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Dopa-responsive dystonia Pathological and biochemical observations in a case.

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Dopa-responsive Dystonia: Pathological and
Biochemical Observations in a Case
A. H. Rajput, FRCPC,* W. R. G. Gibb, MRCP,t X. H. Zhong, PhD,$ K. S. Shannak, BSc,J
S. Kish, PhD,I: L. G. Chang, MSc,+ and 0. Hornykiewicz, MDI§
We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had
onset of foot dystonia at age 5 years and by age 8 years i t was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until
death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons. normal tyrosine
hydroxylase (TH) immunoreactivity and T H protein in the SN, no inclusion bodies or gliosis, and no evidence of a
degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and
striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution a?in idiopathic Parkinson’s disease. In the striaturn, TH protein and T H activity was reduced, with the loss more
pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate
and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic
capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive
Rajput AH, Gibb WRG, Zhong XH, Shannak KS, Kish S, Chang LG, Hornykiewicz 0. Dopa-responsive
dystonia: pathological and biochemical observations in a case. Ann Neurol 1994;35:396-402
Dopa-responsive dystonia (DRD), which constitutes
approxim;rtely 5 to 10% of primary dystonia of childhood and adolescence, is characterized by a dramatic
response to low-dose levodopa (LD) and absence of
the severe LD related motor fluctuations [l). The genetic pattern in D R D is consistent with autosomal
dominant inheritance with variable penetrance and
many cases appear to be sporadic [l, 2). Unlike idiopathic torsion dystonia (ITD) the frequency of D R D
is not increased in Ashkenazi Jews 11). D R D is twice
as common in females as in males El). The symptoms
usually begin in the lower limbs during childhood [ 11,
and diurnal fluctuations are reported in 66% [ 2 } to
76% [ 3 } of cases.
The available indirect evidence suggests disturbed
monoamine, especially dopamine (DA) metabolism in
DRD. This includes low cerebrospinal fluid homovanillic acid (HVA) and tetrahydrobiopterin (cofactor for
tyrosine hydroxylase {TH)) levels [4, 51, reduced fluorodopa uptake in the striatum in some patients 16, 71,
and shorter DA half-life [S}. Together with the LD
sensitivity of DRD patients, these observations point
to the nigrostriatal DA system as a possible site of
In the following, we report a D R D case who was
From the *University of Saskatchewan, Saskacoon, Saskatchewan,
and $Clarke Institute of Psychiatrv, Toronto, Ontario, Canada; i u n i versity Department of Neurology, Institute of Psychiatry, Denmark
~of ~ i ~ ~ ~pharmacology,
~ h ~ ~~ i
~ i l iLondon,
England;and g
University of Vienna, Austria.
clinically evaluated prior to and while on LD therapy.
A detailed histological and biochemical study of the
patient’s nigrostriatal system was conducted after autopsy.
Patient Report
A left-handed female of English-Irish ancestry was the youngest of 6 children. There was no family history of similar
disorder. Birth and development was normal until age 5 years
when she started walking on tiptoes, and progressively she
could not keep up with other children. By age 7 years there
was an intermittent involuntary flexion of the right wrist and
a tendency to fold the right arm across the chest. As a rule
she was worse in the morning, and after being up and about
for awhile, she would function better. As she got tired, she
became worse. O n walking for a short distance, the right foot
would turn in and a similar foot posture would evolve on the
left side after prolonged walking. When examined at age 8
years, the right foot tended to turn in and plantarflex (equinovarus), thus making her walk on the right and occasionally
o n both tiptoes, and the right arm was folded across the chest
when she walked. Dystonic hypertonicity was noted at the
right ankle and at the right wrist. Forearm pronationisupination, piano playing finger movements and foot tapping were
all slower on the right than the left side. There were no other
neurological abnormalities. There was no difference in size
between the sides in upper or lower limbs.
