Seizure 21 (2012) 316–321

Contents lists available at SciVerse ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Review

Epilepsy in mitochondrial disorders

Josef Finsterer a,*, Sinda Zarrouk Mahjoub b
a
Danube University Krems, Krems, Austria
b
Genetics Laboratory, Research Unit ‘‘Genetics Epidemiology and Molecular’’ Faculty of Medicine Tunis, Tunisia

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: Information about epilepsy in mitochondrial disorders is scarce although a number or
Received 1 February 2012 syndromic and non-syndromic mitochondrial disorders frequently manifest with focal or generalized
Received in revised form 4 March 2012 seizures. Aim of the review was to describe epilepsy in syndromic and non-syndromic mitochondrial
Accepted 5 March 2012
disorders with epilepsy as a dominant or collateral feature of the phenotype.
Methods: Literature search via Pubmed using the key words ‘‘mitochondrial’’, ‘‘epilepsy’’, ‘‘seizures’’, and
Keywords: all acronyms of syndromic mitochondrial disorders.
Mitochondrial disorder
Results: Syndromic mitochondrial disorders obligatory associated with epilepsy include Alpers-
Epilepsy
Huttenlocher-syndrome (AHS), ataxia neuropathy spectrum (ANS), Leigh-syndrome, MELAS-syndrome,
Seizure
EEG myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA) syndrome, and MERRF-syndrome,
Central nervous system involvement Occasionally, epilepsy is a phenotypic feature in IOSCA, KSS, LHON, LBSL, or NARP, All types of seizures
Antiepileptic drugs occur but most frequently generalized tonic–clonic seizures, partial seizures, myoclonic jerks, or West-
syndrome was reported. Treatment of epilepsy in patients with mitochondrial disorders is not at variance
from epilepsy of other causes but mitochondrion-toxicity of various antiepileptic drugs, such as valproic
acid, carbamazepine etc. has to be considered to avoid severe complications or deterioration of the
underlying disease.
Conclusions: Epilepsy is a common phenotypic feature of syndromic as well as non-syndromic
mitochondrial disorders. Treatment of epilepsy in mitochondrial disorders is not at variance from
treatment of epilepsy due to other causes but mitochondrion-toxic drugs should be avoided.
ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction mitochondrial recessive ataxia syndrome (MIRAS) and sensory

The central nervous system (CNS) is the organ second most
frequently involved in mitochondrial disorders.1 Among the
various clinical CNS manifestations, such as stroke-like episodes,
movement disorders, hypopituitarism, cognitive dysfunction,
dementia, psychosis, transverse syndrome, or motor neuron
disease, epilepsy is one of the most frequent.2 This mini-review
focuses on the description of syndromic and non-syndromic
mitochondrial disorders in which epilepsy is a dominant (frequent
seizures) or collateral (rare seizures) feature of the phenotype.
2. Epilepsy in mitochondrial disorders
ataxia with neuropathy, dysarthria and ophthalmoparesis
(SANDO)-syndrome,3 Leigh-syndrome,5–7 mitochondrial enceph-
alopathy, lactacidosis and stroke-like episodes (MELAS)-syn-
drome,8,9 myoclonic epilepsy, myopathy and sensory ataxia
(MEMSA)-syndrome also known as spino-cerebellar ataxia with
epilepsy (SCAE),3 and myoclonic epilepsy with ragged-red fibers
(MERRF)-syndrome.10–12 Syndromic mitochondrial disorders with
rare seizures include infantile-onset spino-cerebellar ataxia
(IOSCA),13,14 Kearns-Sayre-syndrome (KSS),15,16 Leber’s hereditary
optic neuropathy (LHON),17 leucencephalopathy with brain stem
and spinal cord involvement and lactacidosis (LBSL)-syn-
drome,18,19 and neuropathy, ataxia and retinitis pigmentosa
(NARP)-syndrome,5,20

Epilepsy may be a phenotypic feature of syndromic as well as

3. Mitochondrial disorders with frequent seizures
non-syndromic mitochondrial disorders. Syndromic mitochondri-
al disorders with frequent seizures include Alpers-Huttenlocher-
3.1. AHS (Alpers-Huttenlocher-syndrome)
syndrome (AHS),3,4 ataxia-neuropathy spectrum (ANS) including

Alpers-Huttenlocher-syndrome (AHS), a fatal disorder of early

* Corresponding author at: Postfach 20, 1180 Vienna, Austria, Europe.
