BRAIN - pdfs.semanticscholar.org€¦ · BRAIN A JOURNAL OF NEUROLOGY Recessive twinkle mutations...

BRAINA JOURNAL OF NEUROLOGY

Recessive twinkle mutations cause severeepileptic encephalopathyTuula Lonnqvist,1 Anders Paetau,2 Leena Valanne3 and Helena Pihko1

1 Division of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland

2 Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland

3 Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland

Correspondence to: Tuula Lonnqvist,

Division of Child Neurology,

Helsinki University Central Hospital,

PO BOX 280, Helsinki, 00029 Finland

E-mail: [email protected]

The C10orf2 gene encodes the mitochondrial DNA helicase Twinkle, which is one of the proteins important for mitochondrial

DNA maintenance. Dominant mutations cause multiple mitochondrial DNA deletions and progressive external ophthalmoplegia,

but recent findings associate recessive mutations with mitochondrial DNA depletion and encephalopathy or hepatoencephalo-

pathy. The latter clinical phenotypes resemble those associated with recessive POLG1 mutations. We have previously described

patients with infantile onset spinocerebellar ataxia (MIM271245) caused either by homozygous (Y508C) or compound hetero-

zygous (Y508C and A318T) Twinkle mutations. Our earlier reports focused on the spinocerebellar degeneration, but the 20-year

follow-up of 23 patients has shown that refractory status epilepticus, migraine-like headaches and severe psychiatric symptoms

are also pathognomonic for the disease. All adolescent patients have experienced phases of severe migraine, and seven patients

had antipsychotic medication. Epilepsia partialis continua occurred in 15 patients leading to generalized epileptic statuses in

13 of them. Eight of these patients have died. Valproate treatment was initiated on two patients, but had to be discontinued

because of a severe elevation of liver enzymes. The patients recovered, and we have not used valproate in infantile onset

spinocerebellar ataxia since. The first status epilepticus manifested between 15 and 34 years of age in the homozygotes, and at

2 and 4 years in the compound heterozygotes. The epileptic statuses lasted from several days to weeks. Focal, stroke-like

lesions were seen in magnetic resonance imaging, but in infantile onset spinocerebellar ataxia these lesions showed no

predilection. They varied from resolving small cortical to large hemispheric oedematous lesions, which reached from cerebral

cortex to basal ganglia and thalamus and caused permanent necrotic damage and brain atrophy. Brain atrophy with focal laminar

cortical necrosis and hippocampal damage was confirmed on neuropathological examination. The objective of our study was to

describe the development and progression of encephalopathy in infantile onset spinocerebellar ataxia syndrome, and compare

the pathognomonic features with those in other mitochondrial encephalopathies.

Keywords: Twinkle; IOSCA; epileptic encephalopathy

Abbreviations: DWI = diffusion weighted images; IOSCA = infantile onset spinocerebellar ataxia; SLE = stroke like episodes

IntroductionInfantile onset spinocerebellar ataxia (IOSCA) (OMIM #271245) is

a progressive neurodegenerative disease, which is caused either by

homozygous (Y508C) or compound heterozygous (Y508C and

A318T) C10orf2 mutations (Nikali et al., 2005; Hakonen et al.,

2007). C10orf2 codes for the mitochondrial (mt)DNA helicase

Twinkle, which works in close connection with mtDNA polymerase

doi:10.1093/brain/awp045 Brain 2009: 132; 1553–1562 | 1553

Received November 9, 2008. Revised January 27, 2009. Accepted January 29, 2009. Advance Access publication March 20, 2009

� The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

For Permissions, please email: [email protected]

gamma (POLG, POLG1) in mtDNA replication. Disorders caused

by either C10orf2 or POLG1 mutations share clinical phenotypes.

