A JOURNAL OF NEUROLOGY
Recessive twinkle mutations cause severe
Tuula Lo ¨nnqvist,1Anders Paetau,2Leena Valanne3and 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 Lo ¨nnqvist,
Division of Child Neurology,
Helsinki University Central Hospital,
PO BOX 280, Helsinki, 00029 Finland
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
Infantile 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/awp045Brain 2009: 132; 1553–1562 |
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.
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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
Our 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).
We 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
or age at
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 EEG
abnormality, 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.
Brain 2009: 132; 1553–1562T. Lo ¨nnqvist et al.
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