infancy, is clinically characterized by developmental delay of
Tel.: +43 1 71165 92085; fax: +43 1 4781711. variable severity, and early onset (<4 years of age) drug-resistant
E-mail address: fifigs1@yahoo.de (J. Finsterer). epilepsy, episodic psychomotor regression, and liver dysfunction

1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.seizure.2012.03.003
 J. Finsterer, S. Zarrouk Mahjoub / Seizure 21 (2012) 316–321
or liver failure following medication with antiepileptic drugs
(AEDs).3,21 AHS is due to POLG1 mutations causing mtDNA
depletion. Two children, who had developed refractory seizures
and myoclonic fits since age 20 and 60 days respectively, were
lastly diagnosed as AHS upon additional clinical features and
biochemical investigations revealing complex-IV (COX)-deficien-
cy.14 In the first case EEG showed low-amplitude, polyspikes,
polyspike-waves, and very slow waves of high amplitude
alternating with a trace of burst-suppression activity.14 In the
second case low-amplitude polyspikes, polyspike-waves, and
occasionally desynchronization of basal trace were recorded. In
the first case cortical blindness and severe hepatic failure
developed while receiving valproate.14 In a recent report about
a single patient drug-refractory status epilepticus could be
terminated only after functional hemispherectomy.22
3.2. ANS (ataxia neuropathy spectrum)
The ataxia neuropathy spectrum includes the mitochondrial
recessive ataxia-syndrome (MIRAS) and sensory ataxia, neuropa-
thy, dysarthria and ophthalmoplegia (SANDO)-syndrome.3 MIRAS
may manifest as childhood-onset encephalopathy with hepato-
pathy, juvenile-onset refractory epilepsy and migraine-like head-
ache, or as adult-onset ataxia and neuropathy.23 It is clinically
characterized by recessive ataxia, coordination deficits, dysarthria,
choreoathetosis, personality change, cognitive impairment, hemi-
anopsia, neuropathy, or epilepsy.24 MIRAS is most frequently due
to POLG1 mutations, such as the mutations p.748W>S in cis or
p.1143E>G.24
3.3. Leigh-syndrome
Leigh-syndrome is either due to mtDNA or nDNA mutations.
Leigh syndrome due to nDNA mutations is much more frequent
than due to mtDNA mutations. Leigh-syndrome due to mtDNA
mutations follows a maternal trait of inheritance. Maternally-
inherited Leigh syndrome is most frequently due to the mutation
m.8993T>G in the ATP6 gene.2,25 Leigh syndrome due to nDNA
mutations is phenotypically not at variance from Leigh-syndrome
due to mtDNA mutations.25 Also the typical, symmetric MRI
abnormalities are similar in both groups. Epilepsy is, among other
CNS abnormalities, a typical phenotypic feature of Leigh-syn-
drome.25 Most frequently these patients develop generalized
tonic–clonic seizures.26 Only rarely epilepsia partialis continua27
or West-syndrome (infantile spasms)28 have been reported.
Epilepsy was one of the main clinical manifestations in addition
to psychomotor retardation and quadruspasticity in a 5 months-
old child with Leigh-syndrome due to a missense mutation in the
SDHA gene.29 When comparing 5 patients with Leigh-syndrome
and West-syndrome with 7 patients with Leigh-syndrome but
without West-syndrome, it turned out that onset of Leigh-
syndrome was <10 months in all 5 patients with Leigh- and
West-syndrome and that infantile spasms developed in all five
patients after detection of Leigh-syndrome.7 There were indica-
tions that the development of West-syndrome was associated with
early-onset Leigh-syndrome, spasticity, nystagmus, apnea, poor
feeding, or cardiac involvement.7 West-syndrome did not influ-
ence the prognosis of Leigh-syndrome or vice versa.7 In a study on
5 patients with Leigh-syndrome and complex-I, complex-IV,
complex-V, pyruvate carboxylase, or pyruvate-dihydrogenase-
deficiency respectively, epilepsy was the initial manifestation in
two.9 Three patients had partial seizures, one patient generalized
tonic seizures, and one patient myoclonic seizures. Focal or
multifocal sharp waves in the occipital projection were recorded in
three patients. Only in one of these patients the EEG was indicative
of generalized epilepsy.9 A status epilepticus was reported in a
317
seven months-old girl with Leigh-syndrome, diagnosed upon
additional clinical features, such as developmental delay and
regression of achieved milestones, and typical features on MRI.30
In a single patient with juvenile-onset Leigh-syndrome due to
the mutation m.14487T>C epilepsy was one of the cardinal
phenotypic features in addition to optic atrophy, ataxia, and
dystonia.31 Epilepsy was also reported in a 17 months-old infant
with lethargy, anorexia, respiratory insufficiency, motor delay,
inappropriate secretion of antidiuretic hormone, and symmetrical
lesions in the cervical cord and lower brain stem.32 Leigh-
syndrome in this patient was due to the m.8344A>G mutation.
Generalized epilepsy was the initial clinical manifestation in a
12yo previously healthy Chinese boy carrying the transition
m.13513G>A who later developed loss of vision and quadruspas-
ticity.33 Epilepsy was also part of the phenotype in another patient
with maternally inherited Leigh-syndrome.6 Only few patients
with maternally inherited Leigh-syndrome predominantly present
with epilepsy but lack other typical phenotypic features of the
syndrome.5
3.4. MELAS (mitochondrial encephalopathy, lactacidosis and stroke-
like episodes)
MELAS is clinically characterized by stroke-like episodes,
encephalopathy, epilepsy, and lactacidosis.8 In 80% of the cases
MELAS is due to the transition m.3243A>G in the tRNA(Leu) gene.
