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Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa-responsive dystonia.

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Biochemical and
Fluorodopa Positron
Emission Tomographic
Findings in an
Asymptomatic Carrier
of the Gene for
Dopa-responsive Dystonia
Hirohide Takahashi, MD,” Robert A. Levine, PhD,t
Matthew P. Galloway, PhD,S
Barry J. Snow, FRACP, FRCPC,*
Donald B. Calne, DM, FRCPC,’ and
Torbjoern G. Nygaard, MD§
In DRD, the therapeutic response to levodopa indicates a deficit in the dopamine pathway. Cerebrospinal
fluid (CSF) levels of homovanillic acid (HVA), tetrahydrobiopterin (BH4, a cofactor of tyrosine hydroxylase), and neopterin (a BH4 metabolite) are reduced
in DRD { 3 } , suggesting the disorder affects the nigrostriatal dopaminergic neurons.
Positron emission tomography (PET) with 6[‘8F]fluoro-l-dopa (FD) evaluates presynaptic nigrostriatal dopaminergic neurons in living humans 141. FDPET studies in DRD have been normal { 5 ] or near
normal 161, localizing the functional lesion proximal to
dopa decarboxylation.
We analyzed CSF dopamine metabolites and performed FD-PET in an asymptomatic DRD gene carrier.
W e report cerebrospinal fluid monoamine metabolite
analyses and G{”F]fluoro-l-dopa positron emission tomography (FD-PET) from an asymptomatic carrier of
the gene for dopa-responsive dystonia. Cerebrospinal
fluid homovanillic acid, tetrahydrobiopterin, and neopterin concentrations were reduced in this man and in
his affected children. His FD-PET was normal, as we
have previously found in dopa-responsive dystonia. Neurological function and FD-PET may be normal despite
marked abnormality i n dopamine metabolism.
Takahashi H, Levine RA, Galloway MP, Snow BJ,
Calne DB, Nygaard TG. Biochemical and
fluorodopa positron emission tomographic
findings in an asymptomatic carrier of
the gene for dopa-responsive dystonia.
Ann Neurol 1994;35 :154-3 56
Dopa-responsive dystonia (DRD) is a disorder typically
characterized by childhood-onset dystonia, concurrent
or subsequent development of parkinsonian features,
and a dramatic and sustained response to small doses
of levodopa {l}.Signs and symptoms in many DRD
patients worsen later in the day (diurnal fluctuation),
or after exercise. Autosomal dominant inheritance of
DR D is likely and women are affected more frequently
than men [23.
From the *NeurodegenerativeDisorder Center, Division of Neurology, University of British Columbia, Vancouver, British Columbia,
Canada; ?William T. Gossett Neurology Laboratories, Henry Ford
Hospital, and $Department of Psychiatry, Wayne Stare University
School of Medicine, Detroit, MI; and $Department of Neurology,
Columbia University, New York, NY.
Received Jul 3, 1993, and in revised form Aug 11. Accepted for
publication Aug 11, 1993.
Address correspondence to Dr Nygaard, Department of Neurology,
Columbia-Presbyterian Medical Center, 7 10 West 168th Street,
New York, NY 10032.
Our 3 subjects came from a Portuguese family with DRD.
The proband (3-1), her younger brother (3-2), and her paternal grandmother (1-2) were affected (Fig 1). Therefore, the
proband’s unaffected father (2-4) was an obligate carrier of
the gene causing DRD. He and his two affected children had
CSF analyses and he underwent FD-PET scanning.
Patient Histories
The proband (3-1 ) is a 16-year-old girl, who developed dystonia of the limbs (L > R) and tremor (L > R) when she was
3.5 years old. H e r dystonia worsened over the following
years; a modest worsening of symptoms occurred through
the day. She started taking levodopa at the age of 12 years,
with dramatic improvement in her symptoms. Her symptoms
are completely controlled by levodopa 125 mg (with carbidopa) a day.
H e r brother (3-2) is age 13 years. He had an uncomplicated forceps delivery at term. His early development was
normal except for delay in walking, which began, with difficulty, at age 18 months; he was diagnosed as having “cerebral
palsy.” H e subsequently developed generalized dystonia;
there was marked worsening of his symptoms through the
day. He became wheelchair bound at the age of 5 years. His
symptoms disappeared following levodopa treatment at the
age of 9 years; he is asymptomatic taking 200 mg of levodopa
a day (with carbidopab
The proband’s 7 1-year-old paternal grandmother (1-2) is
deceased. She developed difficulties running because of equinovarus posturing at the age of 8 to 10 years. However,
this improved spontaneously. In her early thirties, she again
became symptomatic for dystonia in her legs and developed
severe problems with balance. Examination by a neurologist
at age 70 revealed “parkinsonian” signs and dystonia. She
was never treated.
The 36-year-old father of the proband (2-4) has an unremarkable history and is completely asymptomatic. Examination revealed only bilateral pes cavus and mildly hyperactive
reflexes (with flexor plantar responses). H e had no sign of
dystonia o r parkinsonism on examinations at several different
times of the day and night.