Recessive POLG1 mutations cause clinical entities varying from an

infantile hepatoencephalopathy, (Alpers syndrome, OMIM #203700)

(Ferrari et al., 2005; Nguyen et al., 2005), to a mitochondrial spino-

cerebellar ataxia-epilepsy syndrome (MSCAE), also called MIRAS

(mitochondrial recessive ataxia syndrome) (Hakonen et al., 2005;

Tzoulis et al., 2006). The combination of early encephalopathy, sen-

sory axonal neuropathy, epilepsy and hepatopathy with mtDNA

depletion in the liver was found in our compound heterozygotes,

and the three patients with another recessive Twinkle mutation,

T457I. This clinical presentation resembles POLG1 associated Alpers

syndrome (Hakonen et al., 2007; Sarzi et al., 2007). IOSCA and

MSCAE syndromes share clinical features, but spinocerebellar degen-

eration manifests earlier and progresses faster in IOSCA (Koskinen

et al., 1994b; Lonnqvist et al., 1998; Hakonen et al., 2007).

Refractory epilepsy with occipital lobe predilection is common in

MSCAE with the A467T and W748S POLG1 mutations (Engelsen

et al., 2008).

We report on cerebral manifestations in IOSCA, ranging from

migraine-like headaches and psychotic episodes to severe epileptic

encephalopathy. We also present neuroradiological findings during

and after status epilepticus, and neuropathological findings related

to prolonged epileptic statuses in our patients.

Patients and Methods

PatientsOur material consists of 23 IOSCA patients: 21 patients homozygous

for the Y508C mutation and two compound heterozygotes (Y508C

and A318T). All patients, except patient 1 (Table 1), who died in

1988 before our follow-up started, have been examined and

followed-up at the Division of Child Neurology of the Helsinki

University Central Hospital, Helsinki, Finland. We have reported on

the clinical course and neuropathological findings in IOSCA earlier

(Koskinen et al., 1994a,b, 1995a,b; Lonnqvist et al., 1998). It has

become evident that epileptic encephalopathy, psychiatric symp-

toms and migraine are important manifestations of the disease after

childhood. In the following section, we summarize briefly the clinical

course and findings in IOSCA, which we have reported earlier.

The clinical findings are identical in the homozygotes and compound

heterozygotes, but the symptoms appear earlier and progress faster in

the compound heterozygotes (Patients 22 and 23 in Table 1). The first

symptoms—ataxia, muscle hypotonia, athetoid movements and loss of

deep tendon reflexes—were first seen around the age of 1 year in the

homozygotes and at 6 months in the compound heterozygotes.

Ophthalmoplegia and hearing deficit developed soon after the onset

of the disease, and sensory axonal neuropathy and female hyper-

gonadotrophic hypogonadism by teen age. The heterozygotes lost

even their ability to crawl by the end of the first year, while 18 of

the homozygotes learned to walk independently or with a walking-aid,

but became wheelchair bound by adolescence. All homozygous

patients communicated with sign language. Although the patients’

primary capacity was normal, all had learning difficulties. The patients

with an unsuccessful early rehabilitation were moderately mentally

retarded in adolescence, while the patients with a proper rehabilitation

and education were mildly retarded. All routine laboratory and

metabolic screening tests, including plasma and cerebrospinal fluid

(CSF) lactate, were normal in the homozygous patients (Koskinen

et al., 1994b). Mild elevation of serum and CSF lactate, and an inter-

mittent elevation of liver transaminases and �-fetoprotein was

detected in the compound heterozygotes (Hakonen et al., 2007).

Muscle morphology revealed only mild neurogenic atrophy. The bio-

chemical or histochemical COX (cytochrome c oxidase) activity was

slightly diminished in the compound heterozygotes. The structure

and amount of mtDNA was normal in muscle (Koskinen et al.,

1994a; Nikali et al., 2005; Hakonen et al., 2007). The spinocerebellar

degenerative changes—the moderate atrophy of the brain stem and

the cerebellum, and the severe atrophy in the dorsal roots, the poste-

rior columns and the posterior spinocerebellar tracts—were uniform in

IOSCA (Lonnqvist et al., 1998; Hakonen et al., 2007).

