DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW

Peripheral neuropathy associated with mitochondrial disease in

children
MANOJ P MENEZES | ROBERT A OUVRIER

The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Correspondence to Dr Manoj Menezes at The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. E-mail: drmanojpm@yahoo.co.in

PUBLICATION DATA
Accepted for publication 27th January 2012.
Published online 21st March 2012.
ABBREVIATIONS
AHS Alpers–Huttenlocher syndrome
ANS Ataxia neuropathy spectrum
CMT Charcot–Marie–Tooth disease
LBSL Leukoencephalopathy with
brainstem and spinal cord
involvement and lactate elevation
MELAS Mitochondrial myopathy,
encephalopathy, lactic acidosis, and
stroke-like episodes
MNGIE Mitochondrial neurogastrointestinal
encephalopathy
NARP Neuropathy, ataxia, and retinitis
pigmentosa
SNAP Sensory nerve action potential
Mitochondrial diseases in children are often associated with a peripheral neuropathy but the
presence of the neuropathy is under-recognized because of the overwhelming involvement of the
central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their
clinical, neurophysiological, and histopathological characteristics. In this article, we provide a com-
prehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may
help with the identification of the mitochondrial syndrome. While it is not definite that the
characteristics of the neuropathy would help in directing genetic testing without the requirement
for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis
in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and
mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially
when associated with late-onset phenotypes, appear to cause a predominantly sensory
neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to
target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the
peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it
is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative
therapy. We therefore suggest that nerve conduction studies should be a part of the early
evaluation of children with suspected mitochondrial disease.

Mitochondria are subcellular organelles whose most impor-
tant function is oxidative phosphorylation for the generation
of cellular adenosine triphosphate (ATP). This is accom-
plished through four transmembrane respiratory chain com-
plexes that create an electron gradient between them to drive
the final complex (ATP synthase) to make ATP. The compo-
nents of the oxidative phosphorylation pathway are encoded
by mitochondrial DNA (mtDNA) or by nuclear genes, and
mutations in these genes may result in mitochondrial dis-
ease.1,2 Mitochondrial respiratory chain enzyme disorders
have a minimum birth prevalence of one in 7634 live births,
and the onset occurs in childhood in around half of affected
individuals.3 Because of the varied and overlapping clinical fea-
tures, the diagnosis usually requires respiratory chain enzyme
analysis on affected tissue. However, these tests are invasive
and not always abnormal or diagnostic.2
Mitochondrial diseases are often associated with peripheral
nerve dysfunction, and neuropathy in adults with mitochon-
drial disease has been well described.4,5 Although mitochon-
drial diseases in children are often associated with, and
occasionally present as, peripheral neuropathy, the presence of
a neuropathy is underrecognized because of the overwhelming
involvement of the CNS. Colomer et al.6 reported a peri-
pheral neuropathy in 37% of children with mitochondrial
disorders. These mitochondrial neuropathies are hetero-
geneous in their clinical, neurophysiological, and histopatho-
logical characteristics. In this article, we provide a
comprehensive review of childhood mitochondrial neuropa-
thy. While we have attempted to distinguish the peripheral
neuropathy caused by different nuclear and mtDNA muta-
tions, we have classified them according to the age at onset
and clinical phenotype in order to provide a diagnostically
useful guide to the clinician (Table I). These childhood mito-
chondrial neuropathies can also be classified according to
whether the neuropathy is a predominant part of the presenta-
tion (neuropathy, ataxia, and retinitis pigmentosa [NARP];
ataxia neuropathy spectrum [ANS] and sensory ataxic, neuro-
pathy, dysarthria, and ophthalmoparesis (SANDO); mito-
chondrial neurogastrointestinal encephalopathy [MNGIE];
Friedreich ataxia; Charcot–Marie–Tooth disease [CMT] asso-
ciated with MFN2 and GDAP1 mutations) or occurs as part of
a more complex phenotype (mitochondrial depletion syn-
dromes; MTP deficiency; Leigh syndrome; leukoencephalopathy
with brainstem and spinal cord involvement and lactate eleva-
tion [LBSL]; Kearns–Sayre syndrome; mitochondrial myopa-
thy, encephalopathy, lactic acidosis, and stroke-like episodes

ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press DOI: 10.1111/j.1469-8749.2012.04271.x 407

[MELAS]; myoclonic epilepsy with ragged red fibres
[MERRF]; Leber hereditary optic neuropathy).
