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Dopamine transporter density measured by [123I]-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia.

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Dopamine Transporter Densitv Measured by
[123I] P-CIT 'Single-Photon Lmission
n
*
*
Computed Tomography Is Normal in
Dopa-Responsive Dystonia
Beom S. Jeon, MD, PhD,* Jae-Min Jeong, PhD,? Sung-Sup Park, MD, PhD,$ Jong-Min Kim, MD,*
Young-Soo Chang, PharmD,? Ho-Chun Song, M D , t Kyeong-Min Kim, MS,t Keun-Young Yoon, MS,$
Myung-Chul Lee, MD, PhD,t and Sang-Bok Lee, M D , PhD*
The clinical distinction between dopa-responsive dystonia (DRD) and juvenile Parkinson's disease (JPD) can pose a
diagnostic challenge. Both conditions are dopa responsive. However, long-term L-dopa benefit is very different between
the two. The difference in the prognosis is due to presence or absence of nigral cell loss. In JPD, there is degenerative
nigral cell loss, whereas there are enzymatic defects in dopamine synthesis without cell loss in DRD. Mutations have been
found in the GTP cyclohydrolase I (GCH-I) and tyrosine hydroxylase genes in DRD. As the discovered mutations are
multiple and more are expected to be found, it is difficult to confirm or exclude DRD by mutation studies. Measurement
of cerebrospinal fluid (CSF) neopterin will detect DRD from mutations in the GCH-I gene but not from mutations in
tyrosine hydroxylase. The dopamine transporter (DAT) is a protein in the dopaminergic nerve terminals. (lR)-2PCarbo1nethoxy-3P-(4-['~~I]iodophenyl)tropane
(["31]P-CIT) is a ligand for the DAT, and it was shown to be a useful
nuclear imaging marker for neurons that degenerate in Parkinson's disease (PD). As DRD was shown to have a normal
DAT without nigral cell loss in a postmortem study, we predicted that the DAT measured in vivo by nuclear imaging
will be normal in DRD and will differentiate DRD from JPD. Therefore, we performed ['231]P-CIT single-photon
emission computed tomography (["31]p-CIT SPECT) in clinically diagnosed DRD, PD, and JPD, and examined
whether DAT imaging can differentiate DRD from PD and JPD. We then examined whether DAT imaging can provide
a screening tool for molecular genetic studies, by studying mutations in the candidate gene GCH-I and measuring CSF
neopterin. Five females (4 from two families, and 1 sporadic) were diagnosed as DRD based on early-onset foot dystonia
and progressive parkinsonism beginning at ages 7 to 12. All patients were functioning normally on L-dopa 100 to 250
mg/day for up to 8 years. SPECT imaging was obtained after intravenous injection of ['231]P-CIT; 15 healthy volunteers
served as normal control, and 6 PD and 1 JPD as disease controls. [1231]P-CITstriatal binding was normal in DRD,
whereas it was markedly decreased in PD and JPD. Gene analysis showed a novel nonsense mutation in the GCH-I gene
in one family. No mutation was found in the other family or in the sporadic case. CSF neopterin was markedly decreased
in the 4 tested patients. [1231]p-CITSPECT is a sensitive method for probing the integrity of nigrostriatal dopaminergic
nerve terminals. A normal striatal DAT in a parkinsonian patient is evidence for a nondegenerative cause of parkinsonism and differentiates DRD from JPD. Finding a new mutation in one family and failure to demonstrate mutations in
the putative gene in other cases supports the usefulness of DAT imaging in diagnosing DRD.
Jeon BS, Jeong J-M, Park S-S, Kim J-M, Chang Y-S, Song H-C, Kim K-M, Yoon K-Y, Lee M-C, Lee S-B.
Dopamine transporter density measured by ['231]P-CIT single-photon emission computed tomography
is normal in dopa-responsive dystonia. Ann Neurol 1998;43:792- 800
When a young person presents with parkinsonism and
dystonia, dopa-responsive dystonia (DRD) and juvenile
Parkinson's disease (JPD) are two major differential
diagnoses. Both conditions present with early-onset
parkinsonism and dystonia. 1-3 Diurnal fluctuation and
early L-dopa response do not differentiate the two.
Both are familial in a high percentage of the patients.