MethodsWe present clinical and radiological follow-up data on epilepsy,

migraine and psychiatric symptoms in 23 IOSCA patients. The patients

were clinically examined by one of us (T.L., formerly T.K.) between

1 and 2 year intervals. EEG was recorded 1–5 times on patients with

seizures (18/23 patients). MRI or CT was performed on ten patients

during and/or after status epilepticus. Three patients without epilepsy

Table 1 The psychiatric symptoms and epilepsy in infan-tile onset spinocerebellar ataxia

Patient Psychiatricsymptoms

Age atonset ofepilepsy (yrs)

Statusepilepticus(number)

Present ageor age atdeath (yrs)

1 m � 30 1 30e

2 f � ne 0 48

3 m + 30 6 41

4 f + 22 11 41

5 f + 26 2 26e

6 f � 12a 0 39

7 m � 19 5 37

8 m + 20 4 24e

9 m + 34 2 36

10 m + ne 0 35

11 m + 27 d 34

12 f � 23 6 34

1 m + 31 d 33

14 f � 21 2 21e

15 f � Ne 0 28

16 f � 15 7 21e

17 m � Ne 0 23

18 m � 13b 0 22

19 f � 16 5 17e

20 m � 11c 0 16

21 f � Ne 0 14

22 m � 4.5 1 4.5e

23 m � 2 5 4.5e

Patients 1�21 = homozygotes; patients 22�23 = compound heterozygotes.

Yrs = years; m = male; f = female; + = medication for psychiatric symptoms;�= no or minimal psychiatric symptoms; ne = no epilepsy.a At 12 years of age a focal and a generalized seizure with focal EEGabnormality, later seizure free.b short day-time absences, interictal EEG normal.c short tonic seizures at night, interictal EEG normal.d only epilepsia partialis continua, no generalization.

e age at death.

1554 | Brain 2009: 132; 1553–1562 T. Lonnqvist et al.

were imaged in order to assess the development of supratentorial

brain atrophy. Diffusion weighted images (DWI) with apparent diffu-

sion coefficient (ADC) were available in two patients (Patients 3 and

19 in Table 1). The images were performed 4 days (Patient 19) and

2 weeks (Patients 3) after the onset of status epilepticus. Autopsy

findings of five patients are re-evaluated. Histopathological and immu-

nohistochemical methods have been described in detail in our previous

reports (Lonnqvist et al., 1998; Hakonen et al., 2007).

Results

Migraine and psychiatric symptomsAll adolescent IOSCA patients have had episodes of migraine-like

headache. Severe generalized headache preceded epileptic seizures

in some cases, but attacks of migraine with nausea, vomiting and

lethargy appeared independently, too. The severity of the attacks

and the intervals between the migraine episodes varied in individ-

ual patients and between patients.

Poor sleep and nocturnal restlessness was common in young

IOSCA-patients, but psychiatric symptoms requiring treatment

appeared gradually during adolescence. The patients became tear-

ful and somnolent, or agitated with uncontrolled rage attacks.

They could, for example, crash into furniture or other people

with their wheelchair. Seven patients had medication for their

symptoms (Table 1). We have used selective serotonin reuptake

inhibitors (SSRI) and antipsychotic medication (older neurolepts,

risperidone or olanzapine) with a cautious dosage in the begin-

ning. Five patients were treated by psychiatrists communicating

with sign language. According to the psychiatrists, the episodes

fulfilled diagnostic criteria of psychosis and three patients were

treated with psychotherapy in addition to medication. The psychi-

atric symptoms appeared in five patients before the onset of epi-

lepsy (Patients 3, 5, 9, 10 and 11 in Table 1).

EpilepsyEighteen patients had seizures, which developed into an epileptic

encephalopathy in 15 (65%) of them. The process started at the

ages of 2 and 4 years in the compound heterozygotes and

between the age of 15 and 34 years (mean = 24 years) in the

homozygotes. The seizures manifested as myoclonic jerks or

focal clonic seizures and progressed to epilepsia partialis continua

in 15 patients and further to a generalized status epilepticus in

13 of them (Table 1).