MELAS may be associated with partial seizures or generalized
seizures, including status epilepticus.34 In a study on 31 patients
with a mitochondrial disorder and epilepsy, 5 were classified as
MELAS-syndrome.9 Seizure onset was between 14 and 39y of age
in these patients. Prior to onset of seizures, these patients had
developed stroke-like episodes (n = 3), migraine (n = 2), diabetes
(n = 2), or psychomotor delay (n = 2). Four patients had developed
partial seizures and one tonic–clonic seizures. EEG-recordings in
these patients showed diffuse slowing (n = 4), unilateral slowing
(n = 1), focal posterior sharp waves (n = 4), symmetrical sharp
waves (n = 2), or photosensitivity (n = 2).9 In other patients with
MELAS-syndrome recurrent complex partial seizures and non-
convulsive status epilepticus were reported.35 In patients who
carry the m.3243A>G mutation and predominantly manifest with
diabetes and deafness but variably develop additional phenotypic
features, epilepsy has been only rarely reported.36 In two German
families with maternally-inherited diabetes and deafness due to
the m.3243A>G mutation, some of the family members presented
with seizures, Parkinson’s disease, and endocrinopathies.36 In a
three-generation family carrying the m.3243A>G mutation,
generalized epilepsy with tonic–clonic seizures was a dominant
feature of the phenotype.37
3.5. MEMSA (myoclonic epilepsy, myopathy and sensory ataxia (SCAE
(spino-cerebellar ataxia with epilepsy)))
Myoclonic epilepsy, myopathy and sensory ataxia (MEMSA)
represents a disorder previously referred as spinocerebellar ataxia
with epilepsy (SCAE).3 MEMSA is most frequently due to POLG1
mutations.38 MEMSA is clinically characterized by ataxia, myo-
clonic epilepsy, and myopathy. Cerebellar ataxia is generally the
first sign beginning in early adulthood.3 Myopathy is the next
manifestation and may be distal or proximal, or may manifest
exclusively as exercise intolerance. Though the prevalence of
MEMSA is low, myoclonic epilepsy is an invariable feature of these
patients. Epilepsy develops in later years and begins often focally in
the upper limbs with secondary generalization.3 Seizures may be
refractory to conventional AED treatment, and even to anaesthesia.
Recurrent seizure activity is usually accompanied by progression
of the encephalopathy.3
318 J. Finsterer, S. Zarrouk Mahjoub / Seizure 21 (2012) 316–321
3.6. MERRF (myoclonic epilepsy with ragged-red fibers)
The main clinical manifestations of MERRF-syndrome include
ataxia, myopathy and myoclonic epilepsy.10,11 The mutation most
frequently causing MERRF-syndrome is the transition m.8344A>G.
Myoclonic epilepsy was also reported in a female carrying the
m.8363G>A mutation.12 Her daughter and half-sister were
affected by Leigh-syndrome and died both in early infancy.12 In
a study on 5 patients with MERRF-syndrome onset of epilepsy
ranged between 7 and 50y of age.9 Seizures were classified as
myoclonic (n = 5) or as tonic–clonic (n = 1). EEG showed diffuse
slowing (n = 2), focal posterior sharp waves (n = 1), polyspike-
waves (n = 3), or symmetric sharp waves with photosensitivity
(n = 1).9
4. Mitochondrial disorders with rare seizures
4.1. IOSCA (infantile-onset spino-cerebellar ataxia)
Infantile onset spinocerebellar ataxia is clinically characterized
by infantile-onset spino-cerebellar ataxia due to mutations in the
POLG1 gene.39 Infantile onset spinocerebellar ataxia is occasionally
associated with epilepsy. Particularly in the late stages of the
disease, myoclonic jerks and focal seizures have been reported.14
Among 19 Finnish patients with infantile-onset spinocerebellar
ataxia epilepsy was a late clinical manifestation of the disease.40
Epilepsy with tonic–clonic seizures was also a phenotypic feature
in other patients with infantile-onset spinocerebellar ataxia.13,40
4.2. KSS (Kearns-Sayre-syndrome)
KSS is clinically characterized by CPEO, pigmentary retinopa-
thy, cardiac conduction defects and variable additional phenotypic
manifestations. KSS is due to single large-scale mtDNA deletions.