The critical difference between these two condit-ions is
long-term L-dopa benefit. L-Dopa response is sustained
and dopa-related complications such as motor fluctuation and dyskinesia do not appear in DRD,* whereas
L-dopa dosage needs to be increased and there is an
From the Departments of *Neurology, ?.Nuclear Medicine, and
$Clinical Pathology, College of Medicine, Seoul National University, Seoul National University Hospital, Seoul, Korea.
Address correspondence to D r Jeon, Department of Neurology,
Seoul National University Hospital, Seoul 110-744, Korea.
Received Jun 11, 1997, and in revised form Sep 25. Accepted for
publication Jan 6, 1998.
792 Copyright 0 1998 by the American Neurological Association
early development of motor fluctuation and dyskinesia
in JPD.4 As the prognosis is very different in DRD and
JPD, clinical distinction becomes very important.
The differences in long-term L-dopa benefit and
prognosis in these two conditions are due to underlying neuropathological and biochemical differences.
Pathological studies in JPD, although very limited in
number, show that there is degenerative neuronal loss
and that there are Lewy bodies in the substantia
nigra5z6suggesting that JPD is on a spectrum with Parkinson's disease (PD), whereas there are enzymatic defects in dopamine synthesis without nigral cell loss in
DRD.7p9Progressive nigral cell loss in JPD limits the
capacity in the nerve terminals to take up L-dopa, metabolize it into dopamine, and store and release dopamine in a steady fashion, and thus allows wide fluctuation in striatal dopamine levels and the appearance of
fluctuations and dyskinesia in later stages of the disease. In DRD, there is no nigral cell loss.' (Even
though reported as DRD, the case of Olsson and colleagues6 is believed to be JPD based on clinical description.) Genetic defects in dopamine synthetic pathway
limit dopamine formation. Mutations were discovered
in the GTP cyclohydrolase I (GCH-I)7" and tyrosine
hydroxylase (TH) genes. l o Tetrahydrobiopterin (BH4)
is a cofactor for TH (Fig 1). GCH-I is an initial and
rate-limiting enzyme in the synthesis of BH4. Mutations in the GCH-I and T H genes limit formation of
L-dopa from tyrosine. Therefore, giving L-dopa bypasses this defective step and can restore dopamine forFig I . The biosynthetic pathway of tetrahydrobiopterin (BH4)
JFDm guanosine rriphosphate (GTP). BH4 is a cofictor of ty-
rosine hydroxylase (TH). TH is a rate-limiting enzyme in
dopamine synthesis. GTP ryclohydrolase I (GCH-I) is an initial and rate-limiting step in the synthesis of BH4. Therefore,
decrease in TH or GCH-I activity results in decreased dopamine synthesis. Neopterin is a degradation product of dihydroneopterin triphosphate, which is the intermediate formed by
GCH-I. Therefore, neopterin level indirectly rejects GCH-I
activity. ~-Pyruvoyl-tetrahydropterinsynthase (6-PPH4 synthase), sepiapterin reductase, and dihydropteridine reductase
(DHPR) are other enzymes in the BH4 metabolism. Defects
in 6-PPH4 synthase and DHPR have been reported to cause
dystonia responsive to L-Dopa (see text for details).
Guanosine triphosphate(GTP)
NeoDterin
1 [GCH-I]
I
*---Dihydroneopterin triphosphate(NH,P.)
6-PPH. synthase
I
6-Pyruvoyl-tetrahydro~terin(6-PPHJ
1 spiapterin r d w t a s c 1
1
Tetrahydrobimterin(EH.)
Dom
quinonoid Dihydrobio~terierin(qEH~)
mation. As conversion of L-dopa into dopamine is
steady, fluctuation and dyskinesia do not appear.