MITOCHONDRIAL SYNDROMES WITH AN ONSET IN
INFANCY OR EARLY CHILDHOOD
Mitochondrial depletion syndromes
Mitochondrial DNA depletion syndromes are disorders of
oxidative phosphorylation characterized by a reduction in
mtDNA copy number in the affected tissues and caused by
mutations in genes associated with mitochondrial nucleotide
metabolism. Early-onset mitochondrial depletion syndromes
may be hepatocerebral (POLG1, PEO1, DGUOK, MPV17) or
encephalomyopathic (RRM2B, TK2, SUCLA2, SUCLG1).
Hepatocerebral mitochondrial depletion syndromes
Alpers–Huttenlocher syndrome. Alpers–Huttenlocher syn-
drome (AHS) is a hepatocerebral mtDNA depletion syn-
drome, often with infantile or early-childhood onset,
characterized by refractory seizures, psychomotor delay or
regression, and progressive liver dysfunction. AHS is most
commonly caused by recessive POLG1 mutations but muta-
tions in PEO1 have also been implicated. When seizures are
not a prominent feature and POLG1 and PEO1 sequencing
are negative, mutations in DGUOK and MPV17 should be
looked for.1
Table I: Classification of childhood mitochondrial neuropathy
Mitochondrial syndromes with an onset in infancy or early childhood
Mitochondrial depletion syndromes
Hepatocerebral MDS
POLG1, PEO1, DGUOK, MPV17
Encephalomyopathic MDS
SUCLA2
Complete MTP deficiency
Leigh syndrome
Various nuclear and mtDNA mutations including SURF1, MTATP6,
and PDHA1
NARP
LBSL
Kearns–Sayre syndrome
Mitochondrial syndromes with an onset in late childhood
MELAS
MERRF
Late-onset syndromes due to POLG1 (ANS, MEMSA, and arPEO)
MNGIE
Mitochondrial optic neuropathies
Leber hereditary optic neuropathy
Dominant optic atrophy (OPA1)
Friedreich ataxia
Mitochondrial neuropathies presenting as CMT
MFN2, GDAP1
MDS, mitochondrial depletion syndrome; MTP, mitochondrial
trifunctional protein; NARP, neuropathy, ataxia, and retinitis
pigmentosa; LBSL, leukoencephalopathy with brainstem and spinal
cord involvement and lactate elevation; MELAS, mitochondrial
myopathy, encephalopathy, lactic acidosis, and stroke-like episodes;
MERRF, myoclonic epilepsy with ragged red fibres; ANS, ataxia
neuropathy spectrum; MEMSA, myoclonus, epilepsy myopathy,
sensory ataxia; arPEO, autosomal recessive progressive external
ophthalmoplegia; MNGIE, mitochondrial neurogastrointestinal
encephalopathy; CMT, Charcot–Marie–Tooth disease.
408 Developmental Medicine & Child Neurology 2012, 54: 407–414
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What this paper adds
• A comprehensive review of the clinical, neurophysiological, and histopathologi-
cal characteristics of peripheral neuropathy in children with mitochondrial
disease.
• This is the first paper to describe the characteristics of the peripheral
neuropathy according to the underlying gene mutation.
