Parkinsonism associated with the homozygous W748S
mutation in the POLG1 gene
A.M. Remesa,b,*, R. Hinttalaa,b, M. Ka ¨rppa ¨a, H. Soinia,b,
R. Takaloc,d, J. Uusimaab,e, K. Majamaaa,b,f
aDepartment of Neurology, University of Oulu, Box 5000, FIN-90014, Oulu, Finland
bClinical Research Center, Oulu University Hospital, Oulu, Finland
cDivision of Nuclear Medicine, Oulu University Hospital, Oulu, Finland
dDepartment of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland
eDepartment of Pediatrics, University of Oulu, Oulu, Finland
fDepartment of Neurology, University of Turku, Turku, Finland
Received 21 September 2007; received in revised form 3 January 2008; accepted 6 January 2008
Parkinsonism has been described in patients with mutations in POLG1 gene. The W748S mutation is one of the most common mutations in
this gene and it has been found to be a frequent cause of autosomal recessive ataxia in adults and the Alpers syndrome in children. We found the
W748S mutation in a 65-year-old man with a late-onset syndrome consisting of ataxia, parkinsonism, ophthalmoplegia, peripheral neuropathy,
and sensorineural hearing loss. Parkinsonism is one of the phenotypic features associated also with the W748S mutation.
? 2008 Elsevier Ltd. All rights reserved.
Keywords: Mitochondria; Parkinson’s disease; Genetics; Dystonia
Deficiency of the respiratory chain enzyme complex I has
been demonstrated in tissues of patients with Parkinson’s dis-
ease (PD) suggesting mitochondrial involvement. Mutations in
genes encoding the mitochondrial protein PINK1 and two
other proteins related to mitochondrial function, parkin and
DJ-1, have been associated with autosomal recessive and
early-onset forms of PD . Mutations in mitochondrial
DNA (mtDNA) polymerase g (POLG1, NM_002693) may
also be present with parkinsonism  or with parkinsonism
associated with chronic progressive ophthalmoplegia (CPEO)
[3,4]. Interestingly, the W748S mutation in POLG1 has been
found to be a frequent cause of autosomal recessive ataxia
in the Finnish population , but this mutation appears to be
rare in sporadic idiopathic PD [6,7]. We report here a patient
with parkinsonism, CPEO, ataxia, peripheral neuropathy and
sensorineural hearing loss associated with the homozygous
W748S mutation in the POLG1 gene.
2. Case report
age 90 years. His father had died from acute myocardial infarc-
tion at age 70 years. The patient noticed gait and balance
difficulties at age 46 years. Five years later moderate ataxia
and CPEO were diagnosed after a neurological examination.
Brain CT showed mild cortical and cerebellar atrophy. EEG
was normal. Blood lactate and pyruvate concentrations were
normal, but CSF lactate was 3.6 mmol/l (laboratory reference
<2.8 mmol/l). Electrophysiologic
genic atrophy was seen in muscle and, furthermore, electron
microscopy revealed increased fat and accumulations of mito-
chondria with a few paracrystalline and numerous globular
* Corresponding author. Department of Neurology, University of Oulu, Box
5000, FIN-90014, Oulu, Finland. Tel.: þ358 8 3154245; fax: þ358 8 3154544.
E-mail address: firstname.lastname@example.org (A.M. Remes).
1353-8020/$ - see front matter ? 2008 Elsevier Ltd. All rights reserved.
Parkinsonism and Related Disorders 14 (2008) 652e654
osmiophilic inclusions. Other organ manifestations were not
detected. Oral glucose tolerance test was abnormal at the age
of 56 years.
Symmetrical bradykinesia and rigidity but only mild tremor
was noticed at the age of 60 years. Paranoid delusions also
appeared. Single photon emission tomography (SPECT) re-
vealed a markedly decreased123I-b-CIT uptake bilaterally in
putamen (Fig. 1). Levodopa was started and mild improvement
in motor functions was seen. Blood lactate (1.93e2.31 mmol/l;
laboratory reference 0.33e1.33 mmol/l) and pyruvate (107e
157 mmol/l; laboratory reference 30e80 mmol/l) were now
elevated. During the last 2 years of life he had marked rigidity,
dysphagia, myoclonic jerks and dystonia. He died at the age of
65 years from pneumonia. Autopsy was not done.