There are several difficulties in making an accurate
diagnosis of DRD. Clinical differentiation from JPD is
often difficult without long-term follow-up. There are
reports of DRD that were later shown to be JPD based
on the appearance of motor fluctuation and dyskine~ i a . The
~ , ~broad clinical spectrum of DRD is another
difficulty in making a clinical diagnosis. There have
and
been cases of DRD mimicking cerebral
adult-onset parkinsonism. l 3
Recent studies in molecular genetics and biochemistry have been very helpful in understanding the pathogenesis, and can help in making the diagnosis. There
are, however, limitations in making the diagnosis by
molecular genetic and biochemical studies. The mutation sites in the GCH-I gene are multiple, and different families have different mutation^.^,^,'^ Therefore, it
is necessary to fully sequence the entire gene to detect
possible mutations. In addition, a mutation in the TH
gene was found in an autosomal recessive DRD family.'" Thus, there are already multiple mutations linked
to DRD, and more mutations are expected to be
found. Therefore, it is difficult to diagnose or exclude
DRD by mutation studies. This point is further emphasized by the reports that no mutations were found
in some DRD
Neopterin is a degradation product of dihydroneopterin triphosphate, which is the first intermediate in
the biosynthesis of BH4 from GTP (see Fig 1). Dihydroneopterin triphosphate is formed from GTP by
GCH-I. Therefore, cerebrospinal fluid (CSF) neopterin
reflects the activity of GCH-I. CSF neopterin was decreased in DRD and differentiated DRD from earlyonset parkinsonism-dy~tonia.~~~
CSF neopterin will
detect DRD from mutations in the GCH-I gene, however, but not from mutations in other candidate genes
such as TH.
The dopamine transporter (DAT) is a protein located in the presynaptic dopaminergic nerve terminals,
and it provides a marker of dopaminergic innervation.15 It is logical to assume that the DAT is decreased in PD where there is nigral cell loss, and normal in DRD where there is no nigral cell loss. A
postmortem study showed that the DAT was decreased
in PD and correlated well with the dopamine level.'6
In vivo measurement of the DAT by nuclear imaging
also showed decreased DAT in PD.'7,'8 In contrast,
the DAT was normal when measured in vitro in an
autopsied case of DRD,' consistent with our logic.
Therefore, we predicted that in vivo measurement of
the DAT by nuclear imaging will show normal striatal
DAT in DRD, and will differentiate DRD from PD
and JPD.
(1R)-2~-Carbomethoxy-3~-(4-['231]iodophenyl)tropane (['231]P-CIT) is a ligand for the DAT and was
Jeon et al: Dopa-Responsive Dystonia
793
found to be a useful marker for dopamine neurons that
degenerate in PD. ['231]P-CITlabels the DAT with
high affinity a n d low nonspecific binding in prim a t e ~O
. ~n e~ clinical study demonstrated loss of striatal DAT by using ['231]P-CIT as a probe i n PD.18
[1231]P-CIT striatal binding correlated with severity of
the disease,20'21 and furthermore demonstrated bilateral loss of the DAT in hemi-PD,22 indicating that this
is a very useful and sensitive probe for nigrostriatal dopaminergic integrity.
Therefore, w e performed [lZ3I] P-CIT single-photon
emission computed tomography (SPECT) in clinically
diagnosed D R D , PD, a n d J P D , a n d examined whether
the DAT measured by i n vivo nuclear imaging study
will differentiate DRD from PD a n d JPD. W e then
examined whether ">AT imaging can provide a screening tool for molecular genetic studies by studying m u tations in the candidate gene GCH-I a n d by measuring
CSF neopterin i n clinically diagnosed and DAT studysupported DRD patienrs.
Patients and Methods
Since 1986, we have followed 9 (8 from two families, and 1
sporadic) DRD patients. Diagnosis of DRD was made by
the history of early-onset dystonia, parkinsonism, diurnal
fluctuation, and excellent L-dopa response without doparelated complications during long-term treatment. Workups
for the patients, which included routine blood chemistry, serum copper, ceruloplasmin, 24-hour urine copper, thyroid
function test, electroencephalography, electromyography, visual evoked potential, brainstem auditory evoked potential,
somatosensory evoked potential, and brain magnetic resonance imaging, were normal. The pedigrees are shown in
Figure 2. Clinical summaries of all patients are in the Table.
See the Table for patient identification. Among 9 cases of
DRD, 4 familial cases (2 from each family; see Fig 2, arrows)
and 1 sporadic case (Patient 9) were studied by using
[ i231]P-CIT SPECT. Numbered members in the pedigree
are the ones who had a gene study performed. Members who
are not numbered do not have any neurological symptoms
by history. CSF neopterin was measured in 4 patients (Patients 2, 6, 7 , and 9). [i231]p-CIT SPECT study and CSF
sampling for neopterin were approved by the Institutional
Review Board of the Hospital. Patients were informed of the
experimental nature of the study, and written consent was
obtained.
