;64(2):371–373.
Hultman E, Söderlund K, Timmons JA, et al. Muscle creatine loading in men. J Appl
Physiol 1996;81(1):232–237.
Jaksch M, Horvath R, Horn N, et al. Homozygosity (E140K) in SCO2 causes delayed

infantile onset of cardiomyopathy and neuropathy. Neurology 2001a;57(8):1440–1446.
121
Jaksch M, Paret C, Stucka R, et al. Cytochrome c oxidase deficiency due to mutations
in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in
human myoblasts. Hum Mol Genet 2001b;10(26):3025–3035.
Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in

MELAS: a randomized, controlled clinical trial. Neurology 2006;66(3):324–330.
Kirby DM, Boneh A, Chow CW, et al. Low mutant load of mitochondrial DNA G13513A
mutation can cause Leigh’s disease. Ann Neurol 2003;54(4):473–478.
Klopstock T, Querner V, Schmidt F, et al. A placebo-controlled crossover trial of creatine in

mitochondrial diseases. Neurology 2000;55(11):1748–1751.
Lamperti C, Naini A, Hirano M, et al. Cerebellar ataxia and coenzyme Q10 deficiency.
Neurology 2003;60(7):1206–1208.

Lebon S, Rodriguez D, Bridoux D, et al. A novel mutation in the human complex I

NDUFS7 subunit associated with Leigh syndrome. Mol Genet Metab 2007;90(4):379–382.
Lopez-Martin JM, Salviati L, Trevisson E, et al. Missense mutation of the COQ2 gene
causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet
2007;16(9):1091–1097.
Mahoney DJ, Parise G, Tarnopolsky MA. Nutritional and exercise-based therapies in the
treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care 2002;5(6):619–629.
Mancuso M, Salviati L, Sacconi S, et al. Mitochondrial DNA depletion: mutations in

thymidine kinase gene with myopathy and SMA. Neurology 2002;59(8):1197–1202.
Mandel H, Szargel R, Labay V, et al. The deoxyguanosine kinase gene is mutated

in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 2001;29(3):
337–341.
Marti R, Spinazzola A, Tadesse S, et al. Definitive diagnosis of mitochondrial

neurogastrointestinal encephalomyopathy by biochemical assays. Clin Chem
2004;50(1):120–124.
Matthews PM, Ford B, Dandurand RJ, et al. Coenzyme Q10 with multiple vitamins is
generally ineffective in treatment of mitochondrial disease. Neurology 1993;43(5):
884–890.
McFarland R, Hudson G, Taylor RW, et al. Reversible valproate hepatotoxicity due

to mutations in mitochondrial DNA polymerase gamma (POLG1). Arch Dis Child
2008;93(2):151–153.
Moraes CT, Ricci E, Petruzzella V, et al. Molecular analysis of the muscle pathology
associated with mitochondrial DNA deletions. Nat Genet 1992;1(5):359–367.
Morava E, Rodenburg RJ, Hol F, et al. Clinical and biochemical characteristics in patients
with a high mutant load of the mitochondrial T8993G/C mutations. Am J Med Genet A
2006;140(8):863–868.
Muñoz A, Mateos F, Simón R, et al. Mitochondrial diseases in children: neuroradiological

and clinical features in 17 patients. Neuroradiology 1999;41(12):920–928.
Murphy JL, Blakely EL, Schaefer AM, et al. Resistance training in patients with single,
large-scale deletions of mitochondrial DNA. Brain 2008;131(pt 11):2832–2840.
122
Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and
mitochondrial DNA depletion. Ann Neurol 2004;55(5):706–712.
Naviaux RK, Nyhan WL, Barshop BA, et al. Mitochondrial DNA polymerase gamma
deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol
1999;45(1):54–58.
Nikali K, Suomalainen A, Saharinen J, et al. Infantile onset spinocerebellar ataxia is

caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol
Genet 2005;14(20):2981–2990.
Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE,

a human mitochondrial disorder. Science 1999;283(5402):689–692.