Magnetic resonance imaging (MRI) scans of the brain were
Copyright 0 1994 by the American Neurological Association
Cerebrospinal Fluid Homovanillic Acid, Biopterin,
und Neopterin Levels of SubjectJ
2 -4
Agcat LP
The age-related normal values for homovanillic acid (HVA) and the
normal values for biopterin and neopterin were reported previously
Fig I . Partial family pedigree. AHected family members are
shaded. The PoJitron emission tomogruphy subject zs 2-4.
normal for both children. No other family members, including this man’s siblings and their children, were known to be
$j 0.20
Cerebrospinal Fluid AnaJyses
The 2 affected children had their CSF obtained prior to initial
treatment with levodopa. Subjects remained in bed, fasting,
from 11 PM until their lumbar puncture (between 7 and 9
AM). Successive aliquots of CSF were collected, immediately
put on dry ice, and kept at - 80°C until assayed. An aliquot
from a pool of 6-8 ml of CSF in children and 15-17 ml in
adults was assayed by high-pressure liquid chromatography
for HVA 173,and total biopterin and neopterin [31.
Fluorodopa Positron Emission Tomography
We employed the UBC/TRIUMF PETT VI system in the
high-resolution mode. Normals were age matched with subject 2-4. FD was administered intravenously, 1 hour after
a 100-mg oral dose of carbidopa. A n attenuation scan was
performed with a ring source containing “Ge. During the
scanning period arterial blood samples were drawn to measure total radioactivity, 6 FD, and 3-0-methyl FD fractions.
Twelve sequential, 10-minute duration, emission scans were
performed. We calculated the steady-state FD uptake rate
constant for both whole striata by a graphical method [8}.
Cerebrospinal Fluid
T h e affected children and their father had reduced
H V A , BH4, and neopterin concentrations (Table).
Positron Emission Tomography
T h e FD uptake rate constants for the asymptomatic
carrier (2-4) were within the normal range (Fig 2).
We found evidence of abnormal dopamine (DA) metabolism in the asymptomatic father of our DRD pa-
Fig 2. Plot showing the,flzlorodopa uptake rate constant (mlstriatam-’ minute-!) for the subject and the normal controls.
tients. This was reflected in his severely reduced CSF
HVA. Although increased D A turnover shifts the normal HVAiDA ratio and may obscure their precise correlation C93, the substantial reduction in H V A in our
subject suggests a severe impairment in his DA production. His BH4 level was also significantly reduced,
well below levels found in early PD [lo]. Both this
and his level for the BH4 metabolite neopterin were
consistent with levels found in DRD {?I]. The findings
suggest that he not only has the DRD gene but also
has a dopaminergic deficit similar to his symptomatic
family members.
FD-PET was normal in this man despite the method
being sensitive enough to detect dopaminergic dysfunction in asymptomatic subjects with degenerative
nigrostriatal disease El 11. T h e neuropathological findings in the brain of a woman with D R D may provide
a basis for reconciling the PET, CSF, and clinical obser-
Brief Communication: Takahashi et al: FD-PET in Dopa-responsive Dystonia
vations [ 12). Striatal dopamine levels were severely
reduced (putamen 8%, caudate 18% of control) with
a normal number of nigral neurons; these neurons,
however, had reduced pigment. There was no evidence
of a degenerative process. Tyrosine hydroxylase (TH)
protein levels in the substantia nigra were normal while
TH protein levels and TH activity were reduced 40 to
88%) in the striatum. The parallel degree of reduction
of TH in this brain and the reduction of BH4 in our
subjects may indicate that BH4 is a marker for reduced
TH in DRD.
FD-PET measures neither the activity of TH (the
rate-limiting step in the metabolism of endogenous
DA) nor the intrinsic striatal pool of DA. FD is taken
up across the blood-brain barrier, decarboxylated to
fluorodopamine, and stored, probably in vesicles. A
defect at, or before, the hydroxylation of tyrosine
would therefore result in a reduced pool of striatal
DA (and reduced CSF metabolites) but may not affect
FD-PET. The PET findings therefore suggest structural
integrity of the nerve terminals, at least for DA storage.
This conclusion is bolstered by the normality of DA
transporter in the DRD brain (only 10% below control
mean in the caudate). Thus, our subject may have intact mechanisms to deal with a DA deficit, including
changes in the release, reuptake, and destruction of
DA [131. There may be other compensatory mechanisms, such as changes in postsynaptic DA receptor
density or sensitivity, which contribute C 141, however,
these have not been explored in DRD. Our subject
may have an even lower threshold for developing clinical symptoms than the 80% reduction in striatal DA
estimated as the threshold at which symptoms occur in
PD [I 51 because compensatory mechanisms are presumably impaired in PD. Thus, factors related to the
cause of dopaminergic dysfunction, and its impact on
related mechanisms, may be more important than the
degree of dysfunction in affecting FD-PkT.
This view is consistent with the late-onset parkinsonism seen in elderly relatives of patients with DRD [ 161;
these relatives also have normal FD-PET and presumably have a similar dopaminergic deficit to their young
dystonic relatives. Normal age-related attrition of the
nigrostriatal dopaminergic pathway I171 may have exceeded the level at which the compensatory mechanisms can maintain a person symptom free.
This work was supported, in part, by the Dystonia Medical Research
Foundation, the Medical Research Council of Canada, NIAAGIO687 (R.A.L.), and NIH-HD00914 (T.G.N.), PHS#MOlRR00645 (Pediatric Clinical Research Center and General Clinical
Research Center).
We are grateful to Carol B. Moskowitz, RN, and Linda M. Winfield,
R N , for their help in the CSF collections and to the members of
the UBC/TRIUMF PET group for their assistance.
356 Annals of Neurology Vol 35 No 3 March 1994
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carrier, dopa, responsive, tomography, dystonic, emissions, genes, positron, findings, biochemical, asymptomatic, fluorodopa
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