[1231]fl-CITSPECT Study
[ Iz3I]P-CIT was prepared from the corresponding trimethylstannyl precursor (Research Biochemicals International,
Natick, MA) and high radionuclidic puriry ['"I]NaI (Korea
Atomic Energy Research Institute, Seoul, Korea) by using
the method described by Zea-Ponce and colleaguesz3 with
minor modifications. Medication was stopped for 48 hours,
and 450 mg of iodine solution was given to the patients 1
day before the study. Each subject received an intravenous
bolus injection of 10 mci [Iz3I]P-CIT (370 MBq) at 6 PM.
Studies were performed by using a double-headed SPECT
camera (Prism 2000, Picker, Highland Heights, O H )
equipped with medium-energy collimators. The subject was
laid in a supine position, and the head was positioned to
obtain images in a plane parallel to the orbitomeatal line.
Scans were done at 1, 2, 18, 21, and 24 hours after injection.
Data were acquired with a 20% symmetric window centered
at 159 keV, 128 X 128 matrix (pixel size = 4.67 mm, slice
thickness = 4.67 mm), and reconstructed with a Butterworth filter (cutoff = 0.4 cycle/cm, order = 7). Attenuation
correction was performed by using Chang's method (linear
attenuation coefficient CI. = O.l/cm). Reconstructed images
were used to identify the brain anatomy and measure the
radioactivity. Striatal and occipital regions of interest (ROIs)
were positioned visually in the three contiguous brain slices
showing the highest radioactivity in the striatal region. The
striatal ROI was in an elliptical shape of 5 X 7 pixel size
(23.4 mm X 32.7 mm) to include whole striatum; and the
occipital ROI was positioned within each occipital area in a
round shape of 6 X 6 pixel size (28 mm X 28 mm). Ra-
Fig 2. Pedigrees of Dopa-responsive dystonia fdmilies K and C. Affected members are shown by filled circles (all the affected were
females). The ones numbered were examined and underwent a gene study. Arrows indicate those who underwent the [i2331]P-CIT
single-photon emission computed tomographic study.
Family K
Family C
I
I-
I1
I
I1
I11
111.1
~~
w
I
I 0
~~~
794 Annals of Neurology
111-3
111-2
~~
Vol 43
1114
~~
No 6
June 1998
I
I
11-2
rib
UL-5
1u-6
Table. Clinical Summary of tbe Patients
Age
Onset
(yr)/Sex (yr)
Initial Symptom
Patient 1
(K 11-2)
42/F
12
Patient 2
(K 11-31
30lF
7
Patients 3, 4
(K 11-4, 5)
24/F
11
Patient 5
(K 111-1)
6/F
1
Patient 6
(C 111-2)
241F
12
Patient 7
(C 111-4)
19lF
9
Patient 8
(C 111-6)
6/F
1
21lF
10
Patient 9
Additional Features
when Full Blown
Initial Examination
Walking difficulty, ante- Masked face, equinus
collis, trunk tilt,
and striatal toes, bradykinesia, Lt arm
speech difficulty,
both feet equinus, Lt
tremor, Lt hemiparehand tremor
sis, increased DTRs,
postural instability
Lt foot dystonia
Lt hand tremor, Lt el- Bradykinesia, postural
and rest tremor,
bow flexion on walkmaking a fist with Lt
ing, Lt thumb hyperflexion, scoliosis,
hand, torticollis,
torticollis, fatigue
trunk tilt on walking
Rt foot inversion
Trunk anteflexion, mak- Trunk anteflexion,
ing fist with both
making fist with
hands, Lt arm dystoboth hands, Lt arm
nia, writing difficulty,
dystonia
postural tremor of
both hands
Walking difficulty
Poor balance and hand Both feet equinovarus,
with tip-toeing
coordination, writing
impaired hand dexdifficulty
terity, scoliosis, increased DTRs
Lt foot equinovarus Writing and walking
Lt foot equinovarus,
difficulty, scoliosis,
both leg spasticity,
torticollis, fatigue
bradykinesia, postural
instability
Lt foot equinovarus Torticollis, tremor in
Both feet equinovarus,
making fist with
both hands, fatigue,
writing and walking
both hands, striatal
difficulty, dysarthria,
toe on Lt, increased
leg weakness
DTRs
Difficulty with writing
Walking difficulty
Lt hemiparesis, making
and piano-playing
a fist with Lt hand,
increased DTRs,
spastic wide based
gait
Twisting of body and
Torticollis, parkinsonLt foot dragging
ism
neck, walking and
writing difficulty
Hyperflexion of
both toe
L-Dopa Wearing
(mg)"
Off
250
2 days
100
36 hr
100
2-3 days
100
3 days
200
2 days
100
2 days
100
3 days
100
3 days
-
"L-Dopa was given with L-aromatic amino acid decarboxylase inhibitors.
