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Metabolic Characterization of Spinocerebellar Ataxia Type 6
Bing-wen Soong, MD, PhD;
Ren-shyan Liu, MD;
Liang-chih Wu, PhD;
Yi-chun Lu, MS;
Hsiang-ying Lee, MS
Arch Neurol. 2001;58:300-304.
ABSTRACT
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Background Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder
characterized by slowly progressive ataxia and dysarthria. The mutational
basis is an expanded CAG repeat sequence within the coding regions of the CACNL1A4 gene. Basic clinical, neuroimaging, and pathological,
and epidemiological features have been described in the literature. However,
the metabolic features of SCA6 have not been elucidated.
Objective To investigate the metabolic features of SCA6.
Patients and Methods Seven patients with SCA6 and 7 healthy individuals underwent positron
emission tomography using fluorodeoxyglucose F 18.
Results Cerebral glucose utilization in the 7 patients with SCA6 was characterized
by significant hypometabolism in widespread structures, including cortical
regions and basal ganglia, as well as the cerebellar hemispheres and brainstem.
Conclusions The results of the multiple-regional brain hypometabolism suggest that
brain dysfunction associated with SCA6 may not be limited to the cerebellum
and inferior olive, as previously suggested by the results of other pathologic
studies.
INTRODUCTION
DOMINANTLY inherited spinocerebellar ataxia (SCA) consists of a clinically,
pathologically, and genetically heterogeneous group of neurodegenerative disorders
that share clinical characteristics of progressive deterioration in gait and
balance (due to degeneration of the cerebellum and its pathways) and various
combinations of cerebral, extrapyramidal, bulbar, spinal, and peripheral nervous
system involvement.1, 2, 3
Classification of dominant SCAs on the basis of clinical symptoms has been
quite controversial because of the overlap in the clinical presentations.4 The genes causing 8 of these diseases, ie, SCA type
1 (SCA1),5 SCA2 (SCA2),6, 7, 8
Machado-Joseph disease and SCA3 (MJD/SCA3),9 SCA6 (SCA6),10
SCA7 (SCA7),11 SCA8
(SCA8),12 SCA12 (SCA12),13 and dentatorubral-pallidoluysian
atrophy (DRPLA),14, 15
have been identified. The mutational basis for all of the disorders except
that of SCA8 is expanded CAG repeat sequences within the coding regions of
the involved genes. Detection of these trinucleotide repeat mutations has
enabled the classification of dominant SCAs on the basis of molecular analyses.
Spinocerebellar ataxia type 6 (Online Mendelian Inheritance
in Man 183086) was originally identified using the expansion of polymorphic
CAG repeats at the 3' end of the human  1A voltage-dependent
calcium channel subunit gene (CACNL1A4), which is
known to be important for Purkinje cell function and survival.10, 16
In the same gene, 4 missense mutations that cause familial hemiplegic migraine
and 2 mutations that disrupt the reading frame responsible for episodic ataxia
type 2 have also been identified.17
Clinically, SCA6 has been characterized as a "pure" cerebellar syndrome
belonging to autosomal dominant cerebellar ataxia type 3.10, 18, 19, 20
Magnetic resonance imaging of the brain in patients with SCA6 has demonstrated
cerebellar atrophy with no evidence of brainstem involvement.19, 21
Single-photon emission tomography has shown moderately decreased tracer uptake
in the cerebellum.22 Neuropathological study
results have shown marked cerebellar atrophy and very mild atrophy of the
brainstem.23 Microscopic examination results
have revealed severe loss of cerebellar Purkinje cells, moderate loss of granule
cells and dentate nucleus neurons, and mild to moderate neuronal loss in the
inferior olives.10, 23, 24, 25
However, the metabolic characteristics in the brain of individuals with SCA6
remain unclear. Positron emission tomography (PET) has been a useful tool
in elucidating the pathophysiological and metabolic characteristics of various
movement disorders, including Huntington disease,26
Parkinson disease,27 progressive supranuclear
palsy,28 and spinocerebellar degeneration.29, 30, 31, 32
In the present study, the objective was to clarify the metabolic characteristics
associated with SCA6 mutation using PET with fluorodeoxyglucose
F-18 (FDG).
