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An Apparently Sporadic Case With Parkin Gene Mutation in a Korean Woman
Beom S. Jeon, MD, PhD;
Jong-Min Kim, MD;
Dong-Soo Lee, MD, PhD;
Nobutaka Hattori, MD, PhD;
Yoshikuni Mizuno, MD, PhD
Arch Neurol. 2001;58:988-989.
ABSTRACT
Objective To report the clinical features and results of iodine I 123-2ß-carbomethoxy-3ß-(4-iodophenyl)-tropane
(CIT) single photon emission computed tomography and molecular genetic analysis
in a Korean woman with juvenile Parkinson disease with deletion in exon 4
of the parkin gene.
Design Case report with molecular genetic analysis.
Patient and Results The patient had bradykinesia, postural imbalance, and postural tremor
since the age of 12 years. She developed wearing off early in the disease
course. The [123I]-2ß-carbomethoxy-3ß-(4-iodophenyl)-tropane
single photon emission computed tomography showed severe reduction of specific
striatal CIT binding, comparable to that of Parkinson disease. The polymerase
chain reaction products from the parkin gene showed
homozygous exon 4 deletion.
Conclusion In this sporadic juvenile Parkinson disease case, severe nigrostriatal
dopaminergic damage and homozygous exon 4 deletion in the parkin gene were demonstrated.
INTRODUCTION
KITADA ET AL1 reported a new gene defect
causing autosomal recessive juvenile Parkinson disease in Japan. Since their
report, evidence of other ethnic groups showing mutations in the same gene
has been published,2, 3, 4
and the phenotype is not limited to juvenile onset,2
signifying the importance of this parkin gene. As
a part of a systemic search for the genetic cause of parkinsonism in the Korean
population, we are screening mutations in the parkin
gene in patients with earlier onset of Parkinson disease. We identified a
patient with juvenile Parkinson disease who had a homozygous exon 4 deletion.
PATIENT AND METHODS
The patient was briefly described as having juvenile Parkinson disease
by Jeon et al.5 This 20-year-old woman had
bradykinesia and tremor at the age of 12 years. She noted micrographia, leg
dragging, and a tendency to fall. When seen at the age of 15 years, she had
an impassive face, bradykinesia, mild rigidity that was worse on the left
side, postural imbalance, and postural tremor. She did not have autonomic
and cognitive changes. She had mild sleep benefit. Her father died of injuries
sustained in a motor vehicle accident at the age of 40 years. At the time
of the accident, he was reportedly healthy. Her mother and younger brother
are healthy. Combined treatment with levodopa (100 mg) and benserazide (50
mg) (Madopar), 100 mg/d, and lisuride, 0.2 mg thrice a day, was started with
complete resolution of neurological deficits. In 6 months, she developed wearing
off. A combination of slow-releasing levodopa (200 mg) and benserazide (25
mg) (Madopar HBS), 100 mg twice a day, and lisuride, 0.4 mg 3 times a day,
were prescribed with a good response for 4 years. She is taking a combination
of selegiline hydrochloride, 5 mg twice a day, and levodopa, 200 mg, and carbidopa,
50 mg 3 times a day (Sinemet CR 1T) with motor fluctuation and dyskinesia.
The iodine I 123-2ß-carbomethoxy-3ß-(4-iodophenyl)-tropane(CIT)
single photon emission computed tomography (SPECT) was done at the age of
17 years. An [123I]-ß-CIT SPECT was performed and analyzed
by the procedures described by Jeon et al.5, 6
To investigate mutations in the parkin gene, we used the methods
described in Kitada et al.1
Informed consent was obtained from all the participants after explaining
about the experimental nature of the analysis of parkin gene
and CIT SPECT study. The institutional review board of the hospital approved
the genetic study and [123I]-ß-CIT SPECT study.
RESULTS
The [123I]-ß-CIT SPECT showed severe reduction of specific
striatal CIT binding; specific striatal-to-occipital binding ratios were 2.35
on the right side and 2.57 on the left side (Figure 1B, and the case of juvenile Parkinson disease reported in
Jeon et al5). The CIT SPECT done on her mother
showed specific striatal-to-occipital binding ratios of 4.42 on the right
side and 4.57 on the left side, which are normal for her age (Figure 1C).
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Figure 1. The iodine I 123 -2ß-carbomethoxy-3ß-(4-iodophenyl)-tropane
(CIT) single photon emission computed tomography in a normal subject (A),
our patient (B) (Reprinted with permission from Annals of Neurology6), and our patient's mother (C). The
CIT binding is high in the striatum in the normal subject. Striatal CIT binding
is decreased in our patient, but is normal in our patient's mother. See "Methods"
section in Jeon et al.5 Parkin indicates Parkinson
disease.
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Gene study showed homozygous deletion of exon 4 of parkin gene (Figure 2). This
mutation was not seen in her mother or in her younger brother.
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Figure 2. Polymerase chain reaction analysis
of our patient. Lane 1 is a 100–base-pair ladder marker. Lanes 2 through
6 are polymerase chain reaction products of the numbered exon from the parkin gene. In lane 4, the polymerase chain reaction product is absent.
See "Methods" section in Kitada et al.1
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COMMENT
The classic phenotypes of patients with parkin
gene mutation are juvenile onset, autosomal recessive inheritance, sleep benefit,
early good levodopa response and rapid appearance of motor complication, and
the absence of cognitive and autonomic dysfunction. However, gene testing
has shown that the onset may be as late as age 58 years, it may appear sporadic,
and sleep benefit may not be prominent. Even though our patient does not have
a family history for the parkin gene, she has homozygous
exon 4 deletion, suggesting that prevalence of heterozygous exon 4 deletion
is high. Lewy body, which is considered a pathologic hallmark of Parkinson
disease,7 is conspicuously absent in an autopsied
case with parkin gene mutation.8
However, CIT SPECT study of our patient showed that the pattern of decrease
in the dopamine transporter (ie, worse in the caudal part of the striatum)
is quite similar to that of Parkinson disease. The degree of decrease in striatal
CIT binding was very severe compared with other patients with Parkinson disease
in our study. Severe nigrostriatal dopaminergic damage and absence of nonmotor
symptoms in our patient suggest that the pathologic process is very selective
in this disease. Striatal CIT binding in the mother was normal, supporting
that this disease is a recessive disorder, and half of the gene is enough
to maintain the dopaminergic cell viability.
AUTHOR INFORMATION
Accepted for publication April 18, 2000.
The [123I]-ß-CIT SPECT study was supported in part by
grant 95-0403-96-3 from the Korea Science Foundation, Seoul, South Korea (Dr Jeon).
We gratefully acknowledge the technical assistance of Kyung-Min Kim,
MD, Seoul National University Hospital.
Data from the [123I]-ß-CIT SPECT study of normal control
subjects and patients with idiopathic Parkinson disease were described in
the authors' previous articles.5, 6
From the Departments of Neurology (Drs Jeon and Kim) and Nuclear Medicine
(Dr Lee), Seoul National University College of Medicine, and the National
University Hospital, Clinical Research Institute (Drs Jeon, Kim, and Lee),
Seoul, South Korea and the Department of Neurology, Juntendo University College
of Medicine, Tokyo, Japan (Drs Hattori and Mizuno).
Corresponding author and reprints: Beom S. Jeon, MD, PhD, Department
of Neurology, Movement Disorder Division, Seoul National University Hospital,
Chongno-Ku Yunkeun-Dong 28, Seoul 110-744, South Korea (e-mail: jeonmd{at}snu.ac.kr).
REFERENCES
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1. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605-608.
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