Lt = left; Rt = right; DTR = deep tendon reflex.
dioactivities of striatal and occipital ROIs (expressed as
counts per pixel per minute, counts/pixel/min) in the three
slices were summed. Striatal radioactivities were summed
separately in the right and left, and occipital radioactivities
were summed together. Striatal specific binding was estimated by subtracting occipital counts/pixel/min from striatal
counts/pixellmin, based on the low density of the DAT in
the occipital region.'* The right and left specific striatal-tooccipital binding ratios (S/O ratios) were calculated by dividing the right and the left striatal specific binding by the
mean occipital binding. Mean S/O ratios were used for data
presentation and analysis. Fifteen healthy volunteers (6 men
and 9 women) of ages 20 to 64 years (mean, 40.3 years) and
6 PD patients (2 men and 4 women) of ages 43 to 60 years
(mean, 53.2 years) served as controls. Five patients were in
Hoehn-Yahr stage 1, and one was in stage 2. A 17.5-yearold girl with JPD was also studied. This girl started having
parkinsonism at age 12, and has been showing motor fluctuation and dyskinesia for 1 year.
Gene Study
Venous blood was sampled in EDTA tube from all the numbered members in the pedigree and Patient 9. Genomic
DNA was isolated from white blood cells by the salting out
method. Genomic DNA was studied for mutations in the
GCH-I gene by using the method modified from Ichinose
and associates.'
CSF Neopterin
CSF was obtained in Patients 2, 6, 7, and 9. The patients
did not have any inflammatory or neoplastic conditions at
the time of the CSF examination. CSF was sampled between
9 and 10 AM, and stored in a -80°C freezer until assayed.
Jeon et al: Dopa-Responsive Dystonia
795
Total neopterin was measured by high-performance liquid
chromatography with a fluorometric detector. As a disease
control, CSF neopterin was measured in 4 patients with parkinsonism or dystonia from causes other than DRD.
Results
['"Ilp-CIT SPECT Study
The results from measurements at 18, 21, and 24
hours were similar, and the results at 18 hours are described. Figure 3 shows the SPECT images of a 20year-old normal control, 30-year-old DRD Patient 2,
and a 17-year-old JPD patient. In normal controls,
[1231]P-CIT binding was very high in the striatal region and low in other areas including the occipital areas as shown in Figure 3a. In the PD patients, ["31]pCIT binding was severely decreased in the striatal
region most pronounced in the caudal part. In JPD,
['231]P-CIT binding was severely decreased as in PD,
as shown in Figure 3b. [1231]P-CITbinding was normal in DRD as shown in Figure 3c. The S/O ratios
ranged from 4.5 to 9.67 (mean, 6.22; SD, 1.32) in
normal controls (n = 15), and from 6.98 to 9.24
(mean, 8.15; SD, 0.90) in DRD (n = 5). In PD (n =
6), the S/O ratios ranged from 2.66 to 4.35 (mean,
3.78; SD, 0.65). In the JPD patient, the right and left
S/O ratios were 2.35 and 2.57. Figure 4 summarizes
the results of the S/O ratios in these four groups. The
S/O ratios in DRD were within the normal range and
clearly higher than those of PD without overlap. The
JPD patient showed a very low S/O ratio, in the PD
range.