POLG1. A peripheral neuropathy is only infrequently
described in children with AHS and AHS-like syndrome with
homozygous or compound heterozygous POLG1 mutations,
possibly because of overwhelming progressive encephalopathy,
hepatic failure, and early death.7–9
PEO1. Recessive mutations in PEO1, a gene that codes for
mitochondrial Twinkle helicase, result in two similar syn-
dromes: an early-onset encephalopathy resembling AHS with
symptom onset at around 6 months of age, and an infantile-
onset spinocerebellar ataxia with symptom onset at an average
age of 14 months.10 Reported with both homozygous and
compound heterozygous PEO1 mutations, the early-onset
syndrome is characterized by psychomotor regression, truncal
hypotonia, growth failure, ophthalmoparesis, epileptic
encephalopathy, lactic acidosis, and elevation of liver transam-
inases with mtDNA depletion in the brain and liver. Affected
children have an axonal sensory neuropathy with loss of large
myelinated fibres on sural nerve biopsy.10,11
Infantile-onset spinocerebellar ataxia is characterized by
ataxia, hypotonia, athetosis, hearing loss, ophthalmoplegia,
and predominantly sensory axonal neuropathy. The onset of
epilepsy is usually after the second decade of life. Children
with infantile-onset spinocerebellar ataxia experience loss of
touch, proprioception, and vibration sense with preserved pain
and temperature responses, and may develop distal weakness
and pes cavus.12 Sensory nerve action potentials (SNAPs) are
usually unrecordable by 5 to 15 years of age. The motor con-
duction velocities in the lower limbs are normal initially but
show a gradual decline in the second decade of life. The sural
nerve biopsy shows an axonal neuropathy with pronounced
loss of large myelinated fibres.13 MtDNA depletion is limited
to the brain in infantile-onset spinocerebellar ataxia.14 In both
syndromes, difficult micturition, urinary incontinence, consti-
pation, and dry eyes indicate the presence of an autonomic
neuropathy.10,12
DGUOK. Children with homozygous or compound hetero-
zygous DGUOK mutations have progressive liver failure and
variable neurological involvement. A sensorimotor neuropathy
was identified in two out of nine children in a case series of
children with DGUOK mutations.15
MPV17. Homozygous or compound heterozygous muta-
tions in the MPV17 gene have been described in affected chil-
dren with an infantile onset of progressive liver failure, ataxia,
hypotonia, dystonia, and psychomotor regression. Also
described as Navajo neurohepatopathy, the syndrome is char-
acterized by a severe sensorimotor neuropathy with severe
anaesthesia, corneal ulceration, painless fractures, acral mutila-
tion, and distal weakness. Nerve conduction studies show
reduced motor conduction velocities, with ulnar nerve con-
duction velocities of 28 to 36ms)1 reported in two individuals
aged 8 and 6 years. Sural nerve biopsies show complete loss of

myelinated fibres and degeneration and regeneration of unmy-
elinated fibres. MPV17 encodes for a protein located on the
inner mitochondrial membrane of unknown function.16–18
Encephalomyopathic mitochondrial depletion syndromes
SUCLA2. SUCL is a mitochondrial enzyme associated with
the Krebs cycle that catalyses the conversion of succinyl-CoA
to succinate. Individuals with recessive mutations in SUCLA2
and SUCLG1, genes encoding the b2 and a subunits of SUCL,
have an encephalomyopathy and mild methylmalonic aciduria
with mtDNA depletion in muscle and, to a lesser extent,
the liver.19 There are multiple reports of children with
homozygous or compound heterozygous SUCLA2 mutations,
but a peripheral neuropathy, particularly affecting the
lower limbs, has been described in only two children from an
inbred family from the Faroe Islands, while other affected
individuals in the family had normal nerve conduction
studies.20,21
Complete mitochondrial trifunctional protein (MTP)
deficiency
MTP is a multi-enzyme complex bound to the inner mitochon-
drial membrane that is involved in the b-oxidation of long-
chain fatty acids. Homozygous or compound heterozygous
mutations in the HADHA (encoding the a-subunit) or HADHB
(encoding the b-subunit) genes have been recognized in com-
plete mitochondrial trifunctional protein deficiency. Complete
MTP deficiency may present in an early-onset rapidly progres-
sive form with hypoketotic hypoglycaemia and cardiomyopa-
thy, with high mortality due to metabolic decompensation and
cardiac failure, or an insidious neuromyopathic form. In the
series described by den Boer et al.22, 11 of 14 children had a
peripheral neuropathy at diagnosis. In the later-onset neuro-
myopathic form, the chronic neuropathic weakness often
precedes episodes of recurrent myoglobinuria and can cause
distal weakness, foot deformity, and loss of ambulation.