Received Jul 21, 1993, and in revised form Nov 24. Accepced for
oublicdtion Uec 20. 1993.
to Dr Raipw Division of Neurology,
~i Address
d ~ correspondence
Royal University Hospital, Saskatoon, Saskatchewan, Canada S7N
396 Copyright 0 1994 by the American Neurological Association
O n LD (without decarboxylase inhibitors) 250 mg three
times a day, there was a remarkable improvement within 2
weeks. She could now climb stairs, ride a bicycle, play hopscotch, and even her handwriting improved. Additional improvement over 6 months on treatment was noted and subsequently she remained stable. She had occasional abdominal
cramps after LD intake, which was controlled by taking the
medication after meals. After 7 months on LD, posture, tone,
and gait were normal and no neurological abnormality could
be detected. She remained well controlled on the same LD
dose for the remainder of her life. She finished high school
and held three different jobs, performing well at each one.
None of the other employees recognized that she had a disability. She died in an automobile accident at age 19 years.
Materials and Methods
Autopsy was performed 16 hours after death, caused by multiple chest and abdominal injuries, including a ruptured right
atrium. There was n o significant head trauma. The brain was
of normal external appearance and was frozen at -70"C,
immediately after autopsy. Blocks taken from left frontal,
temporal, parietal, and occipital regions of cerebral cortex,
hippocampus, basal forebrain, lentiform nucleus, caudate nucleus, thalamus, cerebellum, midbrain, pons, and medulla
were later fixed in neutral formol-saline and processed for
histology. Midbrain and pons were examined from 4 control
cases aged 15 to 23 years who died from hanging, supratentorial glioma, arteriovenous malformation, and human immunodeficiency virus (HIV) disease. Striatal tissue from 2 other
controls, aged 18 arid 20 years (sudden traumatic deaths),
was also examined. Sections of paraffin wax-embedded material ar 7-pm and 10-p.m thickness were prepared with classical histological stains. Counting of the pigmented and nonpigmented cells of the substantia nigra pars compacta was
done in two horizontal sections. Masson-Fontana stain was
used to identify melanin in the substantia nigra (SN) and the
locus ceruleus (LC), and the proportion of ventral and dorsal
tier nigral cells containing any visible melanin was examined
at 400 x magnification. For immunochemistry the peroxidase-antiperoxidase method and a streptavidin-biotin system
were used. Antisera to glial fibrillary acidic protein (GFAP)
at 1: 200 dilution (Dako Ltd, U.K., catalog no. 2 334), ubiquitin at 1 : 500 (Dako Ltd, catalog no. 2 438), and TH at
1 : 100 (affinitp-purified polyclonal, Pel-Freez Biologicals,
Rogers, AR, catalog no. P40101.0) were used in the SN, LC,
striatum, thalamus, and hypothalamus. Antiserum to calbindin D28kat 1 :800 (polyclonal, PC Emson) was used in the
Striatal Dissection and Biochemical Analyses
For biochemical anaiyses, striatal slices were taken from the
right frozen hemisphere. Striatal subdivisions were anatomically defined as previously published [9] throughout the rostrocaudal extent of the striatum and were taken from three
coronal ( 3 mm thick) slices of caudate (slice 2, rostral; slice
4,intermediate; and slice 7 , caudal) and putamen (slices 4 ,
7, and 10). I n addition, each slice was divided horizontally
into dorsal, intermediate, and ventral portions. The topographic details of the striatal slicesisubdivisions are shown in
Figure 1 of our previous publication [9}. Autopsy brains from
4 patients, with no neurological or psychiatric disease, of
mean age 20 t 4 years and mean interval between death
and freezing the brain, 13 ? 3.3 hours, were also studied.
Measurement of Dopamine NoviozJanillicAcid,
Tyrosine Hydroxylase Activity, and Tymrine
Hydroqlaj-e Protein Level
Dopamine and HVA levels were measured using the HPIelectrochemical procedure of Felice and colleagues IlO].
The TH activity was determined using minor modifications
of the procedure described by Nagatsu and co-workers El 11
and TH protein level was measured by western blot analysis
essentially as described by Labatut and associates 112) using
polyclonal antibodies (Pel-Freez Biologicals, catalog no.
Y40101.0, 1 : 500 dilution). The antigen-antibody complex
was visualized by the enhanced chemiluminescence western
blotting derection system (Amersham, RPN 2 106) following
incubation with protein A-horseradish peroxidase conjugate.