Gene Study
Initial workup to examine the originally described four
mutations in the GCH-I gene failed to show any mutations in all the samples. However, further examination of all six exons of the GCH-I gene demonstrated
a previously undescribed nonsense mutation at codon
position 114 (TCA -+TGA) in exon 1 of the GCH-I
gene in Family K (Fig 5). This mutation results in a
substitution of serine residue with a termination codon
(Ser'I4Ter). The patients were heterozygous in terms
of this mutation. The mutation was found in Family K
1-1, 11-2 (Patient l), 11-3 (Patient 2), 11-4 (Patient 3),
11-5 (Patient 4), and 111-1 (Patient 5), 111-2, 111-4, but
not 111-3. In Family C and Patient 9, mutations were
not found in all the six exons of the GCH-I gene.
Neopterin
Neopterin was less than 1 pmol/ml in all 4 DRD patients tested. In 4 disease control patients, the neopterin
level ranged from 2 to 5 pmol/ml (mean, 3 pmol/ml).
Discussion
Based on the history of early-onset dystonia, parkinsonism, diurnal fluctuation, and excellent L-dopa response without dopa-related complications during
long-term treatment, the clinical diagnosis of DRD is
firm. It is unlikely that they have JPD because of excellent L-dopa response without dopa-related complications for up to 8 years of treatment, and extremely
early-onset cases in some family r n e r n b e r ~ . Family
~.~~ K
(Patients 1-5) and C (Patients 6-8) are consistent
Fig 3. (1231]p-CITsingle-photon emission computed tomographic images of a normal control, a juvenile Parkinson j disease (JPD)
patient, and a patient with Dopa-responsive dystonia (DRD). [IZ3IJ/3-CITbinding is v e y high in the striatum in the 20-year-old
normal control (a) and the 30-year-old DRD Patient 2 (c), and is markedly decreased in the 17-year-old JPD patient (6).
796 Annals of Neurology
Vol 43
No 6 June 1998
0
..c.,
El 0
I
i
0
Normal
DRD
PD
JPD
Fig 4. Summary result of the [1z31]fl-CITspecific striataloccipital binding ratios (90 ratios) in the normal control, a
patient with Dopa-responsive dystonia (DRD), a patient with
Parkinson ? disease (PO), and a patient with juvenile Parkinson? disease (/PO. The ranges of the YO ratios in the normal control (n = 15) and DRD (n = 5) are similar. All the
S/O ratios in PD (n = 8 are below the ranges of the normal
control and DRD without overlap. The S/O ratio in /PO
(n = 1) is even lower, that is, in the PD range.
with autosomal dominant inheritance with incomplete
penetrance. Patient 9 may be sporadic, autosomal recessive, or from a family with incomplete penetrance.
As neopterin was decreased in Patient 9, she is most
likely to have a mutation in the GCH-I gene, and be
from a family with incomplete penetrance.
Our data demonstrate that the striatal DAT measured
by ['231]P-CIT SPECT clearly distinguishes PD and
from normal controls. A single case of JPD showed
severely decreased DAT in the lower PD range, consistent with the data that there is nigral cell loss in JPD,
and with the suggestion that JPD is on a spectrum with
PD. Five of our 6 PD patients were in Hoehn-Yahr
stage 1. The S/O ratios were lower than normal even in
the striatum ipsilateral to the clinically symptomatic side
in these hemi-PD patients, in agreement with the previous report that there is bilateral loss of the DAT in
hemi-PD.22
Our data that the striatal DAT is normal in DRD,
when measured in vivo by [1231]p-CITSPECT, are consistent with our prediction based on lack of nigral cell
loss, and in vitro measurement by [3H]GBR-12935.x
Previous fluorodopa positron emission tomography
studies demonstrated normal fluorodopa uptake in
DRD, 13226-28 whereas fluorodopa uptake was decreased
in JPD26 and adult-onset dystonia-parkinsonism.28 Although the fluorodopa positron emission tomographic
study differentiates DRD from JPD and PD, it examines a complex of decarboxylation, vesicular uptake, and
storage of fluorodopa. As DAT imaging directly measures the DAT density, it provides more pertinent information in this clinical setting. Positron emission tomographic scanners are not available in many centers;
however, DAT imaging can be done on SPECT scanners, and is therefore more accessible.