Nerve conduction studies reveal an axonal sensorimotor
neuropathy.23
Leigh syndrome ⁄ neurogenic muscle weakness, ataxia, and
retinitis pigmentosa (NARP)
Leigh syndrome (subacute necrotizing encephalopathy) is a
clinically and genetically heterogeneous group of neurodegen-
erative disorders that have similar features on CNS imaging
and histopathology. The onset of symptoms is usually in
infancy or early childhood, and children may have progressive
psychomotor retardation, hypotonia, weakness, ataxia, optic
atrophy, ophthalmoplegia, nystagmus, dystonia, evidence of
brainstem dysfunction, and lactic acidosis.24 Neuroimaging
demonstrates high T2 signal, most frequently in the caudate
nucleus and putamen, but sometimes involving the thalamus,
periaqueductal grey matter, tegmentum, red nuclei, and den-
tate nuclei.25,26 A large number of different mitochondrial and
nuclear gene mutations have been reported in Leigh syn-
drome, of which SURF1 is the most common nuclear gene
involved and MTATP6 the most common mitochondrial
gene.24
14698749, 2012, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04271.x by CAPES, Wiley Online Library on [09/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
NARP syndrome is characterized by neuropathy, ataxia
with cerebellar atrophy on magnetic resonance imaging, and
pigmentary retinopathy with optic atrophy on ophthal-
mological examination. MTATP6 is the only gene reported
to be mutated in this syndrome, with the m.8993T>G
mutation being the most common, although m.8993T>C and
m.9185T>C mutations have also been described.27
SURF1. SURFEIT1 or SURF1 is the most commonly
mutated nuclear gene in Leigh syndrome with both homo-
zygous and compound heterozygous mutations being
reported.24 Two case reports of children with Leigh syndrome
(16mo and 3y of age) due to SURF1 mutations described a
demyelinating neuropathy with motor conduction velocities in
the median and peroneal nerves of 20 to 26.6ms)1.28,29 Sural
nerve biopsy in one child showed reduced myelinated fibres
with a complete absence of fibres of larger diameter and thin
myelin sheaths in the remaining fibres. Schwann cell mito-
chondria were enlarged with rounded cristae.29
MTATP6. In a small case series that included both children
and adults, the median age at onset of symptoms was 4 to
5 months for those with an m.8993T>G mutation compared
with 4 years for the m.8993T>C mutation. Around 30% of
individuals with m.8993T>G and m.8993T>C mutations in
MTATP6 were found to have a peripheral neuropathy.30 The
peripheral neuropathy presents with ataxia, pes cavus, and
absent ankle jerks. Diminished responses to pinprick and
vibration have been described. An axonal sensory neuropathy
is described in adults with the m.8993T>G mutation but
reports of well-characterized nerve conduction studies in
children with this mutation are lacking, probably because
of the earlier onset and prominent CNS involvement.31,32 An
axonal neuropathy has been reported in children and adults
with the m.8993T>C and m.9185T>C mutations. Sural
nerve biopsy shows active Wallerian degeneration of both
myelinated and unmyelinated fibres.33–36 Childs et al.37
described a family with the m.9185T>C mutation where
affected individuals had either an axonal or demyelinating
neuropathy, but nerve conduction velocities were not
reported.
PDHA1. The pyruvate dehydrogenase complex (PDHc) is a
multi-enzymatic complex with three catalytic subunits. PDHc
deficiency is most frequently caused by a deficit in the a
subunit of E1, due to mutations in the E1a subunit gene,
PDHA1.38 Affected children may present acutely with
weakness and motor regression. Symptoms and nerve con-
duction velocities may improve after treatment with thiamine
in deficiency of the PDHc E1 subunit, a thiamine pyro-
phosphate-dependent decarboxylase.39,40 Seven per cent of
reported cases with PDHc deficiency had an associated
peripheral neuropathy.38 PDHc deficiency is associated with
an axonal or mixed sensorimotor neuropathy, with normal or
mildly reduced motor conduction velocity (‡30ms)1), low
amplitude or absent SNAPs, and evidence of denervation dis-
tally on electromyography.40–45 The sural nerve biopsy usually
shows only a mild reduction in myelinated fibre density.42
Di Rocco et al.39 reported a 5-year-old male with a more
significant reduction in motor conduction velocity (19.8ms)1
Review 409

in the median nerve) which improved to 37.9ms)1 after treatment
with thiamine.