Relative amount of TH was quantified using an LKB UltroScan XL laser densitometer and results were expressed in
absorbance units (AU).
GBK Binding Assay
['H)GBR 12935 binding assay to measure presynaptic dopamine reuptake sites was performed using a modified procedure by Hitri and collaborators { 131. Membrane preparation
from 1 mg of human putamen or caudate was incubated in
1 ml of buffer containing 50 mM Tris, p H 7.4, 120 mM
CaCI, 5 mM KCI, and 1.1 nM I3H)GBR 12935 (specific
activity, 53.1 Ciimmol, New England Nuclear). Nonspecific
binding was defined by 1 p.M mazindol.
Tissue morphology was affected by freezing. The SN
and the paranigral nucleus showed a normal cell count
without gliosis. However, the number of cells that contained melanin was markedly reduced, notably in the
ventral tier of the SN pars compacta (Table 1) [14].
Numbers of medium and large nerve cells in other
tegmental nuclei, namely the Y group, retrorubral nucleus (A@, intracapsular nucleus, and central linear
nucleus were also normal. Despite distortions caused
by rhe freeze artifact, neuronal morphology in the
midbrain appeared normal. There were no abnormal
intraneuronal inclusions such as Lewy bodies (LB) or
neurofibrillary tangles, and there was no neuronal
irnmunostaining with ubiquitin. Round ubiquitin immunoreactive bodies often witnessed to be swellings
of nerve cell processes were frequent in the SN and
other parts of the midbrain in the D R D case, as well
as in the controls, but none in the distal nigrostriatal
tracts. Elongated swellings suggestive of LB were not
The degree of melanization in the normally pigmented SN cells was markedly reduced compared with
any of the control cases (Fig l A , B). Few ventral tier
Rajpur et al: Dopa-responsive Dystonia
Tuble 1 , Percentage of CelLr Containing Melanin in Ventral
and Dor.rai Tiers of Substuntia h'igra Pars Compacta
Dorsal Tier
51.1 f 1.6
dystonia patient
98.1 2 0.43
97.8 2 0.47
98.6 ? 0.37
94.4 t 0.73
85.4 t 1.10
89.9 t 0.99
Mason-Fontana stain was used and cells were examined at 400 x .
Values are mean I?r SEM. Differences between the patient and 3
controls and between the ventral and dorsal tiers of the pdtient are
highly significant ( p < 0.001). The lower percentage of melanized
cells in rhe dorsal tier of controls is probably due to inclusion of
pars reticulata cells in these counts.
nerve cells contained melanin and about half the dorsal
cells contained melanin (see Fig IA), but the amount
in each cell was below normal. The greatest proportion
of the cells containing any melanin was in the paranigral
nucleus, but here, too, the total quantity of melanin
remained low. The melanin content of TH-positive
cells in the other tegmental nuclei was also lower than
the controls. The striatum was of normal structure and
cell content; there was no gliosis and a normal population of calbindin immunoreactive cells. TH immunoreactivity in nerve cells and processes in the SN was
similar to controls, as was the normally greater intensity of immunoreactivity in the other tegmental nuclei. Bundles of strongly positive TH immunoreactive
fibers, of normal morphology, could be traced through
the zona incerta and through the putamen and caudate
tlucleus 'Fig 2A' *)' The Lchad a
and TH immunoreactivity'
Examination of other brain regions, particularly the
globus pallidus, putamen, and thalamus, found no
Table 2 shows markedly reduced D A level in the striatal nuclei of the DKD patient compared with agematched controls. In the whole caudate nucleus the
DA concentration was 18%, and in the whole putamen, 8C4 of the mean value for the controls. The concentration of D A metabolic end-product HVA was less
markedly reduced, being 42% of the control mean
value in the whole caudate nucleus and 41% in the
whole putamen. The ratio of HVA to DA was shifted
in favor of H V A in the caudate nucleus from the control value of 0.88 to 1.64 and in the putamen from the
control level of 1.05 to 4.44 (see Table 2). The SN
presented a picture similar to the striatum, with DA
level I!b of the normal and the HVAIDA ratio shifted
from 5.79 in controls to 23.25 in the D R D case.