Pineda M, Ormazabal A, López-Gallardo E, et al. Cerebral folate deficiency and
leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol
2006;59(2):394–398.
Rodriguez MC, MacDonald JR, Mahoney DJ, et al. Beneficial effects of creatine, CoQ10,
and lipoic acid in mitochondrial disorders. Muscle Nerve 2007;35(2):235–242.
Roef MJ, de Meer K, Reijngoud DJ, et al. Triacylglycerol infusion improves exercise
endurance in patients with mitochondrial myopathy due to complex I deficiency.
Am J Clin Nutr 2002;75(2):237–244.
Saada A, Shaag A, Mandel H, et al. Mutant mitochondrial thymidine kinase in

mitochondrial DNA depletion myopathy. Nat Genet 2001;29(3):342–344.
Saneto RP, Friedman SD, Shaw DW, et al. Neuroimaging of mitochondrial disease.
Mitochondrion 2008;8(5–6):396–413.
Savoiardo M, Zeviani M, Uziel G, Farina L. MRI in Leigh syndrome with SURF1 gene
mutation. Ann Neurol 2002;51(1):138–139.
Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in
113 pediatric patients with mitochondrial disease. Pediatrics 2004;114(4):925–931.
Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease
in adults. Ann Neurol 2008;63(1):35–39.
Schiff M, Miné M, Brivet M, et al. Leigh’s disease due to a new mutation in the PDHX
gene [published erratum appears in Ann Neurol 2006;59(6):990]. Ann Neurol 2006;
59(4):709–714.
Sijens PE, Smit GP, Rödiger LA, et al. MR spectroscopy of the brain in Leigh syndrome.
Brain Dev 2008;30(9):579–583.
Singh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber’s
hereditary optic neuropathy. N Engl J Med 1989;320(20):1300–1305.
Taivassalo T, Fu K, Johns T, et al. Gene shifting: a novel therapy for mitochondrial

myopathy. Hum Mol Genet 1999;8(6):1047–1052.
Taivassalo T, Gardner JL, Taylor RW, et al. Endurance training and detraining in
mitochondrial myopathies due to single large-scale mtDNA deletions. Brain 2006;
129(pt 12):3391–3401. 123
Taivassalo T, Haller RG. Exercise and training in mitochondrial myopathies. Med Sci Sports
Exerc 2005;37(12):2094–2101.
Tarnopolsky M. Exercise testing as a diagnostic entity in mitochondrial myopathies.

Mitochondrion 2004;4(5–6):529–542.
Tarnopolsky M, Stevens L, MacDonald JR, et al. Diagnostic utility of a modified forearm

ischemic exercise test and technical issues relevant to exercise testing. Muscle Nerve
2003;27(3):359–366.
Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical

therapy in mitochondrial cytopathies. Adv Drug Deliv Rev 2008;60(13–14):1561–1567.

Tarnopolsky MA, Baker SK, Myint T, et al. Clinical variability in maternally inherited Leber
hereditary optic neuropathy with the G14459A mutation. Am J Med Genet A
2004;124A(4):372–376.
Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular
energy dysfunction in neurological disorders. Ann Neurol 2001;49(5):561–574.
Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance,

and treatment options. Med Sci Sports Exerc 2005;37(12):2086–2093.
Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine
monohydrate in patients with mitochondrial cytopathies. Muscle Nerve
1997;20(12):1502–1509.
Taylor RW, Chinnery PF, Turnbull DM, Lightowlers RN. Selective inhibition of mutant
human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet
1997;15(2):212–215.
Thorburn DR, Sugiana C, Salemi R, et al. Biochemical and molecular diagnosis of