Leukoencephalopathy with brainstem and spinal cord
involvement and lactate elevation (LBSL)
LBSL is characterized by a childhood onset of slowly pro-
gressive cerebellar ataxia, spasticity due to pyramidal involve-
ment, and dorsal column dysfunction. Mild cognitive decline
is seen in some affected individuals. Magnetic resonance
imaging is characteristic and shows signal changes in the
cortical white matter and in specific tracts through the brain-
stem and spinal cord. LBSL occurs as a result of compound
heterozygous, and rarely homozygous, mutations in the
DARS2 gene that encodes mitochondrial aspartyl-transfer
RNA (tRNA) synthetase.46,47 A neuropathy, often subclinical,
is associated with LBSL, although it may be symptomatic
with pes cavus and distal weakness. Nerve conduction studies
show an axonal neuropathy with preserved or mildly reduced
SNAPs, reduced compound muscle action potentials, pre-
served or mildly reduced conduction velocities, and denerva-
tion in distal muscles on electromyography.48,49 Interestingly,
mutations in genes encoding cytoplasmic aminoacyl-tRNA
synthetases have been reported to cause CMT, of which only
KARS, a lysyl-tRNA synthetase, appears to have an additional
role in mitochondrial protein translation.50
Kearns–Sayre syndrome
Kearns–Sayre syndrome is a multisystem disorder caused by
single large deletions in mtDNA and characterized by retinitis
pigmentosa and progressive external ophthalmoplegia, devel-
oping before the age of 20 years. In addition, affected individ-
uals have at least one of the following: cardiac conduction
block, cerebrospinal fluid protein concentration >100mgdL)1,
or cerebellar ataxia. Cognitive impairment, sensorineural deaf-
ness, cardiomyopathy, short stature, endocrinopathies, and
dysphagia are associated features.2
Reports in adults with Kearns–Sayre syndrome document
either normal nerve conduction studies or an axonal peripheral
neuropathy.51,52 An axonal sensorimotor peripheral neuro-
pathy has been described in childhood with gait ataxia, glove–
stocking paraesthesia, distal weakness, and areflexia. The
muscle biopsy may show evidence of denervation with type 2
atrophy, and sural nerve biopsy in severe neuropathy shows
prominent endoneurial fibrosis with few remaining axons. In
sural nerve biopsies in adults, enlarged mitochondria with
abnormal cristae may be seen on electron microscopy in the
Schwann cells as well as in endoneurial capillaries and small
arterioles of the sural nerves.53–55
MITOCHONDRIAL SYNDROMES WITH AN ONSET IN
LATE CHILDHOOD
Mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes (MELAS)
While 80% of individuals with MELAS have the m.3243A>G
mutation in the mtDNA MT-TL1 gene, which encodes
mitochondrial tRNA for leucine, mutations in several other
mitochondrial genes have been described as causing this syn-
410 Developmental Medicine & Child Neurology 2012, 54: 407–414
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drome, which is characterized by stroke-like episodes with sei-
zures, intermittent episodes of encephalopathy, vomiting,
migraine-like headaches, ataxia, and cognitive impairment.2
Between 22% and 77% of adults with the m.3243A>G muta-
tion have neurophysiological evidence of a peripheral neuro-
pathy, which is predominantly axonal.56,57 Stickler et al.58
reported that children with MELAS commonly had a mixed
neuropathy.
Myoclonic epilepsy and ragged red fibres (MERRF)
Myoclonic epilepsy and ragged red fibres is caused most com-
monly by an m.8344A>G point mutation in the mtDNA
(MT-TK) gene, which encodes mitochondrial tRNA for lysine,
although mutations in several other mitochondrial genes can
be associated with this progressive neurodegenerative disorder
that is characterized by myoclonic seizures among other
seizure types, myopathy with ragged red fibres on muscle
biopsy, ataxia, optic atrophy, pyramidal signs, and hearing
loss.2 An axonal or mixed neuropathy is most commonly
reported in adults.59 Erol et al.60 reported a child with the
m.8344A>G mutation and combined central and peripheral
demyelination, with reduced motor conduction velocities
(31ms)1 in the peroneal and 41ms)1 in the median nerves) and
absent SNAPs.
Late-onset syndromes associated with POLG1 mutations
Homozygous or compound heterozygous mutations in
POLG1 have been identified as causing varied late-onset dis-
ease phenotypes that include: (1) ANS disorders including
mitochondrial recessive ataxia syndrome (MIRAS) and spino-
cerebellar ataxia and epilepsy (SCAE); (2) myoclonus, epilepsy
myopathy, sensory ataxic (MEMSA) and (3) autosomal reces-
sive progressive external ophthalmoplegia (arPEO) including
the sensory ataxic, neuropathy, dysarthria, and ophthalmo-
paresis (SANDO) syndrome.61 DNA polymerase-c is required
for the genetic stability of mtDNA, and its exonuclease
domain increases the fidelity of mtDNA replication by confer-
ring a proofreading activity on the enzyme.62
A peripheral neuropathy is commonly described as a com-
ponent of the clinical phenotype in a number of overlapping
syndromes including ANS, MEMSA, and arPEO.61,63–65
These syndromes with predominant ataxia and peripheral
neuropathy have an onset in late adolescence or adulthood,
whereas those with a prominent encephalopathy or hepa-
topathy usually have a much earlier onset in infancy or early
childhood.61,66,67 Older children and young adults with reces-
sive POLG1 mutations present with deterioration of gait and
progressive unsteadiness and demonstrate a loss of kinaes-
thetic and vibration sensation, positive Romberg sign, and
ataxia and areflexia on examination, consistent with a sensory
ataxic neuropathy. Nerve conduction studies show a predom-
inantly sensory axonal neuropathy. Sural nerve biopsy shows
loss of large and small myelinated and unmyelinated fibres.