There has been diagnostic difficulty in reliably distinguishing DRD from JPD. Previous reports of DRD,
which were later shown to be ]PD based on a later
appearance of motor fluctuation and d y s k i n e ~ i a , ~ . ~ , ~ '
testify to this difficulty. Because (1) mutations in the
GCH-I gene were different in different families, (2)
mutations were not found in the GCH-I gene in some
clinical DRD cases, and (3) a mutation was found in
the TH gene in an autosomal recessive DRD family, it
is difficult to diagnose and exclude DRD by mutation
studies. Furthermore, deficiencies in dihydropteridine
reductase (DHPR)30 and 6-pyruvoyl-tetrahydropterin
synthase (6-PPH4 ~ y n t h a s e ) , ~ two
l - ~ ~other enzymes in
BH4 metabolism (see Fig l), may present with dystonia responsive to L-dopa, thus bringing these and other
candidate genes into the scene. CSF neopterin will detect DRD cases from mutations in the GCH-I gene
but not from mutations in other candidate genes such
as TH.
The clinical diagnosis of DRD in our cases is
strongly supported by normal DAT on ['231]P-CIT
SPECT, an evidence for normal dopaminergic innervation in the striatum and a nondegenerative basis of parkinsonism and dystonia. Demonstration of a novel mutation in one family further supports our diagnosis of
DRD and our proposal that [1231]P-CIT SPECT is a
useful tool to screen DRD for detailed molecular genetic studies.
The mutation in Family K is believed to be functionally significant. TCA + TGA is a nonsense mutation (Ser1l4Ter), so that translation will be stopped
prematurely at this position in exon 1, resulting in a
nonfunctional short polypeptide of 113 amino acids.
(The mutation in Patient 3 of Furukawa and coworkers' is the same nonsense mutation, TCA +
TAA, at the same position.) Direct measurement of
GCH-I activity will examine the functional significance
of this mutation. CSF neopterin was measured in one
of this Family K (Patient 2), and was less than 1 pmol/
ml. As neopterin reflects the activity of GCH-I activity,
we consider it as an indirect evidence of low GCH-I
activity.
In Family C (Patients 6 and 7) and Patient 9, low
CSF neopterin suggests low activity of the GCH-I enzyme. Absence of mutations in the exons of the
GCH-I gene suggests that mutations lie outside the exons in these cases. It makes the genetic confirmation of
the diagnosis more difficult, again emphasizing the
Jeon et al: Dopa-Responsive Dystonia
797
Fig 5. Sequence analysis of the GTP cyclohydrohse I (GCH-I) gene in Family K Direct sequencing of exon I shows a G -+ C
heterozygous mutation in the antisense strand (C + G in the sense strand) in all cases except K 111-3. K II-2, 11-4, and 11-5 are
not shown in the figure. Codon number includes initiation codon. See Figure 1 far patient ident$cation. K 11-3 and III-1 are the
symptomatic members, and show the mutation. K I-1, 11-1, III-2, and III-4 are asymptomatic, reflecting incomplete penetrance.
Cerebral palsy phenotype (K 111-1) has the same mutation as classic childhood-onset dystonia-parkinsonism phenotype (K 11-3). The
methods are as follows. Genomic D N A wdc isolatedfrom white blood cells by the salting out method. Exon I of the GCH-I gene
was amplijed by polymerase chain reaction (PCR), using primers of Ichinose and c01Leagues.~PCR was pe$ormed in a final volume of 50 pL, containing 200 ng genomic DNA, I0 mM Tris-HCl, pH 8.3, 1.5 mM MgC& 50 m M KCl, 250 p M each
dNTP, 25 pmol each primer, and 1.25 U Taq polymerase (Boehringer Mannheim, Indianapolis, IN). The DNA was denatured at
94"Cfor 5 minutes, then 32 cycles at 94"Cfor I minute, 60"Cfar 1 minute, and 72"Cfor I minute were pevformed, fallowed
by a final extension at 72"Cfor 7 minutes. PCR products were directly sequenced with the same primers, using Thermo Sequenase
radiolabeled terminator cycle sequencing kit (Amersham, UK).
need for other means of supporting the clinical diagnosis.
The concept and definition of Segawa disease or
DRD has been clinical. However, the broad clinical
spectrum makes the clinical definition less useful. Diurnal fluctuation and L-dopa response ate not limited
to DRD. The dramatic and sustained L-dopa response
can confirm the diagnosis; however, it requires a longterm follow-up. We now know that decreased dopamine synthesis from mutations in the dopamine synthetic pathway is the underlying basis of DRD.