The subregional D A distribution in the caudate nucleus and the putamen in the patient, when compared
with the normal controls, revealed an uneven rostro-
398 Annals of Neurology Vol 35 No 4 April 1994
(A)Ventval tier of the substuntia riigra pars compactu
in the dopa-responsizje dystonia case shouing a normal population of ce1l.C with pirtuall) no yijible melanin. IB/ Normal melanin
of ventral tier
in a contra(, (Masjon-Pontanu
Jtain, 400 before52% veduction,,
Fig I .
caudal and dorsoventral pattern of D A loss (Table 3).
Thus, in the caudate nucleus the rostral division suffered greater loss ( - 86%') than the caudal division
( - 78c/c).By contrast, in the putamen the caudal subdivision was more markedly affected (-77%) than the
rostral portion ( - 87% 1.
In all three analyzed rostrocaudal subdivisions of the
putamen, the dorsal and intermediate portions were
consistently more affected (average 97%: and 93%
loss, respectively) than the ventral (839%loss) portion.
In the head of caudate nucleus only the intermediate
rostrocaudal subdivision of the caudate head (slice 4)
showed a similar dorsoventral difference. The other
two rostrocaudal subdivisions of the caudate head
(slices 2 and 7) had a DA gradient in the opposite
direction; i.e., ventral portions were more affected.
The levels of HVA, although in each striatal subdivision lower than the corresponding mean control value,
did not strictly follow the rostrocaudal pattern of DA
loss (data not shown). This lack of parallelism can be
attributed to up-regulation of DA turnover in the remaining neurons (see Discussion) and was especially
apparent in the putamen.
As summarized in Table 4, TH activity was reduced
in both striatal nuclei of the DRD patient, with the
reduction in the putamen ( - 88%) being much higher
than in the caudate nucleus (-45%'~).
The TH protein was reduced ( - 81%) in the putamen and caudate (-40%)) of the D R D subject. The
TH protein level in the SN in the D R D case (mean
value of 2.95 Au) was not different from the controls
(2.75 i 1.24; n = 3).
Compared with the mean control value, the binding
of GBR 12935 to the DA transporter in the DRD
patient was not different from the control mean in the
caudate nucleus (-9%) but was at the lower end of
the range of controls in the putamen (see Table 4).
To our knowledge, this represents the first combined
clinical, pathological, and neurochemical study of a
D R D case. Our major findings include normal dopaminergic SN cell body density, TH immunoreactivity,
and TH protein level, but subnormal melanin and DA,
and a reduction of DA, TH activity, TH protein, and
1'H)GBR 12935 binding in the striatum.
In a previous study of 2 patients with ITD we did
not observe any change of striatal DA in the unresponsive case { 151; but in the other patient not given LD,
there was a mild striatal DA reduction {15]. In 2 additional LD-unresponsive ITD patients analyzed in our
laboratory, no striatal DA abnormality was detectable
(unpublished). The marked DA loss in the striatum of
the present case who showed an excellent response to
LD can, therefore, be taken as representing an important neurochemical feature setting it apart from the LD
unresponsive group of ITD patients.
The striatal D A in our patient was clearly below the
lower range of controls. Compared with the range of
Fig 2. (A) Tyrosine hydroxylase immunoreactive cells in the
dorsal substantia nigra in dopa-responsive dystonia (DRD).
(Bi Tyrosine bydroxylase immunoreactive fibers in the nigrostriatal bundle in DRD brain. (Hematoxylin countwstain,
x I00 before 32% reduction.)
Table 2. Doparnine and Hornovanillic Acid in Catldate Nucleus and Putamen in a Patien1
with Dopa-responsive Dystonia-Cornparicon with Controls
Caudate Nucleus (Whole)
(n = 4 )
Dopamine (DA)
Homovanillic acid (HVA)
Molar ratio of HVAiDA
5.94 ? 1.39
5.03 +. 0 87
(0.35- 1.35)
of Controls
Putamen (Whole)
of Controls
8.01 -t 1.59
(4 98-10.25)
8.15 2 1.60
(5.12- 10.61 )
105 t 0.39
(0.43- 1.83)
Values are mean 2 SEM (mrh ranges in parentheses), expressed as micrograms per gram of hesh tissue
DRD = dopa-responsive dystonia
Rajput et al: Dopa-responsive Dystonia
Y able -3.