Epilepsy is not a classical phenotypic manifestation of KSS but has
been observed in single patients. Long-term follow-up EEG-
recordings in KSS patients usually show only generalized slowing
of background activity.41 Generalized epilepsy since childhood was
reported in a 33yo patient with KSS.16 Partial and generalized
seizures were reported in a patient with incomplete KSS.15
4.3. LBSL (leucencephalopathy with brain stem and spinal cord
involvement and lactacidosis)
Leucencephalopathy with brain stem and spinal cord involve-
ment and lactacidosis (LBSL) is clinically characterized by slowly
progressive pyramidal, cerebellar, and dorsal column dysfunction,
and decreased vibration and position sense.42 Additional mani-
festations include mild mental impairment, slowly progressive
ataxia, spasticity, or neuropathy.18 LBSL is due to mutations in the
DARS2 gene encoding the mitochondrial aspartyl-tRNA syn-
tethase.18 LBSL has an infantile or juvenile onset and patients
become wheel-chair bound by their teens or twenties.19 Only
single patients develop epilepsy.19
4.4. LHON (Leber’s hereditary optic neuropathy)
Leber’s hereditary optic neuropathy (LHON) is clinically
characterized by severe central loss of vision and optic atrophy
most frequently affecting young men.17 Leber’s hereditary optic
neuropathy is most frequently due to one of the three primary
homoplasmic LHON mutations m.3460G>A, m.11778G>A, or
m.14484T>C in the ND1, ND4, or ND6 gene respectively.6
Occasionally, patients may develop extra-ocular manifestations
such as migraine, mental retardation, or epilepsy (LHON plus).17 In
some of these patients epilepsy may even precede the onset of
ocular manifestations.43 Occasionally, epilepsy may be the
dominant manifestation of the disease and may be refractory to
AED treatment.44
4.5. NARP (neuropathy, ataxia and retinitis pigmentosa)
NARP syndrome is clinically characterized by neuropathy,
ataxia and retinitis pigmentosa. The mutation most frequently
responsible for the phenotype is the transition m.8993T>G in the
ATP6 gene.45 Epilepsy with severe seizures is particularly reported
in early-onset forms of the disease but is rare in cases with
adolescent or adult onset.20 Single patients may present without
seizures but may show epileptic discharges on EEG.20 Such
patients may develop epilepsy with progression of the mitochon-
drial disorder.20 Seizures were also reported in a study on an eight-
member family carrying the m.8993T>G mutation with atypical
phenotype.5 In a single patient with NARP-syndrome progressive
myoclonic epilepsy was reported.46
4.6. Non-syndromic mitochondrial disorders
Several non-syndromic mitochondrial disorders have been
reported in which epilepsy was one of the phenotypic features.47 In
dizygotic twins the m.8363G>A mutation manifested phenotypi-
cally with mental retardation, ataxia, deafness, myopathy, and
myoclonic epilepsy.48 No detailed information about the AED
treatment and the course of epilepsy were provided. Among 4
adult patients with non-syndromic mitochondrial disorder,
seizures were tonic–clonic (n = 1), myoclonic (n = 1), motor
(n = 1), and somatosensory (n = 1).9 EEG showed diffuse slowing
(n = 2), focal anterior sharp waves (n = 1), symmetrical polyspike-
waves (n = 1), and photosensitivity (n = 1). Among the two patients
with partial seizures, one experienced episodes of epilepsia
partialis continua. Among the two patients with generalized
seizures one had rare tonic–clonic seizures associated with
progressive mental impairment and cerebral atrophy. The first
patient had sharp-waves over the parieto-occipital projection and
the other symmetric polyspike-wave complexes on photostimula-
tion.9 In a study on 12 patients with non-syndromic mitochondrial
disorder, epilepsy was the initial manifestation in seven of them.
Eight of these patients had partial seizures and four generalized
seizures. The mitochondrial disorder was due to PDH-deficiency in
6, complex-IV deficiency in 3, and due to multiple respiratory chain
complex deficiencies in 3 patients. In a Japanese family carrying
the m.3291T>C mutation (tRNA gene), the phenotypic presenta-
tion included cerebellar ataxia, myopathy, headache, and myo-
clonic epilepsy with considerable intra-familial heterogeneity,
observed with many pathogenic tRNA point mutations.49 Among
seven families with mutations in the tRNASer(UCN) gene, those
carrying the m.7472insC or the m.7512T>C mutation presented
with myoclonic epilepsy, deafness, ataxia, and cognitive im-
pairment.50 Epilepsy was also a feature of the phenotypic spectrum
in a number of other non-syndromic mitochondrial disorders.51
5. Frequency of epilepsy in mitochondrial disorders
There are no systematic studies available in how many of the
patients with syndromic or non-syndromic mitochondrial disorders
epilepsy occurs, but epilepsy is definitively more frequent in some
mitochondrial disorders than in others. In some of the mitochondrial
disorders epilepsy even dominates the phenotype, such as in Alpers-
Huttenlocher-syndrome, ataxia-neuropathy spectrum, Leigh-syn-
drome, MELAS-syndrome, MEMSA, or MERRF-syndrome (Table 1).
In the other syndromic mitochondrial disorders epilepsy occurs in
only some of the patients. Disregarding the frequency of epilepsy
within a MID, the intra- and inter-familial phenotypic variability
 J. Finsterer, S. Zarrouk Mahjoub / Seizure 21 (2012) 316–321
Table 1
Syndromic and non-syndromic mitochondrial disorders associated with epilepsy.
Frequent
AHS [4]
ANS (MIRAS, SANDO) [3]
LS (mitochondrial, nuclear) [5–7,9,29]
MELAS [35]
MEMSA (SCAE) [3]
MERRF [67]
Occasional
IOSCA [14]
KSS [15,16,41]
LBSL [19]
LHON [43]
NARP [20,46]
Not reported
CMT (mitofusin) [None]
MNGIE [None]
PS [None]
of seizures is high. Among pediatric patients with epilepsy due to a
mitochondrial disorder, half of the patients present with a non-
syndromic phenotypes.52
6. Characterization of epilepsy in mitochondrial disorders
Only few studies are available, which describe the clinical and
EEG characteristics of epilepsy in mitochondrial disorders. In a
study on 31 patients with a mitochondrial disorder and epilepsy,
epilepsy was found as the initial manifestation in 53% of them.9
Mitochondrial disorders were classified as non-syndromic in 43%
of the adult-onset cases and in 70% of the infantile-onset cases.9 In
71% of the patients partial seizures with predominantly motor
symptoms and focal or multifocal EEG epileptiform activity
characterized the epileptic presentation.3 Myoclonic seizures were
found in only 16% of the patients. They all presented with MERRF-
syndrome due to the classical m.8344A>G mutation.9 Photopar-
oxysmal EEG responses were recorded in patients with MERRF-
syndrome, patients with MELAS-syndrome, in patients with Leigh-
syndrome, and in patients with non-syndromic mitochondrial
disorders.9 In patients with MERRF-syndrome generalized epilep-
tiform discharges or generalized photoparoxysmal responses
during intermittent photic stimulation may be recorded.53
7. Treatment of epilepsy in mitochondrial disorders
Treatment of epilepsy in mitochondrial disorders is generally
not at variance from treatment of epilepsy due to other causes.