SUBJECTS AND METHODS
SUBJECTS
Seven healthy individuals (4 men and 3 women) and 7 patients (4 men
and 3 women) with SCA6 underwent clinical evaluations by a board-certified
neurologist (B.W.S.). Age at onset was provided by the patient or close relatives.
Informed consent was obtained from all subjects before participation in the
study.
MOLECULAR STUDIES
Genomic DNA was isolated from peripheral leukocytes as previously described.33 Polymerase chain reaction analysis was performed
using the primers S-5-F1 and S-5-R1 for SCA6.10 The polymerase chain reaction condition was as described
in the original report.10 Alleles were separated
using electrophoresis on 6% polyacrylamide gels in parallel with an M13 sequencing
ladder and were analyzed as previously described.29, 33
PET STUDIES
The 7 patients with SCA6 (mean ± SD age, 51.7 ± 6.5 years),
identified by the presence of expanded CAG repeats in the SCA6 gene, and the 7 healthy control subjects (mean ± SD age,
46.0 ± 10.3 years) underwent PET using FDG. All subjects were awake,
taking no medication known to affect central nervous system function, and
blindfolded during the examination. The imaging device was an 8-ring whole-body
PET scanner (Scanditronix PC4096-15WB; Scanditronix, Uppsala, Sweden) with
an axial resolution of 6 mm and an in-plane resolution of 8 mm at the center
of the field of view. Twenty-two frames of dynamic PET images were acquired
for 120 minutes after intravenous injection of 370 MBq of FDG. Arterial blood
samples were drawn manually for use in obtaining the input function variables
for modeling cerebral metabolic rate of glucose (CMRGlc). Thirty-one regions
of interest (ROIs) were drawn manually for each patient in the cerebellar
hemispheres, brainstem, thalami, basal ganglia, and frontal, parietal, temporal,
and occipital cortices, and the corresponding time-activity curves were generated.
The mean (± SD) size of the ROIs was 1.6 ± 0.4 cm2
(range, 0.8-3.0 cm2). Extreme caution was exercised in the placement
of ROIs to avoid potential signal contamination from adjacent anatomical structures.
A modified Sokoloff 3 compartment model34, 35, 36
was used to describe and evaluate the CMRGlc in milligrams per minute per
milliliter using the graphic method of Patlak et al.37, 38
The physiological variable CMRGlc was defined as follows:
CMRGlc = Cp/LC x K,
where LC was the lumped constant that summarized
the differences between FDG and glucose in transportation and phosphorylation,
and was equivalent to 0.404 as previously reported39, 40;
Cp, the average glucose concentration in plasma from the blood samples during
the last 30 minutes; and K, the slope of the Patlak plot.37, 38
STATISTICAL ANALYSIS
Statistical analyses were performed using commercially available software
(SAS; SAS Institute Inc, Cary, NC). The null hypothesis was rejected for P<.01. Group data were compared using the Wilcoxon rank
sum test. The relationships between regional cerebral glucose metabolism and
age at onset, age at the time of PET examination, and duration of SCA6 illness
were assessed using Pearson correlation analysis.
RESULTS
CLINICAL FEATURES OF SCA6
The main clinical features of the 7 individuals with SCA6 in this study
are summarized in Table 1.
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Table 1. Clinical Features of 7 Patients With SCA6*
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PET STUDIES
Glucose metabolism rate was significantly lower not only in the cerebellar
hemispheres, but also in the brainstem, basal ganglia, and frontal, temporal,
and occipital cerebral cortices (Table 2 and Figure 1). However,
the ages at onset and at the time of PET examination and duration of the illness
did not correlate with CMRGlc.
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Table 2. Cerebral Glucose Metabolic Rate in Patients With SCA6 and
Healthy Controls*
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Fluorodeoxyglucose F 18 (FDG) positron emission tomography in patient
3 with spinocerebellar ataxia type 6 (SCA6) (A and B) and in a healthy control
subject (C and D). Relative to the healthy controls, the FDG uptake in the
cerebellar hemispheres, brainstem, basal ganglia, and frontal, temporal, and
occipital cortices was lower in all subjects with SCA6.