mitochondrial respiratory chain disorders. Biochim Biophys Acta 2004;1659(2–3):121–128.
Torraco A, Diaz F, Vempati UD, Moraes CT. Mouse models of oxidative phosphorylation
defects: powerful tools to study the pathobiology of mitochondrial diseases. Biochim
Biophys Acta 2009;1793(1):171–180.
Tzoulis C, Engelsen BA, Telstad W, et al. The spectrum of clinical disease caused by the
A467T and W748S POLG mutations: a study of 26 cases. Brain 2006;129(pt 7):1685–1692.
Uusimaa J, Hinttala R, Rantala H, et al. Homozygous W748S mutation in the POLG1

gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia
2008;49(6):1038–1045.
Valanne L, Ketonen L, Majander A, et al. Neuroradiologic findings in children with

mitochondrial disorders. AJNR Am J Neuroradiol 1998;19(2):369–377.
Vanopdenbosch L, Dubois B, D’Hooghe MB, et al. Mitochondrial mutations of Leber’s

hereditary optic neuropathy: a risk factor for multiple sclerosis. J Neurol 2000;247(7):
535–543.
Verhoeven K, Claeys KG, Züchner S, et al. MFN2 mutation distribution

and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.
124 Brain 2006;129(pt 8):2093–2102.
Verny C, Loiseau D, Scherer C, et al. Multiple sclerosis-like disorder in OPA1-related

autosomal dominant optic atrophy. Neurology 2008;70(13 pt 2):1152–1153.
Vilarinho L, Maia C, Coelho T, et al. Heterogeneous presentation in Leigh syndrome.

J Inherit Metab Dis 1997;20(5):704–705.
Wenz T, Diaz F, Hernandez D, Moraes CT. Endurance exercise is protective for mice
with mitochondrial myopathy. J Appl Physiol 2009;106(5):1712–1719.
White SL, Collins VR, Wolfe R, et al. Genetic counseling and prenatal diagnosis for the
mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 1999;65(2):474–482.
Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis

and respiration through the thermogenic coactivator PGC-1. Cell 1999;98(1):115–124.

Zhang Y, Yang YL, Sun F, et al. Clinical and molecular survey in 124 Chinese patients with
Leigh or Leigh-like syndrome. J Inherit Metab Dis 2007;30(2):265.
Zhu Z, Yao J, Johns T, et al. SURF1, encoding a factor involved in the biogenesis of
cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998;20(4):337–343.
Züchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase

mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A [published erratum appears
in Nat Genet 2004;36(6):660]. Nat Genet 2004;36(5):449–451.
125

Mitochondrial Cytopathies in Children and Adults

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mitochondrial Cytopathies in Children and Adults

Uploaded by

Copyright:

Available Formats

KEY POINT

INTRODUCTION onset mitochondrial cytopathies are

Copyright # 2009, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 6-1 Examples of Common Types of Mitochondrial Disorders in Children

Disease Genetics Clinical Presentation/Features

MELAS 3423 A>G Infancy: rare (less than 1% of cases)

CPEO Deletions of mtDNA Adult: slowly progressive weakness of muscles involved in

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Schiff et al, 2006; Zhang et al, 2007; Zhu Cardiomyopathies

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

2007; Lopez-Martin et al, 2007). This tration in skeletal muscle to below

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Peripheral neuropathy and other pain, cramps, and diarrhea predominate.

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" Treat Underlying Neurologic Issues

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 6-3 Examples of Commonly Used Vitamins, Cofactors, and

Medication Mechanism of Action Dose Range

Coenzyme Q10 Bypass complexes I and II 5 mg/kg/d to 10 mg/kg/d

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Amati-Bonneau P, Valentino ML, Reynier P, et al. OPA1 mutations induce mitochondrial

Continuum Lifelong Learning Neurol 2009;15(6)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Antonicka H, Mattman A, Carlson CG, et al. Mutations in COX15 produce a defect in

Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase

Barshop BA. Metabolomic approaches to mitochondrial disease: correlation of urine

Berger I, Hershkovitz E, Shaag A, et al. Mitochondrial complex I deficiency caused by

Blazquez A, Gil-Borlado MC, Morán M, et al. Infantile mitochondrial encephalomyopathy