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Biogenic amine metabolism in tourette syndrome.

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Biogenic Amine Metabolism
in Tourette Syndrome
Ian J. Butler, MB, FRACP, Stephen H. Koslow, PhD, William E. Seifert, Jr, PhD,
Richard M. Caprioli, PhD, and Harvey S. Singer, M D
Biogenic amine metabolism in the central nervous system of 9 children with Tourette syndrome was evaluated by
quantitation of their metabolites in cerebrospinal fluid by a gas chromatographic/mass spectrometric method.
Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene
glycol
(MHPG) were measured in CSF before and after oral administration of probenecid. Dopamine metabolism appeared
defective, as both baseline and accumulated levels of HVA after probenecid were decreased. Serotonin metabolism
also appeared defective in some patients with low baseline and low accumulated levels of 5-HIAA after probenecid.
Taken together with other clinical features of this disease, the results suggest an underlying disorder of dopamine
and serotonin metabolism in Tourette syndrome.
Butler IJ, Koslow SH, Seifert WE Jr, e t al: Biogenic amine metabolism in Tourette syndrome.
Ann Neurol 6:37-39, 1979
The syndrome of Gilles de la Tourette is characterized by childhood onset of chronic motor tics and
involuntary vocalizations [ 121. The precise cause has
remained speculative despite increasing evidence to
support a neurological [12, 163 and genetic [191 basis
for the disorder. The often dramatic response to
treatment with haloperidol, a dopamine receptor
blocking agent [l], the precipitation of the disorder
in some patients following administration of sympathomimetic agents [7], and the similarity of the
movements to those seen in patients with Ldihydroxyphenylalanine intoxication have suggested
that excessive dopamine may have a role in Tourette
syndrome [141.
Cerebrospinal fluid levels of biogenic amine
metabolites have been used as indicators of normal
and abnormal catecholamine and indoleamine metabolism in the central nervous system [7]. Probenecid loading with analysis of accumulated acidic
metabolites in CSF has permitted estimation of the
turnover of dopamine and serotonin [l o] and detection of neurotransmitter abnormalities not readily
discovered through analysis of metabolites under
steady-state conditions.
This study was done t o evaluate CNS dopamine
and serotonin metabolism in 7 children with
Tourette syndrome by quantifying homovanillic acid
(HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in
CSF before and after oral probenecid loading.
Norepinephrine metabolism in 6 children with
Tourette syndrome was studied by baseline measurements in CSF of the metabolite 3-methoxy-4hydroxyphenylethylene glycol (MHPG) [2].
From the University of Texas Medical School at Houston,
the National Institute Of Mental Health and St.
Houston,
Elizabeth's Hospital, Washington, DC, and The Johns HoPkins
University School of Medicine, Baltimore, MD.
Accepted for publication Jan 2, 1979.
Address reprint requests to Dr Butler, Department of Neurology,
The university of T~~~ Medical School at H
~ p o B~~
~
20708, Houston, TX 77025.
TXl
Clinical Material and Methods
Nine children (7 boys and 2 girls) 5 to 13 years old (mean,
9.9) were studied. Each patient met the diagnostic criteria
of Tourette syndrome as outlined by Shapiro and associates
[12]; the clinical features in all but 1 patient have been
previously reported [ 131. Seven patients were studied before treatment with haloperidol or other medication, and in
2 children (Patients 7 and 8) haloperidol was discontinued
three weeks before the neurotransmitter studies. A single
baseline sample of lumbar CSF was obtained from 39 control children 2 to 15 years old (mean, 7.9) who were being
investigated for neurological and other disorders, e.g.,
neuromuscular conditions, headache, cerebral palsy, psychomotor retardation, and suspected infection of the CNS.