Progressive ataxia due to a combination of cerebellar and sen-
sory deficits is seen in a majority of affected individuals and
results in significant disability and wheelchair depen-
dence.63,64

Mitochondrial neurogastrointestinal encephalomyopathy
(MNGIE)
MNGIE is caused by homozygous or compound hetero-
zygous mutations in the TYMP gene, which encodes thymi-
dine phosphorylase, and is associated with multiple deletions
and depletion of mtDNA in skeletal muscle.68–70 MNGIE is
characterized clinically by severe gastrointestinal dysmotility,
cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, and
leukoencephalopathy. The thymidine phosphorylase enzyme
catabolizes thymidine to thymine and 2-deoxy-D-ribose
1-phosphate. In individuals with MNGIE, reduced thymidine
phosphorylase activity alters deoxynucleoside and nucleotide
pools and consequently impairs mtDNA replication and
repair.71 Recently, mutations in RRM2B, a gene encoding
cytosolic p53-inducible ribonucleoside reductase small subunit
(RIR2B), have been described as causing the MNGIE-like
phenotype in an adult.72
The age at onset of symptoms is usually during the second
decade of life (median 18y), and individuals commonly present
initially with gastrointestinal symptoms, although a small num-
ber may have a peripheral neuropathy as the first symptom. All
affected individuals will ultimately develop a peripheral
neuropathy.71 Individuals with MNGIE often present with
numbness, paraesthesia, and a burning pain in their feet. Dete-
rioration in gait and hand weakness may also be presenting
symptoms or develop soon afterwards. Examination reveals dis-
tal weakness and atrophy, areflexia and sensory loss, including
pain and vibration, in a glove–stocking distribution.71,73–75
On nerve conduction studies, a demyelinating sensorimotor
neuropathy with reduced motor conduction velocities and low
amplitude or absent SNAPs is seen.73–75 Prolongation of
F-waves and presence of a conduction block may lead to a
misdiagnosis of chronic inflammatory demyelinating neuro-
pathy.73,75 Biopsies from the lumbar and brachial plexus show
lost or markedly attenuated myelin sheaths with comparatively
little axonal loss. Sural nerve biopsy shows thin myelin sheaths
around axons and axonal loss. While there may be no ultra-
structural mitochondrial abnormalities in the peripheral nerve
biopsy, the cytoplasm of ganglion cells on rectal biopsy may
show numerous megamitochondria with an expanded matrix
and reduced cristae.74,75 Sustained biochemical and clinical
improvement has been described after allogenic bone marrow
transplantation for MNGIE.76 It is recommended that
transplantation be carried out early in the disease course where
the potential for optimum recovery may be higher.77
MITOCHONDRIAL OPTIC NEUROPATHIES
Leber hereditary optic neuropathy (LHON)
LHON usually has an onset between 15 and 30 years of age
and is characterized by bilateral acute or subacute visual loss.
Ninety-five per cent of cases of LHON are caused by
m.3460G>A, m.11778G>A, and m.14484T>C mutations in
mtDNA. Cardiac arrhythmias, postural tremor, myopathy,
and movement disorder may be associated.78 A peripheral
neuropathy with mild to moderate reduction of motor con-
duction velocities may be seen in up to 20% of adults with
LHON but is often mild or subclinical.79,80
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Dominant optic atrophy (OPA1 gene)
Dominant mutations in OPA1, which encodes a dynamin-
related adenosine triphosphatase, are a common cause of auto-
somal dominant optic atrophy. Affected individuals present
with visual loss in the first two decades of life and have
dyschromatopsia, central or paracentral scotomas, and optic
disc pallor.78,81 Yu-Wai-Man et al.82 reported an axonal sen-
sory and ⁄ or motor neuropathy in 31 of 104 individuals with
OPA1 gene mutations. In this cohort, one-third of children
below 18 years of age had evidence of a neuropathy.