The patient was the third of seven siblings. The two elder
siblingshadbeen affected andtheyhadhadtheirfirstsymptoms
in their forties. The sister had developed progressive ataxia and
cerebellar atrophy had been detected in CT. It was also reported
that she had had tremor, difficulties in swallowing and marked
memory impairment in the later stages of the disease. She had
died at the age of 60 years. The brother had suffered from
progressive ataxia and epilepsy. Cognitive decline, fluctuating
double vision and sensory polyneuropathy were also present.
Cortical and cerebellar atrophy had been seen in brain CT. It
was also reported that later he had had mild tremor, abnormal
movements and memory impairment, but no difficulties in
swallowing. Before death he had suffered from frequent epilep-
tic seizures. He had died at the age of 64 years.
The protocol was approved by the Ethics Committee of the
Medical Faculty, University of Oulu, Oulu, Finland, and in-
Analysis of the entire mtDNA sequence revealed polymor-
tiple mtDNA deletions were seen in the muscle with extra long
(XL)-PCR. Sequencing of the exons in POLG1 revealed the
c.2243G /C transversion in exon 13 predicting a p.W748S
change in the linker region of POLG1, and the c.3428A /G
transition in exon 21, predicting a p.E1143G replacement.
We found the homozygous W748S mutation in the POLG1
gene in a man who was diagnosed with ataxia, CPEO, periph-
eral neuropathy and sensorineural hearing loss at the age of 50
years and who developed parkinsonism 10 years later. In
SPECT a markedly decreased123I-b-CIT uptake was observed
bilaterally in putamen supporting an idiopathic parkinsonism.
The patient had no vascular risk factors and had not suffered
from cerebrovascular events. Mild neuroleptic treatment was
started in the later stage of the disease.
Four dominant mutations in the POLG1 gene (Y831C,
Y955C, R953C, A1105T) have previously been found in
patients with parkinsonism and CPEO [3,4], while compound
heterozygote of mutations G737R and R853W has been
detected in association with parkinsonism without CPEO .
Interestingly, all the dominant mutations associated with par-
kinsonism and CPEO are located in the polymerase domain,
whereas the W748S mutation is in the linker region.
The W748S mutation results in the substitution of a highly
conserved amino acid and is a common cause of recessive
ataxia in the European population . The phenotype associ-
ated with the W748S mutation may vary from infantile Alpers
syndrome to adult-onset ataxia, peripheral neuropathy, dysar-
thria, mild cognitive impairment, involuntary movements,
psychiatric symptoms and epileptic seizures [5,8e10]. This
phenotype variation was also seen within the present family.
The initial manifestations of the proband were ataxia, ophthal-
moplegia, polyneuropathy and muscle weakness, while parkin-
sonism appeared in his sixties. The siblings had presented with
adult-onset ataxia and peripheral neuropathy resembling the
mitochondrial recessive ataxia syndrome (MIRAS) phenotype,
but they also had developed tremor or dystonia in their later
Fig. 1. Transaxial123I-b-CIT SPECT images showing (A) normal striatal dopamine transporter density in healthy control and (B) reduction of dopamine trans-
porters in striatal regions, especially bilaterally in putamen, of a patient with the W748S mutation in POLG1.
A.M. Remes et al. / Parkinsonism and Related Disorders 14 (2008) 652e654
life. The present case shows that parkinsonism is one of the Download full-text
phenotypes associated with W748S mutation in POLG1 and
suggests that the phenotype variation of this mutation is
This work was supported by grants from the Research
Council for Health at the Academy of Finland, the Finnish
Medical Foundation, Pa ¨ivikki and Sakari Sohlberg Founda-
tion, the Sigrid Juselius Foundation and the Neurology Foun-
We thank Ms Anja Heikkinen and Ms Pirjo Kera ¨nen for
their excellent technical assistance.
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