CSF was obtained by spinal puncture in the lateral decubitus position at approximately 9:00 AM after a 12-hour
period of bed rest and fasting with plentiful fluid intake.*
T h e initial 4 to 5 ml of CSF was collected in glass tubes
containing sodium metabisulfite, 10 mglml, or ascorbic
acid, 2 mglml, as preservative, and rapidly transported on
ice and stored at -70°C. Probenecid, 125 mg per kilogram
"This project was approved by an institutional committee for
human studies, and informed consent for lumbar punctures and
probenecid loading was obtained from parents or guardians or
from the child or adolescent in appropriate subjects.
0364-5134/791070037-03~01.25@ 1978 by Ian J. Butler
37
~
~
of body weight (3 patients) o r 175 mgikg (6 patients), was
administered orally in three or four divided doses. Eighteen hours after probenecid was started and 0 hours after
the last dose, a further sample of lumbar CSF was obtained
at 9:00 AM 111, 171. HVA, 5-HIAA, arid MHPG were
assayed by a quantitative gas chromatographdmass spectrometric method Ll5l and probenecid by a modified gas
chromatographic method [20].The data were analyzed by a
standard statistical method using t values computed for the
means of two populations.
Results a n d Discussion
The Table shows the results of CSF analyses for
HVA, 5-HIAA, and probenecid in the 9 Tourette
patients. In 6 patients the mean baseline level of
MHPG was 11.1 k 3.8 ng/ml; it was 13.0 5 4.0
ngiml in 36 control subjects.
Methods used in this study to investigate biogenic
amine metabolism in the CNS are those currently
available for studying patients with neurological disorders. Levels of H V A in CSF correlate with
dopamine levels in brain, particularly in neuronal
collections adjacent to the ventricles such as the basal
ganglia [g]. Levels of 5-HIAA in CSF reflect serotonin levels i n brain and spinal cord [GI and may not
necessarily indicate metabolism in serotonergic neurons adjacent to brain ventricles.
Most investigators measure the ratio of H V A or
5-HIAA levels in CSF before and after probenecid
loading to indicate dopamine and serotonin metabolism [8, 11, 171. Others use a single lumbar puncture
technique in which the ratio of metabolite to probenecid level in CSF is measured [31. In the 3 patients receiving probenecid at a dosage of 125 mgikg,
the levels of probenecid measured in CSF are known
to block egress of acidic metabolites from CSF to
blood and thus indicate CNS turnover of dopamine
and serotonin. In 1 7 neurological patients studied by
probenecid loading (Butler IJ, Seifert WE, Caprioli
RM: unpublished data, 1978) using a dose of 125 to
150 mg per kilogram of body weight, we have found
similar levels of probenecid (range, 17.3 to 47.1 with
a mean of 29.6 pg/ml of CSF). T h e value is comparable to that found in other studies using similar
techniques [3, 111. Because of ethical constraints, we
did not perform probenecid loading studies on nonneurological control children and instead correlated
our results with published H V A and 5-HIAA ratios
in adult control subjects [8, 11, 171.
The clinical features of Tourette syndrome suggest
excessive amounts of o r response to dopamine in the
CNS. Dopamine metabolism in the CNS is reflected
in baseline and accumulated levels of H V A in CSF
after probenecid IS, 171. O u r results show a significantly low mean baseline level of H V A in CSF
( p < 0.025) compared to age-matched control subjects (see the Table). In all children the ratios of
Monoamznr Metaboltter in CSF and Results of Prnbenerzd Loading in Tourette Syndrome"
Patient N o
Age (yr),
and Sex
.
I. 6, F
2 . 12, M
3. 5 , M
4.13, M
5 . 10, M
6. 10, F
7. 12, M
8. 10, M
9. 11, M
Probenecid
(wdml)
...
...
...
...
...
...
26.0
60. 5
38.3
Toure t te
children
(N
=
HVA
Before
After
42.2
42.9
99.0
42.6
34.7
68.0
60.9
81.3
79.1
124
187
67 3
61.2"
222.2
139
147
394
473.3
422.3
497.0
HVA
Ratio
Afteri
Before
2.9
4.4
6.8
3.3
4.2
5.8
7.8
5.2
6.3
339.6
iI 197.1
HVA
(after)/
Probenecid
Ratio
5-HlAA
Before
...