Friedreich ataxia
Friedreich ataxia is caused by hyperexpansion of GAA repeats
in the first intron of the FXN gene that codes for frataxin, a
protein that is a component of iron–sulphur clusters and is
involved in mitochondrial respiratory chain activity.83 Friedr-
eich ataxia is characterized by ataxia, sensory neuropathy,
muscle weakness, scoliosis, hypertrophic cardiomyopathy,
optic atrophy, sensorineural hearing loss, and diabetes.84
Although onset is commonly in the second decade, onset
before the age of 10 years is well described.85 Nerve conduc-
tion studies reveal an axonal sensory neuropathy with severely
reduced or absent SNAPs, and sural nerve biopsy shows loss
of myelinated fibres, particularly those of large diameter. The
severity corresponds to the size of the GAA repeat and does
not worsen with duration of the disease.86
MITOCHONDRIAL NEUROPATHIES PRESENTING AS
CHARCOT–MARIE–TOOTH DISEASE
The characteristics of the peripheral nerve disorders associated
with abnormalities of genes that are known to be important
for mitochondrial aggregation provide a framework to under-
stand peripheral nerve dysfunction in mitochondrial disease.
The coordinated action of the mitofusins, mfn1 and mfn2,
located on the outer mitochondrial membrane, and OPA1,
located on the inner mitochondrial membrane, is required for
mitochondrial fusion.87,88 Dominant mutations in the gene
encoding mitofusin 2 (MFN2), a large transmembrane
GTPase, are the most common cause of CMT type 2, an axo-
nal sensorimotor peripheral neuropathy.89 Some individuals
with MFN2 mutations have associated optic atrophy.90 Abnor-
mal small, round, and aggregated mitochondria have been
demonstrated on electron microscopy of sural nerve biopsies
of children with MFN2 mutations.91
Mutations in the ganglioside-induced differentiation-
associated protein 1 gene (GDAP1) are associated with both
axonal and demyelinating types of autosomal recessive CMT
(CMT4A), and are also a rare cause of autosomal dominant
axonal CMT (CMT2H ⁄ K).92,93 GDAP1 is located on the
outer mitochondrial membrane and is expressed by both
neurons and myelinating Schwann cells. It promotes mito-
chondrial fission and overexpression results in mitochondrial
fragmentation. Fibroblasts from individuals with GDAP1
mutations show reduced complex 1 activity, a fragmented
mitochondrial network, and abnormally large mitochondria.94
MFN2 and GDAP1 thus have opposing effects on mitochon-
dria and their equilibrium is necessary for normal mitochondrial
Review 411

dynamics.95 The clinical features and neurophysiological
abnormalities associated with these two mutations have been
well described and will not be discussed here.
CONCLUSION
Peripheral nervous system involvement has been described
with a number of mitochondrial syndromes and may be a sig-
nificant part of the presenting phenotype. However, the clini-
cal, neurophysiological, and histopathological characteristics
of these mitochondrial neuropathies are poorly described,
often only in the form of individual case reports and in mainly
adult cohorts. Early recognition of the associated neuropathy
(in NARP, ANS, MNGIE, and the optic neuropathies) may
help with the identification of the mitochondrial syndrome. It
is not definite that the characteristics of the neuropathy would
help in directing genetic testing without the requirement
for invasive skin, muscle, or liver biopsies in mitochondrial
syndromes in which a common phenotype is caused by differ-
ent mutations; however, there appears to be some evidence for
14698749, 2012, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04271.x by CAPES, Wiley Online Library on [09/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
this hypothesis in Leigh syndrome, where nuclear SURF1
mutations cause a demyelinating neuropathy while mtDNA
MTATP6 mutations cause an axonal neuropathy. POLG1
mutations, especially when associated with late-onset pheno-
types, appear to cause a predominantly sensory neuropathy
with prominent ataxia. The identification of the peripheral
neuropathy also helps to target genetic testing in the mito-
chondrial optic neuropathies. Although often subclinical, the
peripheral neuropathy may occasionally be symptomatic and
cause significant disability. Where symptomatic, recognition
of the neuropathy will help with the early institution of reha-
bilitative therapy. We therefore suggest that nerve conduction
studies should be a part of the early evaluation of children with
suspected mitochondrial disease.
ACKNOWLEDGEMENTS
The authors would like to thank Professor Carolyn Sue, Kolling
Institute of Medical Research, Sydney, Australia, for reviewing the
manuscript.

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