The episodes recurred, lasted from several days to weeks, and

the symptoms fluctuated between epilepsia partialis continua and

generalized tonic clonic seizures. Discomfort, abdominal pain,

vomiting, migraine-like headache, restlessness or agitation pre-

ceded the onset of the epileptic status. The seizure episodes

were often precipitated by stressful events like infections or sur-

gery. The onset of epilepsy indicated progression of the disease

with loss of the ability to walk or stand supported, or even to sit in

a wheelchair. Some patients recovered slowly over several months

without regaining their previous condition. Their muscle hypotonia

and weakness increased, they had difficulties in swallowing and

fatigued easily. The first IOSCA-patient with status epilepticus

(Patient 4 in Table 1) is 41-years old, lives in a nursing home

for severely disabled persons and has survived 11 epileptic statuses

during the past 18 years. The death of eight patients was directly

or indirectly related to epilepsy. The time from the first seizures to

death varied from 1 month to 5 years.

Three IOSCA-patients have had seizures of a different kind

(Table 1). A 12-year-old female (Patient 6 in Table 1) had a gen-

eralized convulsion and a complex partial seizure. Her EEGs

showed background abnormality and a temporal slow wave

focus. She was on carbamazepine therapy for 6 years and at the

time the medication was discontinued, her EEG was normal. She

remains seizure-free at her present age of 39. A 13-year-old boy

(Patient 18) had daytime absences, and an 11-year-old boy

(Patient 20) had short nocturnal tonic seizures. Their interictal

EEG recordings showed no epileptogenic activity and both are

seizure free on antiepileptic medication (oxcarbazepine) at ages

of 22 and 16 years, respectively.

Drug treatmentConventional antiepileptic drugs have been ineffective in most of

our patients. We initially treated the patients with prolonged epi-

leptic status with barbiturate anaesthesia but the results were poor.

The seizures continued, and the treatment was complicated with

pneumonia or a urinary tract infection. Early treatment, with ben-

zodiazepine infusion, especially midazolam, was occasionally effec-

tive. Elevation of liver enzymes (alanine aminotransferase or ALAT

232 units/l, ref. 10–35 U/l, and �-GT 160 U/l, ref. 5–50 U/l),

and icterus with elevated bilirubin levels (total: 224 mmol/l, ref.

5–25 mmol/l; conjugated: 160 mmol/l, ref. 1–8mmol/l) was detected

in patient 4 (Table 1) 1 month after initiation of valproate medica-

tion. A similar elevation of transaminases was detected also in

Patient 7 (Table 1). As valproate was discontinued, icterus disap-

peared and the liver enzymes normalized in both patients.

Phenytoin or phosphenytoin were ineffective and caused an eleva-

tion of the liver enzymes. Oxcarbazepine had some effect on the

seizures, but hyponatremia was a troublesome side effect. Some

patients benefited from lamotrigine or levetiracetam.

EEG findingsThe EEG was initially normal in all patients, but the frequency of

background activity decreased with advancing age (Koskinen

et al., 1994b). Focal continuous or periodic discharges with slow-

ing of the background activity were seen during epilepsia partialis

continua and the discharges became generalized during the status

epilepticus. The epileptic activity often continued for weeks with

fluctuation between these two states. Periodic lateralized epilepti-

form discharges (PLEDs) were common (Fig. 1A and B). The back-

ground activity was progressively abnormal after each epileptic

status (Fig. 2A).

MRI findingsWe have described the sequence of MRI findings from cerebellar

cortical to olivopontocerebellar and finally to spinocerebellar atro-

phy (Koskinen et al., 1995b). The supratentorial findings—cortical

Recessive twinkle mutations Brain 2009: 132; 1553–1562 | 1555

oedema and later cortical and central atrophy—appeared at the

time and after the onset of epilepsy. The cortical oedema was of a

non-vascular distribution. The oedematous area varied from mul-

tiple small cortical lesions to the involvement of the whole hemi-

sphere, thalamus and caudate nucleus (Fig. 1C). In diffusion

weighted imaging (DWI, b = 1000), the lesions showed restricted

diffusion 4 days after the onset of status epilepticus [Patient 19,

Fig. 1D, thus behaving like early ischemic changes with decreased

apparent diffusion coefficient (ADC) values]. The ADC values were

normal or slightly increased 2 weeks after the onset of the insult

(Patient 3, Fig. 2B). Some of these lesions were reversible.