Some peculiarities of epilepsy treatment in mitochondrial
disorders, however, should be kept in mind. Concerning the use
of AEDs in patients with mitochondrial disorders it is important to
avoid AEDs with mitochondrion-toxic side-effects, since they may
cause severe, fulminant, sometimes fatal side-effects, may trigger
or worsen epilepsy, or may make epilepsy intractable. The AED
with the most well-known mitochondrial toxicity is valproic-acid
(VPA). Particularly, in patients carrying POLG1 mutations (e.g.
Alpers-Huttenlocher syndrome) or in patients with MERRF-
syndrome VPA may exhibit a deleterious effect why VPA but also
other mitochondrion-toxic MIDs should be avoided in these
conditions. In two patients with Alpers-Huttenlocher syndrome
and drug-resistant epilepsy, administration of VPA caused
irreversible liver failure.54 Because VPA causes liver failure also
in other patients with POLG1 mutations, it is absolutely contra-
indicated in these patients. Some authors even claim to test
children with epilepsy for POLG1-mutations before starting VPA.55
Only in patients with mitochondrial disorders due to mutations
other than POLG1, VPA may be tried in case of drug-resistant status
319
epilepticus.56 Replacement of VPA by other AEDs can markedly
improve the outcome of these patients.57
Alternatives to classic AED treatment of epilepsy in patients
with mitochondrial disorders include ketogenic diet (ratio of fat to
carbohydrates and protein is 3:1), L-arginine,58 pyruvate,59 or
ketamine.60 In a patient with Leigh-syndrome due to a mutation in
the PDH E1a-gene, generalized tonic–clonic seizures improved
upon administration of sodium-pyruvate in a dosage of 0.5 g/kg/d
orally.59 Ketogenic diet results in the production of ketone bodies,
which consecutively reduce oxidative stress, reduce excitability
of central neurons, inhibit glycolysis, and retard epileptogen-
esis.61 Ketogenic diet has been shown beneficial in various
patients with epilepsy from a mitochondrial disorder.62–65 Vagal
nerve stimulation has been tried in single patients with
mitochondrial disorders and myoclonic seizures or focal seizures
with secondary generalization, but did not show a beneficial
effect.66
8. Death from epilepsy in mitochondrial disorders
Death from epilepsy in mitochondrial disorders has been only
rarely reported and may occur in form of sudden unexplained
death in epilepsy (SUDEP), intractable epileptic state, or secondary
complications of seizures, such as intracerebral bleeding or head
trauma. In a family with maternally inherited Leigh-syndrome and
myoclonic epilepsy due to the m.8344A>G mutation several
family members had died suddenly during infancy.67 In a study on
6 adults with non-syndromic mitochondrial disorder four of them
died unexpectedly during myoclonic status epilepticus.68
9. Conclusions
Mitochondrial disorders are an important cause of epilepsy,
which may be a phenotypic feature not only of syndromic forms
but also of non-syndromic conditions. In some mitochondrial
disorders the clinical presentation is even dominated by seizures.
In the majority of the mitochondrial disorders, however, epilepsy is
only a collateral feature of the phenotype but there is broad
phenotypic heterogeneity such that single patients may predomi-
nantly present with epilepsy even if the mitochondrial disorder is
usually not associated with epilepsy as a dominant manifestation
of the disease. Though generally all types of seizures occur in
mitochondrial disorders, some are more prevalent than others.
Most frequently patients present with partial or generalized tonic–
clonic or myoclonic seizures. Treatment of epilepsy in mitochon-
drial disorders is not at variance from treatment of epilepsy due to
other causes but care should be taken to avoid mitochondrion-
toxic antiepileptic drugs. Which of the antiepileptic drugs are truly
mitochondrion-toxic and which is the pathogenetic background of
the mitochondrion-toxic effect of an AED remains, however,
elusive in most of the frequently applied AEDs. Further research is
warranted to elucidate the pathogenetic background of epilepsy in
mitochondrial disorders and to optimize treatment in these
patients.
References
1. Finsterer J. Central nervous system manifestations of mitochondrial disorders.
Acta Neurol Scand 2006;114:217–38.
2. Finsterer J, Jarius C, Eichberger H. Phenotype variability in 130 adult patients
with respiratory chain disorders. J Inherit Metab Dis 2001;24:560–76.