Dopamine in a Patient with Dopa-respanshe Dystonza (RvJtroiaudaland DorsofientralGradients-
Comparzson uvth Controls)
Slice 7
Slice 4
Slice 2
Caudate nucleus (head)
Total slice
1n termed iate
5.27 t 1.00
6.75 f 1.67
5.14 +- 0.77
5.48 i 1.02
5.17 ? 1.25
6.29 ? 1.41
6.08 + 1.48
5.70 i 2.06
6.25 f 1.49
7.51 i 1.87
6.34 i 1.6?
Slice 4
Slice 7
Slice 1 0
Total slice
0.7 5
9.52 i 2.33
8.28 f 1.48
8.05 k 1.78
7.45 2 1.69
7.63 5 2.50
Values are mean f SEM and expressed as nanograms per milligram of tissue
Table 4. Tyrostne Hydroxylaset {'H)GBR 12935 Binding, and Dopamine Leiielj in Putamen and Cuiidute fiuileuJ
of the Patient zuzth Dopa-responsive Dystorzza and in Control Patients
Range In = 'r)
DRD patient
96 of reduction
Range (11 = 4)
DRD patient
% of reduction
Total Tyrosine Hydroxylase
Protein (Au)
Tyrosine Hydroxylase
(nmoli10 mg of proteini45 min)
['HIGBR I2935
(fmolimg of protein!
3 04
+ 0.50
4.42 -r 0.90
6.98 ? 1.1j
2.12 2 0.34
4.06 -+ 0.34
956 ? 83
849- 1,160
6.28 t 1.85
Values are mran 5 SEM.
Au = absorbance units; DRD
(pgigm of fresh tissue!
87 3
dopa-responsive dystonia.
"Rostra1 subdivision; bcaudal subdivision.
striatal D A reduction found by us &f in patients with
P D (0.25-1.07 pgigm in caudate, and 0.03-0.26 pgi
gm in putamen), the striatal D A loss in this patient
(caudate nucleus, 1.45 Fgigm; putamen, 0.56 kg/gm)
can be regarded as being in the preparkinsonian range.
Qualitatively, the pattern of the striatal DA reduction
in this case (with the exception of the subregional dorsoventral caudate gradient) was similar to PD [9].Since
our patient had received LD up to the day of death,
the possibility that the degree of DA loss was underestimated requires consideration. However, an acute effect of the last dose of the drug appears unlikely because the brain dopa levels in the patient were well
within the range of the controls (data not shown). Similarly unlikely is a prolonged increase in steady-state
D A levels produced by chronic LD because it would
400 Annals of Neurology
Vol 35 No 4
April 1994
require the improbable precondition of above-normal
storage capacity of the DA neurons.
As in P D and other brain disorders associated with
reduced striatal D A {l6], this case showed a shift in
the molar ratio of striatal HVA to DA in fiavor of
HVA, especially in the putamen. Assuming that the
endogenous HVA levels had not been significantly distorted by the LD therapy, as indicated by the normal
brain dopa levels, the marked shift of the ratio in favor
of the metabolite would reflect a compensatory upregulation of DA turnover in the DRD striatum.
The striatal DA deficit in our patient was accompanied by a reduction in dopaminergic markers that are
sensitive to nerve terminal loss, namely TH activity
and TH protein, suggesting that dopaminergic nerve
endings might have been reduced. Like the D A loss,
these changcs were more pronounced in the putamen
than the caudate. However another marker of D A terminals, i.e., GBR 129.35 binding to DA uptake sites
was normal in the caudate and still within the (lower)
range of controls in the putamen.
Despite the observed marked biochemical abnormalities in the nigrostriatal D A neurons we have not
identified a structural abnormality of these cell bodies
or their striatal projections. Although the melanin content and D A level of the SN neurons were subnormal,
nigral TH protein and immunoreactivity were normal.