However, widening of the ventricles and sulci, consistent with

atrophy, developed (Fig. 3). Supratentorial cortical and central

atrophy was seen in all patients with intractable status epilepticus,

but not in patients without refractory epilepsy (Fig. 4).

NeuropathologyWe discuss the supratentorial neuropathological findings in

patients 5, 8, 14, 16 and 22 (Table 1). Patients 5 and 14 died

Figure 1 EEG and MRI of a female patient (Patient 19 in Table 1) 4 days after the onset of status epilepticus. (A) Varying epileptogenic

activity during a long-lasting status epilepticus with lateralized epileptiform discharges. Longitudinal bipolar montage, 10–20 electrode

placement, 10 s per window. (B) Quantification of the discharges. (C) A T2-weighted MR image during status epilepticus. Note the

increased signal intensity in the right hemisphere, basal ganglia and thalamus. (D) Diffusion weighted images indicate presence of acute

ischemia: hyperintense trace (b = 1000) in the left, and hypointense apparent diffusion coefficient map in the right.


Figure 3 (A) A T2-weighted image of a 34-year-old male patient (Patient 9 in Table 1) with status epilepticus. There are multiple

oedematous lesions on both hemispheres. (B) A T2-weighted image 30 days after recovery. The oedematous lesions have resolved,

but widening of the CSF spaces indicates development of atrophy.

Figure 2 EEG and MRI of a male patient (Patient 3 in Table 1) 2 weeks after the onset of his last epileptic status at the age of 41.

(A) Remarkable slowing of the EEG after status epilepticus. (B) Left: a T2-weighted MR image showing acute lesions with increased

signal intensity on the right hemisphere and atrophy of the left hemisphere 3 months after a status epilepticus. Middle: a diffusion

weighted trace image with increased signal intensity on the right side. Right: apparent diffusion coefficient map showing resuming

signal intensity on the right hemisphere after acute ischaemia.


3 months after the onset of seizures during an intractable epi-

leptic status at the ages of 26 and 21 years, respectively. Their

supratentorial findings were mild without significant cortical

changes. Patient 8 died at the age of 24 years, 4 years after the

onset of epilepsy at the end of an epileptic episode lasting

8 weeks. He had patchy cortical laminar necrosis, also the thalami

and subthalamic nuclei were affected. The amygdala and espe-

cially the left hippocampus showed epileptogenic sprouting of

the granular cell axons into the inner molecular layer (Fig. 5C

and D). Patient 16 died of pneumonia at the age of 21 years,

5 years after the onset of epilepsy. She had been bedridden and

unable to communicate since her first status epilepticus. She had

parieto-occipital cortical atrophy in both parasagittal watershed

regions and the most severe laminar cortical necrosis was seen

on the medial surface of both visual cortices (Fig. 5A and B).

Reduction of the white matter caused a mild central atrophy

with dilatation of the lateral ventricles. Patient 22, a hetero-

zygote, died in a month after the onset of epilepsy. Severe

ischemic changes throughout the cerebral cortex, basal ganglia

and thalami had been detected neuroradiologically and were

histologically confirmed (Fig. 6) (Hakonen et al., 2007).

DiscussionAt the time of our very first report (Koskinen et al., 1994b) all

IOSCA patients but one were alive, the oldest at the age of

34 years. The severity and consistency of cerebral symptoms—

migraine-like headaches, psychotic episodes and catastrophic

epilepsy was not evident at that time. Today most of our patients

have epilepsy, which has directly or indirectly caused the death of

eight of them. The development of epilepsy has not been predict-

able the same way as the spinocerebellar degeneration of the

disease. The atrophy of the sensory and cerebellar pathways and

corticospinal degeneration progress steadily with age, but the age

of onset of epilepsy has been highly variable and a few patients

have been spared of epilepsy altogether. Our oldest patient,

whose brother died during a status epilepticus at the age of 30,

is now 48 and has not had seizures. The other symptoms besides

epilepsy progressed equally in both siblings. The role of external

factors in the development of epilepsy can only be postulated.