After
95.6
63.4
...
10.7
12.1
...
21.0
48.0
...
17.9
18.5
70.0
38.0
25.8
25.2
172
137
179
122.2
219.8
236
26.6
-tlH.2
k65.9
...
...
18.2
7.0
13.0
5-HIAA
Ratio
After/
Before
5-HIAA
(after)i
Probenecid
Ratio
8.9
...
...
...
...
5.2
2.3
9.6
7.4
2.6
...
3.2
4.7
3.6
6.2
8.5
9.4
...
141.4
9),
mean
age 9.9
Control
childrenb
101.5
245.1
%
30.2
16.7
(N = 391,
mean
age 7.9
aHomovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in CSF before and after probenecid administration.
"Mean values ? SD are in n d m l of CSF with the number of subjects in parentheses.
"Significant a t p c 0.025.
38 Anrials of Neurology
Vol 6
No 1 July 1979
HVA levels before and after probenecid were less
than the 9- to 40-fold increase reported in adults by
other investigators using a similar technique [8, 11,
171. One explanation for this apparent decrease in
brain dopamine turnover could be increased sensitivity at the dopamine receptor, resulting in a negative feedback response in the presynaptic dopamine
neuron [51.
The mean baseline level of 5-HIAA in CSF was
not significantly different from that in control subjects ( p > 0.10). However, baseline levels of 5-HIAA
were low in 2 patients (Nos. 1 and 2), and serotonin
turnover appeared impaired in several patients (Nos.
3 , 6 , and 7) as implied by a 5-HIAA ratio before and
after probenecid of less than the 4- to 12-fold increase
reported in adults by other investigators [8, 11, 171.
The reason for an apparent defect in serotonin metabolism in some patients with Tourette syndrome is
not apparent from these studies.
Norepinephrine metabolism in CNS, as reflected
in the baseline levels of MHPG in CSF [2], appears
normal in Tourette syndrome.
Our studies and those of Cohen et a1 [3] indicate a
disturbance in dopamine and possibly serotonin metabolism in brain of patients with Tourette syndrome.
Current treatment of Tourette syndrome includes
the use of agents to block dopamine action postsynaptically [ 11 or to increase serotonin metabolism
using the serotonin precursor 5-hydroxytryptophan
[ 181. Although treatment with haloperidol is successful in 80% of patients with Tourette syndrome
[l] , the lifelong nature of the disorder may necessitate prolonged treatment and thus an increased
possibility for onset of tardive dyskinesia [4].Recent investigations have suggested that heightened
dopamine receptor sensitivity may be the basis for
tardive dyskinesia [5, 211. If in fact Tourette syndrome is partly due to increased dopamine receptor
sensitivity, then treatment with agents which further
augment this sensitivity could potentially complicate
and compound the disorder. Further studies are indicated to define in more detail the demonstrated defect in dopamine and possibly serotonin metabolism
in Tourette syndrome so that more rational modes of
treatment can be developed.
Supported in part by a grant to D r Butler from the Huntington's
Chorea Foundation.
Presented at the Seventh Annual Meeting of the Child Neurology
Society, Keystone, CO, September 1978.
References
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patients with Gilles de IaTourette syndrome. Am J Psychiatry
1 3 3 9 4 4 4 4 7 , 1976
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3. Cohen DJ, Shaywitz BA, Caparulo B, et al: Chronic multiple
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17. Tamarkin NR, Goodwin FK, Axelrod J: Rapid elevation of
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18. Van Woert MH, Rosenbaum D, Howieson J, et al: Long-term
therapy of myoclonus and other neurologic disorders with L-5hydroxytryptophan and Carbidopa. N Engl J Med 296:70-75,
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Butler et al: Biogenic Amines in Tourette Syndrome
39
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