Thus, the cause of the striatal and nigral biochemical
changes could not be loss of the entire nigrostriatal
D A neuron, as in PD, and may reflect an anomaly
of development or regression of the nerve terminals.
Another possibility would be an essentially biochemical lesion such as reduced D A synthetic capacity at the
level of TH activity involving, eg., failure of tetrahyd robiop terin production [ S ) .
The excellent clinical response of D R D patients to
LD therapy lends strong support to a cause-effect relationship between the striatal DA reduction and dystonia in this case. However, in spite of our demonstration
that D R D may have a biochemical brain abnormality
similar to PD, there are several clinical differences between these two conditions. These include the following: (1) Patients with D R D usually respond to LD with
more complete functional improvement than the P D
patients [ 1, 171, and some cases with dystonia of up to
58 years' duration have been found to respond dramatically r3f. (2) D R D patients require a far smaller dose
of LD (sometimes not more than 50 mg every other
day) and derive a more rapid and longer-lasting beneficial effect from a single dose (10-120 hr) than PD
patients [l). And (3), DRD patients maintain the response to LD over many years and do not develop
LD-related motor fluctuations, which are common in
PD El, 3, 181. Our patient had an excellent response
and no side effects after 11 years on LD. These peculiarities of D R D can be explained by our observations.
Thus, these response characteristics to LD could be
due to the less severe dopaminergic denervation compared with P D and the lack of evidence for a progressive pathology.
Juvenile-onset parkinsonism with dystonia can be
confused clinically with DRD in view of the similar
age and mode of onset { 3 , 7). However, like the adult
P D these patients generally develop motor fluctuations
on L-dopa therapy. This DRD case confirms that the
two disorders are pathologically distinct. In the 1 reported case of juvenile parkinsonism, there was selective degeneration of the ventral tier of the SN pars
compacta, and marked reduction of TH activity to
26%, of normal in the putamen and to 13% of normal
in the caudate nudeus E19, 20). Positron emission tomographic ["F)dopa studies show that clinically similar
patients have uptake in the range seen in PD, representing a greater deficit than documented in DRD [73.
Puthophysioloa and Etiolou of
Dopa-responsiw Dystonia
It is unclear why the striatal DA reduction, that was
insufficient to produce parkinsonism, was accompanied
by dystonia. Possibilities include the greater depletion
of ventral caudate DA, especially rostrally than is seen
in PD, and relative cholinergic overactivity in the
In principle, the striatal changes in presynaptic dopaminergic markers could reflect a selective reduction in
the number of D A terminals but with structural preservation of the corresponding nigral perikarya. The absence of gliosis or other obvious histological evidence
for a major nerve terminal loss speaks against a neurodegenerative process. Similarly, the nonprogressive nature of the dystonic condition as well as the distinct
pattern of striatal D A loss seem to exclude aging as
an etiologic factor t21). This favors a developmental
disturbance, such as insufficient embryonic establishment of the normal complement (arborization) of striatal DA terminals, accompanied by a lack of melanization in the nigral perikarya. An alternative explanation
would be grcater than normal retraction (narrowing of
the innervation fields) of the nigrostriatal DA neurons
during early postnatal development. This possibility
would be reminiscent of the reduction in striatal, but
not nigral TH activity, which takes place during the
first decade of life and is apparently unaccompanied by
actual loss of nigral neurons [22]. The above developmental explanations are compatible with our finding of
normal TH protein concentration in the SN, despite
its marked reduction in the striatum. Another possible
explanation for our findings would be reduced D A synthetic capacity of the nigrostriatal neurons.
We recognize that based on a single case all questions on the pathophysiology and etiology of DRD
cannot be answcred. Further studies are necessary for
the understanding of the dopa-sensitive condition associated with a lack of striatal DA.
We arc grateful for the provision of control material for pathological
studies from the MRC Alzheimer's Disease Brain Bank, Institute of
Psychiarry, and for the gift of calbindin antiserum from Dr P. C.
Emson, and to D r P. Siemens for referring this patient, and to Dr
Kail for the autopsy of rhis case.
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dopa, pathologic, observations, responsive, dystonic, case, biochemical
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