Malaise and discomfort experienced by our patients before the

onset of seizures may indicate presence of a metabolic derange-

ment. There is increasing evidence of the role of free radicals in

development of symptoms in mitochondrial diseases. Their role

may be especially significant in the development of epilepsy,

since seizures are known to increase the production of free

radicals, which again induces more seizures (Kovacs et al., 2002;

Liang and Patel, 2006). Thus an isolated seizure in a patient

with already compromised mitochondrial function may lead to

a vicious circle and catastrophic situation as we have seen in

our patients and what others have described in association

with other mitochondrial disorders.

New mechanisms behind neurodegeneration in mitochondiral

diseases have been revealed recently. One of these concerns mito-

chondrial movement. Mitochondria are dynamic organelles, which

migrate, divide and fuse, and through these processes ensure

Figure 4 (A) CT of a 40-year-old male (Patient 3 in Table 1) with several epileptic episodes. There is central and cortical atrophy.

(B) CT of a 34-year-old male patient (Patient 10 in Table 1) with no epilepsy shows normal CSF spaces.


metabolite and mtDNA mixing. This activity has been shown to be

crucial for the mitochondria and disturbances in these dynamic

functions has shown to be an important cause in neurodegenera-

tion (Knott et al., 2008).

We and collaborators have recently reported complex I (CI)

deficiency and mtDNA depletion in IOSCA. MtDNA depletion

was detected in the frontal cortex and cerebellum, and to a

lesser extent also in the liver. MtDNA deletions or point mutations

were not detected. IOSCA can therefore be included in the group

of tissue-specific mtDNA depletion syndromes (Hakonen et al.,

2008). In vitro studies have shown normal helicase function in

the IOSCA (Y508C) mutant Twinkle, while a defective helicase

activity was described in the T457I mutant (Sarzi et al., 2007).

This may explain the neonatal onset and fatal Alpers-like

hepatoencephalopathy in the latter patients. The molecular mech-

anism behind the brain-specific mtDNA depletion in IOSCA can

not be explained by current knowledge.

Stroke like episodes (SLE), migraine, psychiatric symptoms and

epilepsy are common in MELAS, one of the most common mito-

chondrial disease (Feddersen et al., 2003; Iizuka and Sakai, 2005),

and occur also in POLG-related recessive ataxia syn-

dromes (Hakonen et al., 2005; Horvath et al., 2006; Deschauer

et al., 2007). Stroke-like lesions with high signal intensity on

T2-weighted images are typical MRI-findings in MELAS. These

lesions usually decrease in size and intensity over time and may

resolve or reappear in a new location or develop in an area of

atrophy or altered cortical signal intensity (Iizuka et al., 2003).

Similar lesions, sometimes reaching massive dimensions and

encompassing the whole cortex, subcortical white matter and

basal ganglia in one hemisphere were seen in our patients, too.

Diffusion weighted images (DWI), especially apparent diffusion

coefficient (ADC) maps are used to differentiate between vaso-

genic and cytotoxic oedema. DWI (b = 1000, trace) show hyper-

intensity in both instances, while ADC maps show hyperintensity

in vasogenic oedema and hypointensity in cytotoxic oedema typ-

ical for ischemia. Diffusion weighted images in IOSCA maps

showed hyperintensity, and ADC maps were hypointense in the

acute phase, but later turned normal or hyperintense indicating

that the process was of ischemic nature. The ADC maps in

MELAS patients are normal or mildly hyperintense, which is

more consistent with vasogenic than with cytotoxic oedema

(Michelson and Ashwal, 2004). Identical vasogenic oedema is

seen in the posterior reversible leukoencephalopathy syndrome

(PRES) with parieto-occipital predominance (Bartynski, 2008).