3. Cohen BH, Chinnery PF, Copeland WC. POLG-related disorders. 2010 Mar 16. In:
Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle
(WA): University of Washington, Seattle; 1993. Available from http://
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alpers.
4. Castro-Gago M, González-Conde V, Fernández-Seara MJ, Rodrigo-Sáez E, Fer-
nández-Cebrián S, Alonso-Martı́n A, et al. Early mitochondrial encephalomyo-
pathy due to complex IV deficiency consistent with Alpers-Huttenlocher
syndrome: report of two cases. Rev Neurol 1999;29:912–7.
320 J. Finsterer, S. Zarrouk Mahjoub / Seizure 21 (2012) 316–321
5. Tsao CY, Mendell JR, Bartholomew D. High mitochondrial DNA T8993G muta-
tion (<90%) without typical features of Leigh’s and NARP syndromes. J Child
Neurol 2001;16:533–5.
6. Yoshinaga H, Ogino T, Ohtahara S, Sakuta R, Nonaka I, Horai S. A T-to-G mutation
at nucleotide pair 8993 in mitochondrial DNA in a patient with Leigh’s syn-
drome. J Child Neurol 1993;8:129–33.
7. Tsuji M, Kuroki S, Maeda H, Yoshioka M, Maihara T, Fujii T, et al. Leigh syndrome
associated with West syndrome. Brain Dev 2003;25:245–50.
8. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial
myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinc-
tive clinical syndrome. Ann Neurol 1984;16:481–8.
9. Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T, et al.
Epileptic phenotypes associated with mitochondrial disorders. Neurology
2001;56:1340–6.
10. Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F, et al.
Myoclonus epilepsy and ragged-red fibres (MERRF) 1. A clinical, pathological,
biochemical, magnetic resonance spectrographic and positron emission tomo-
graphic study. Brain 1989;112:1231–60.
11. Silvestri G, Ciafaloni E, Santorelli FM, Shanske S, Servidei S, Graf WD, et al.
Clinical features associated with the A–>G transition at nucleotide 8344 of
mtDNA (‘‘MERRF mutation’’). Neurology 1993;43:1200–6.
12. Shtilbans A, Shanske S, Goodman S, Sue CM, Bruno C, Johnson TL, et al. G8363A
mutation in the mitochondrial DNA transfer ribonucleic acidLys gene: another
cause of Leigh syndrome. J Child Neurol 2000;15:759–61.
13. Gribaa M, Salih M, Anheim M, Lagier-Tourenne C, H’mida D, Drouot N, et al. A
new form of childhood onset, autosomal recessive spinocerebellar ataxia and
epilepsy is localized at 16q21-q23. Brain 2007;130:1921–8.
14. Nikali K, Lönnqvist T. Infantile-onset spinocerebellar ataxia. 2009 Jan 27
[updated 2010 Jul 22]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
Available from http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&
part=sca-io.
15. Furuya H, Sugimura T, Yamada T, Hayashi K, Kobayashi T. A case of incomplete
Kearns-Sayre syndrome with a stroke like episode. Rinsho Shinkeigaku
1997;37:680–4.
16. Kosinski C, Mull M, Lethen H, Töpper R. Evidence for cardioembolic stroke in a
case of Kearns-Sayre syndrome. Stroke 1995;26:1950–2.
17. Guerriero S, Vetrugno M, Ciracı̀ L, Artuso L, Dell’aglio R, Petruzzella V. Bilateral
progressive visual loss in an epileptic, mentally retarded boy. Middle East Afr J
Ophthalmol 2011;18:67–70.
18. Isohanni P, Linnankivi T, Buzkova J, Lönnqvist T, Pihko H, Valanne L, et al. DARS2
mutations in mitochondrial leucoencephalopathy and multiple sclerosis. J Med
Genet 2010;47:66–70.
19. Van der Knaap MS, Scheper GC. Leukoencephalopathy with brain stem and
spinal cord involvement and lactate elevation. 2010 May 25. In: Pagon RA, Bird
TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): Uni-
versity of Washington, Seattle; 1993. Available from http://www.ncbi.nlm.-
nih.gov/bookshelf/br.fcgi?book=gene&part=lbsl.
20. Keränen T, Kuusisto H. NARP syndrome and adult-onset generalised seizures.
Epileptic Disord 2006;8:200–3.
21. Gordon N. Alpers syndrome: progressive neuronal degeneration of children
with liver disease. Dev Med Child Neurol 2006;48:1001–3.
22. Lupashko S, Malik S, Donahue D, Hernandez A, Perry MS. Palliative functional
hemispherectomy for treatment of refractory status epilepticus associated with
Alpers’ disease. Childs Nerv Syst 2011;27:1321–3.
23. Hakonen AH, Isohanni P, Rantamäki M, Kälviäinen R, Nordin A, Uusimaa J, et al.
Mitochondrial recessive ataxia syndrome (MIRAS) and valproate toxicity. Duo-
decim 2010;126:1552–9.
24. Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lönnqvist T.
Recessive Twinkle mutations in early onset encephalopathy with mtDNA
depletion. Brain 2007;130:3032–40.
25. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol
2008;39:223–35.