However, the genetic definition and diagnosis of DRD
are neither simple nor practical. There will be cases of
DRD that meet every clinical definition but that cannot be confirmed by genetic study. Genetic testing will
not be able to exclude DRD either. CSF neopterin is a
good test to find DRD patients from the defective
GCH-I enzyme. However, it will not detect cases from
mutations in other candidate genes such as TH.
Therefore, we propose that DRD be defined as a
syndrome of selective nigrostriatal dopamine deficiency
caused by genetic defects in the dopamine synthetic
pathway without nigral cell loss. This definition fits all
the known clinical, biochemical, genetic, and pathological information on DRD. It covers all the typical and
atypical presentations of DRD with proven mutations,
and allows a diagnosis of DRD without requiring the
798 Annals of Neurology
Vol 43
No 6 June 1998
demonstration of gene mutations, which is not practical and may not be possible in some cases. Homozygous defects in GCH-I, DHPR, and 6-PPH4 synthase
can cause dystonia, but also cause other neurological
deficits such as mental retardation and seizures as
ell,^'-^* and therefore will be excluded by the definition because more than the nigrostriatal system is involved. This definition will exclude JPD or other degenerative disorders that have neuronal loss in the
nigra. Pathological demonstration of intact nigral neurons is included in the definition. DAT imaging will
provide the needed information on nigral integrity antemortem. Our definition of DRD is not only simple
but also practical, needing only clinical information
and DAT imaging.
We further propose the term "DRD-plus," defined
as inherited metabolic disorders that have features of
DRD and those features that are not seen in DRD.
This concept is useful in clinical and laboratory evaluation of patients who have some features of DRD but
who also have features that are not reported or expected to be seen in DRD. A comparable example of
nomenclature may be P D and "Patkinson-plus.'' Homozygous defects in GCH-I, DHPR, and 6-PPH4
synthase are good examples of DRD-plus. L-Aromatic
amino acid decarboxylase (AADC) deficiency is another example of DRD-plus. The reported twins had
developmental delay, generalized hypotonia, and oculogyric crisis,35 which can all be seen in early-onset
DRD. They reportedly showed diurnal fluctuation
(Ford B, personal communication). O n careful examination, the patients had features of autonomic instability such abnormal pupillary reactions, orthostatic blood
pressure change, and temperature instability. Laboratory investigation showed AADC deficiency, causing
decrease in both catecholamines and serotonin. In addition to the differences in clinical presentations in
DRD and DRD-plus, L-dopa response is another
hallmark in distinguishing DRD and DRD-plus. We
regard marked L-dopa response as an essential feature
of DRD. L-Dopa only partially reversed neurological
deficits in DHPR and 6-PPH4 synthase deficiency;
and dopamine receptor agonist was partially effective in
AADC deficiency. This is again analogous to the situation with PD and Parkinson-plus. However, the dichotomy may not always be clear-cut. Heterozygous
GCH-I mutations somehow have a selective nigrostriatal dopamine deficiency syndrome (which is DRD).
However, there may be a case of heterozygous GCH-I
mutation that has extreme loss of GCH-I activity, and
affects other neurotransmitter systems in addition to
nigrostriatal dopaminergic system. In this case, DRDplus would be the diagnosis, although the genetic defect is the same as in DRD. O n the other hand, there
may be cases that behave like DRD but have mutations
in the genes that usually cause DRD-plus. The features
of AADC deficiency closely resembled DRD in the
early stage, and the differential diagnosis would have
been difficult without close follow-up examination of
the patients, L-dopa trial, and laboratory investigation.
This clinical overlap between DRD and DRD-plus is,
again, similar to the clinical reality in P D and
Parkinson-plus.
Addendum
A case report that DAT is normal in DRD was published after submission of this m a n ~ s c r i p t . ~ ~
This study was supported in part by the Korea Science Foundation
(95-0403-96-3).
We acknowledge that gene analysis was done with the generous help
of Drs Segawa and Tsuji, in Japan. We thank the patients, the chief
residents of the Department of Neurology, and other participants in
the study. We also thank Dr Paul Greene for giving thoughtful suggestions.
This study was presented in part at the Third International Dystonia Symposium, October 9-11, 1996,j7 and at the 49th meeting of
American Academy of Neurology, April 12-19, 1997.38
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