POLG mutations with occipital predilection in MRI and

EEG share features with PRES (Engelsen et al., 2008). The impor-

tance of timing of the DWI is evident and should be taken into

account when evaluating the pathomechanism of the stroke like

lesions.

Epilepsia partialis continua was first described in MELAS, but it

is emerging as one of the important clinical features indicating

mitochondrial dysfunction in the brain (Canafoglia et al., 2001;

Van Goethem et al., 2003; Tzoulis et al., 2006; Deschauer

et al., 2007). The neuropathological findings are characterized

Figure 5 (A) Midlaminar necrosis of primary visual cortex of a 26-year-old female (Patient 5 in Table 1), spongy necrotic area

devoid of neurons seen between arrows. (B) In neurofilament immunostaining small neurons of lamina 2 are still partly preserved

beneath upper arrow, whereas lamina 3–5 are destroyed. (C) Left: hippocampus of a 24-year-old male patient (Patient 8 in Table 1),

where severe neuronal loss is seen in folium terminale (CA4) and Sommer’s sector (CA1). (D) In MAP-2 immunostaining sprouting

from dentate granular cells (above arrow) into inner molecular layer (IML) can be seen. Paraffin sections, original magnifications

He 4� (A and C), SMI-311 neurofilament immunohistochemistry 100 (B) and MAP-2 (D).


by foci of necrosis, predominantly localized in the cerebral cortex

and in the hippocampus—a highly epileptogenic area (Michelson

and Ashwal, 2004). Similar supratentorial post-mortem findings,

related to the duration and number of epileptic statuses before

death, were found in IOSCA, too. Generalized seizures and myo-

clonias are the typical seizure manifestations of MERRF (mito-

chondrial encephalopathy with ragged red fibres) and the

neuropathological lesions involve preferentially inferior olivary

Figure 6 A male patient (Patient 22 in Table 1). (A) MRI before the onset of status epilepticus. (B) CT at the onset of status epilepticus

with focal clonic seizures in the left arm and leg. Note the hypodense lesion in the right basal ganglia (arrow). (C) CT 2 weeks later

during the generalized and prolonged status epilepticus.


nucleus, the cerebellar dentate nucleus, the red nucleus and the

pontine tegmentum, structures implicated in the genesis of myo-

clonus (Kunz, 2002). Presumably the myoclonic jerks in IOSCA are

caused by the degenerative changes in the inferior olivary nucleus,

pons and cerebellar dentate nucleus. The causal relationship

between epilepsy and laminar cortical necrosis with hippocampal

damage in mitochondrial disorders is far less clear (Iizuka et al.,

2002).

Syndromic epilepsy with occipital lobe predilection has been

described in the mitochondrial spinocerebellar ataxia-epilepsy syn-

drome (MSCAE) (Engelsen et al., 2008). Visual symptoms were

common in epilepsy in MSCAE, but such phenomena could not

be detected in IOSCA. The epilepsy in IOSCA showed no focal

predilection, but focal jerking from one side of the body often

progressed to a generalized status epilepticus making epilepsia

partialis continua with generalization characteristic to IOSCA.

Periodic lateralized epileptiform discharges (PLED) are described

during status epilepticus in MELAS and other mitochondrial dis-

orders (Michelson and Ashwal, 2004), and were seen also in

IOSCA.

Conventional antiepileptic drugs are generally ineffective in

mitochondrial encephalopathies, especially in epilepsia partialis

continua and prolonged statuses associated with SLE and tissue

damage (Kunz, 2002). Valproate and barbiturates may impair

respiratory chain activity and should be avoided in all mitochon-

drial disorders (Finsterer, 2006), and valproate is known to precip-

itate fatal liver failure in patients with recessive POLG1 mutations

(Horvath et al., 2006; Tzoulis et al., 2006; Engelsen et al., 2008).

We used valproate on two patients before the mitochondrial

aetiology of IOSCA was known, but fortunately avoided fatal

complications by discontinuing the treatment. The best option

for intravenous therapy has been midazolam as a continuous

infusion at the onset of the status epilepticus. We have used

oxcarbazepine and/or levetiracetam added with clonazepam for

a variable time after prolonged epileptic statuses.