26. Agapitos E, Pavlopoulos PM, Patsouris E, Davaris P. Subacute necrotizing
encephalomyelopathy (Leigh’s disease): a clinicopathologic study of ten cases.
Gen Diagn Pathol 1997;142:335–41.
27. Elia M, Musumeci SA, Ferri R, Colamaria V, Azan G, Greco D, et al. Leigh
syndrome and partial deficit of cytochrome c oxidase associated with epilepsia
partialis continua. Brain Dev 1996;18:207–11.
28. Tsao CY, Luquette M, Rusin JA, Herr GM, Kien CL, Morrow 3rd G. Leigh
syndrome, cytochrome C oxidase deficiency and hypsarrhythmia with infantile
spasms. Clin Electroencephalogr 1997;28:214–7.
29. Horváth R, Abicht A, Holinski-Feder E, Laner A, Gempel K, Prokisch H, et al.
Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of
succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 2006;77:
74–6.
30. Shrikhande DY, Kalakoti P, Syed MM, Ahya K, Singh G. A rare mitochondrial
disorder: Leigh syndrome – a case report. Ital J Pediatr 2010;36:62.
31. Leshinsky-Silver E, Shuvalov R, Inbar S, Cohen S, Lev D, Lerman-Sagie T. Juvenile
Leigh syndrome, optic atrophy, ataxia, dystonia, and epilepsy due to T14487C
mutation in the mtDNA-ND6 gene: a mitochondrial syndrome presenting from
birth to adolescence. J Child Neurol 2011;26:476–81.
32. Swiderska N, Appleton R, Morris A, Isherwood D, Selby A. A novel presentation
of inappropriate antidiuretic hormone secretion in Leigh syndrome with
the myoclonic epilepsy and ragged red fibers, mitochondrial DNA 8344A>G
mutation. J Child Neurol 2010;25:782–5.
33. Wei XQ, Kong QP, Zhang Y, Yang YL, Chang XZ, Qi Y, et al. A case of Leigh
syndrome associated with respiratory chain complex I deficiency due to
mitochondrial gene 13513G>A mutation. Zhongguo Dang Dai Er Ke Za Zhi
2009;11:333–6.
34. Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS with recurrent complex
partial seizures, nonconvulsive status epilepticus, psychosis, and behavioral
disturbances: case analysis with literature review. Epilepsy Behav 2010;
18:494–7.
35. Worthington JC, Rigby AS, Quarrell OW. Seizure frequency in adults with Wolf-
Hirschhorn syndrome. Am J Med Genet A 2008;146A:2528–31.
36. Thorns C, Widjaja A, Boeck N, Skamira C, Zühlke H. Maternally-inherited
diabetes and deafness: report of two affected German families with the
A3243G mitochondrial DNA mutation. Exp Clin Endocrinol Diabetes 1998;
106:384–8.
37. Schleiffer T, ’t Hart LM, Schürfeld C, Kraatz K, Riemann JF. Maternally inherited
diabetes and deafness (MIDD): unusual occult exocrine pancreatic manifesta-
tion in an affected German family. Exp Clin Endocrinol Diabetes 2000;108:81–5.
38. Naı̈mi M, Bannwarth S, Procaccio V, Pouget J, Desnuelle C, Pellissier JF, et al.
Molecular analysis of ANT1 TWINKLE and POLG in patients with multiple
deletions or depletion of mitochondrial DNA by a dHPLC-based assay. Eur J
Hum Genet 2006;14:917–22.
39. Lamperti C, Zeviani M. Encephalomyopathies caused by abnormal nuclear-
mitochondrial intergenomic cross-talk. Acta Myol 2009;28:2–11.
40. Lönnqvist T, Paetau A, Nikali K, von Boguslawski K, Pihko H. Infantile onset
spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological
features. J Neurol Sci 1998;161:57–65.
41. Tulinius MH, Hagne I. EEG findings in children and adolescents with mitochon-
drial encephalomyopathies: a study of 25 cases. Brain Dev 1991;13:167–73.
42. Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, et al.
Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopa-
thy with brain stem and spinal cord involvement and lactate elevation. Nat
Genet 2007;39:534–9.
43. Niehusmann P, Surges R, von Wrede RD, Elger CE, Wellmer J, Reimann J, et al.
Mitochondrial dysfunction due to Leber’s hereditary optic neuropathy as a
cause of visual loss during assessment for epilepsy surgery. Epilepsy Behav
2011;20:38–43.
44. Grazina MM, Diogo LM, Garcia PC, Silva ED, Garcia TD, Robalo CB, et al. Atypical
presentation of Leber’s hereditary optic neuropathy associated to mtDNA
11778G>A point mutation – a case report. Eur J Paediatr Neurol 2007;
11:115–8.
45. Sciacco M, Prelle A, D’Adda E, Lamperti C, Bordoni A, Rango M, et al. Familial
mtDNA T8993C transition causing both the NARP and the MILS phenotype in
the same generation. A morphological, genetic and spectroscopic study. J Neurol
2003;250:1498–500.
46. Jung J, Mauguière F, Clerc-Renaud P, Ollagnon E, Mousson de Camaret B, Ryvlin
P. NARP mitochondriopathy: an unusual cause of progressive myoclonic epi-
lepsy. Neurology 2007;68:1429–30.
47. Hirano M, Kunz WS, DiMauro S. Mitochondrial diseases. In: Engel J, Pedley TA,
editors. Epilepsy – a comprehensive textbook, III. Part. Philadelphia: Lippincott
Williams & Wilkins; 2008. p. 2621–30.
48. Virgilio R, Ronchi D, Bordoni A, Fassone E, Bonato S, Donadoni C, et al.
Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemi-
cal and pathological study. J Neurol Sci 2009;281:85–92.
49. Sunami Y, Sugaya K, Chihara N, Goto Y, Matsubara S. Variable phenotypes in a
family with mitochondrial encephalomyopathy harboring a 3291T > C muta-
tion in mitochondrial DNA. Neurol Sci 2011;32:861–4.
50. Jaksch M, Klopstock T, Kurlemann G, Dörner M, Hofmann S, Kleinle S, et al.
Progressive myoclonus epilepsy and mitochondrial myopathy associated with
mutations in the tRNA(Ser(UCN)) gene. Ann Neurol 1998;44:635–40.
51. Kang HC, Kwon JW, Lee YM, Kim HD, Lee HJ, Hahn SH. Nonspecific mitochon-
drial disease with epilepsy in children: diagnostic approaches and epileptic
phenotypes. Childs Nerv Syst 2007;23:1301–7.
52. Lee HF, Chi CS, Tsai CR, Chen CH. Epileptic seizures in infants and children with
mitochondrial diseases. Pediatr Neurol 2011;45:169–74.
53. Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Silvado CE, Werneck LC, et al. Clinical
features, muscle biopsy and molecular genetics in Brazilian patients. Mitochon-
drion 2011;11:528–32.
54. Pronicka E, Weglewska-Jurkiewicz A, Pronicki M, Sykut-Cegielska J, Kowalski P,
Pajdowska M, et al. Drug-resistant epilepsia and fulminant valproate liver
toxicity Alpers-Huttenlocher syndrome in two children confirmed post mortem
by identification of p. W748S mutation in POLG gene. Med Sci Monit 2011;
17:CR203–9.
55. Saneto RP, Lee IC, Koenig MK, Bao X, Weng SW, Naviaux RK, et al. POLG DNA
testing as an emerging standard of care before instituting valproic acid therapy
for pediatric seizure disorders. Seizure 2010;19:140–6.
56. Finsterer J, Zarrouk Mahjoub S. Mitochondrial toxicity of antiepileptic drugs
and their tolerability in mitochondrial disorders. Expert Opin Drug Metab Toxicol
2012;8:71–9.
57. Finsterer J, Barton P. Regression of stroke-like lesions in MELAS-syndrome after
seizure control. Epileptic Disord 2010;12:330–4.
58. Toribe Y, Tominaga K, Ogawa K, Suzuki Y. Usefulness of L-arginine infusion for
status epilepticus in mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes. No To Hattatsu 2007;39:38–43.
59. Koga Y, Povalko N, Katayama K, Kakimoto N, Matsuishi T, Naito E, et al.
Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel muta-
tion in PDH E1a gene. Brain Dev 2012;34:87–91.
 J. Finsterer, S. Zarrouk Mahjoub / Seizure 21 (2012) 316–321
60. Prüss H, Holtkamp M. Ketamine successfully terminates malignant status
epilepticus. Epilepsy Res 2008;82:219–22.
61. Kim do Y, Rho JM. The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab
Care 2008;11:113–20.
62. Barnerias C, Saudubray JM, Touati G, De Lonlay P, Dulac O, Ponsot G, et al.
Pyruvate dehydrogenase complex deficiency: four neurological phenotypes
with differing pathogenesis. Dev Med Child Neurol 2010;52:e1–9.
63. Kang HC, Kim HD, Lee YM, Han SH. Landau-Kleffner syndrome with mito-
chondrial respiratory chain-complex I deficiency. Pediatr Neurol 2006;35:
158–61.
64. Lee YM, Kang HC, Lee JS, Kim SH, Kim EY, Lee SK, et al. Mitochondrial respiratory
chain defects: underlying etiology in various epileptic conditions. Epilepsia
2008;49:685–90.
321
65. Seo JH, Lee YM, Lee JS, Kim SH, Kim HD. A case of Ohtahara syndrome with
mitochondrial respiratory chain complex I deficiency. Brain Dev 2010;32:253–7.
66. Arthur TM, Saneto RP, de Menezes MS, Devinsky O, Lajoie J, Murphy PJ, et al.
Vagus nerve stimulation in children with mitochondrial electron transport
chain deficiencies. Mitochondrion 2007;7:279–83.
67. Santorelli FM, Tanji K, Shanske S, Krishna S, Schmidt RE, Greenwood RS, et al.
The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by
analysis in paraffin-embedded sections: revisiting the past. Ann Neurol 1998;
44:962–4.
68. van Domburg PH, Gabreëls-Festen AA, Gabreëls FJ, de Coo R, Ruitenbeek W,
Wesseling P, et al. Mitochondrial cytopathy presenting as hereditary sensory
neuropathy with progressive external ophthalmoplegia, ataxia and fatal myo-
clonic epileptic status. Brain 1996;119:997–1010.