Psychiatric symptoms, mainly depression, has been reported in

mitochondrial diseases (Finsterer, 2006; Fattal et al., 2007). One

may argue that reactive depression after the diagnosis of a severe

progressive disease should not be counted as a symptom of the

disease itself. Similarly uncontrolled rage-attacks in some of our

patients could be counted as a normal reaction in a situation,

where cognitive functions are relatively spared, but ways of

expressing oneself are severely limited. However, the attacks

fulfilled diagnostic criteria of a psychotic episode, and psychi-

atrists and psychotherapists able to communicate with sign

language and proper medication were helpful in treating our

patients.

IOSCA syndrome shares features with other mitochondrial

recessive ataxia syndromes (Table 2). The somatosensory system

conveying proprioseptive information to the brain and cerebellum

is similarly affected in IOSCA and Friedreich’s ataxia (Lonnqvist

et al., 1998). IOSCA patients do not have cardiomyopathy, and

ophthalmoplegia, hearing deficit, cognitive impairment, psychiatric

symptoms and epilepsy are rare or not existing in Friedreich’s

ataxia (Pandolfo, 2008). Mitochondrial spinocerebellar ataxia-

epilepsy syndrome (MSCAE) also called MIRAS (mitochondrial

recessive ataxia syndrome) share clinical features with IOSCA,

but the spinocerebellar degeneration manifests earlier and prog-

resses faster in IOSCA (Hakonen et al., 2005; Engelsen et al.,

2008). Tissue specific mtDNA depletion is detected in IOSCA

and in Alpers syndrome, but the degenerative changes in the

liver and the gliosis and spongiform atrophy of the brain are far

more severe in Alpers syndrome (Ferrari et al., 2005; Hakonen

et al., 2007).

The mtDNA helicase Twinkle-associated epileptic encephalop-

athy share many features with other syndromic epilepsies with

mitochondrial aetiology. These symptoms and signs should alert

the clinician to consider a form of mitochondrial encephalopathies,

even if the laboratory tests typical for mitochondrial disorders

remain negative.

AcknowledgementsWe thank the patients and their families for the participation in

the study.

Table 2 The clinical features and findings in infantileonset spinocerebellar ataxia, Friedreich’s ataxia,Mitochondrial spinocerebellar ataxia-epilepsy syndromeand mtDNA polymerase gamma-Alpers

IOSCA FRDA MSCAE POLG-Alpers

Clinical symptoms

Age at onset 52 y �2–60 y 5–50 y Infancy

Ataxia ++ ++ ++ +

Athetosis ++ (+) (+) +

Muscle hypotonia + � � ++

Ophthalmoplegia ++ � (+) +

Hearing deficit ++ (+) (+) (+)

Sensory axonalneuropathy

++ ++ +a +a

Cardiomyopathy � + � (+)

Cognitive impairment + � + ++

Psychiatric symptoms + � + +

Epilepsy ++b� ++ ++

Liver involvement + c� + ++

MRI

Spinal cord atrophy ++ ++ + +

Brain stem atrophy ++ + + ++

Cerebellar atrophy ++ + + ++

Stroke-like lesions ++ � ++ ++

Supratentorial brainatrophy

+ (+) + ++

mtDNA

Tissue-specificdepletion

+ � � +

Deletions � � + �

FRDA = Friedreich’s ataxia; y = years; �= not detectable; (+) = uncommon, mild;+ = mild to moderate; ++ = severe.

a Sensory and motor axonal neuropathy.b epilepsy in IOSCA occurs after the first decade.c the compound heterozygote IOSCA-patients had transient transaminaseelevation resembling the liver involvement in Alpers’ syndrome, and patientswith IOSCA, MSCAE and Alpers’ syndrome are susceptible to valproate inducedliver toxicity.


FundingHelsinki University Central Hospital EVO; Finnish Foundation for

Pediatric Research.

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