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COMMENT
The predominant clinical feature of our patients with SCA6 was cerebellar
ataxia (loss of balance and dexterity of handwriting) with an onset late in
adult life and a very slowly progressive disease course (Table 1). Although brisk deep tendon reflexes were frequently observed,
plantar response was normal in all of our patients, indicating that the upper
motor neurons were only slightly involved.41
Other noncerebellar features, eg, rigidity, gegenhalten, intellectual impairment,
and sphincter disturbances, were rarely found in our patients with SCA6. Patient
1 had a partial right abducens palsy and exhibited a horizontal diplopia on
looking toward the right side. Many of our patients also had exacerbation
of the sense of imbalance in a visually "busy" environment, as has been previously
reported by others with SCA6 (S. H. Subramony, MD, written communication,
May 10, 1999). Clinical features associated with other disorders caused by
mutations in the CACNL1A4 gene,17
ie, migraine, episodes of hemiplegia, or ataxia were checked for carefully
but rarely found in our SCA6 cohort, which is consistent with the findings
of Matsumura et al19 and Gomez et al.24 In all patients in this study, the disease had an
indolent course, which rarely progressed to severe disability during the first
10 years.
The widespread reduction of glucose metabolism (Table 2 and Figure 1)
ranged from 71% to 78% of the healthy controls in all structures except the
brainstem, where metabolic rate was 66% of that for controls, and cerebellar
hemisphere, where it was 63% of that for controls. These results were unexpected.
We exercised extreme caution during the study and ruled out the possibility
of a systematic error or a statistical phenomenon that might have caused low
values. Positron emission tomography has been shown to be very sensitive in
the detection of subtle subclinical abnormalities.26, 27, 28, 29, 30, 31, 32
The fact that hypometabolism was found in various brain regions does not imply
widespread neuronal degeneration but could simply reflect subclinical neuropathological
features, or metabolic dysfunction in structurally intact neurons. None of
our patients manifested symptoms referable to the basal ganglion or cerebral
cortices. Therefore, the clinical relevance of this observation is not clear.
The findings of several previous studies might add insight to the mechanisms
responsible for these discrepancies. First, a study of SCA1 transgenic mice demonstrated that considerable neuropathological
changes occurred without the manifestation of a neurologic phenotype.42 Second, there have been precedents of minor pathologic
abnormalities in clinically unexpected areas in other "pure system degenerations"
such as hereditary spastic paraparesis. Previous study results have also shown
that overt ataxia occurred in mice only after there was loss or dysfunction
of a substantial number (50%-75%) of the Purkinje cells.43, 44
Thus, it is likely that the absence of cerebral cortical and basal ganglia
symptoms in our patients reflects that neuronal cell dysfunction progression
in these patients occurred at an insufficiently rapid rate to cause symptoms
during the course of our observations. Third, many structures in the cerebellum
influence regional cerebral blood flow. Stimulation of the fastigial nucleus
has been shown to increase neurogenically the mean carotid blood flow in primates.45, 46 The cerebellar vermis projects by
way of the fastigial nucleus to the cortical and brainstem regions.47 Hence, cerebellar vermian atrophy theoretically could
alter the normal physiologic regulation of regional cerebral blood flow mediated
by the fastigial nucleus, resulting in regional hypoperfusion and hypometabolism.48 Further studies are warranted to investigate the
contribution of cerebellar structures to cerebral hypometabolism. Last, the
calcium receptor subunit affected by the SCA6 mutation
has been known to be expressed ubiquitously in neurons of the entire brain,
including the hippocampus, cerebral cortex, thalamus, hypothalamus, medulla,
inferior olivary nucleus, and the horizontal cells of the retina.49 In patients with familial hemiplegic migraine, which
is caused by point mutations in the CACNL1A4 gene,17 altered regional cerebral blood flow and a neuronal
dysfunction have been well described.48, 50, 51, 52
This finding might add to the evidence of the involvement of other cerebral
structures in calcium channel dysfunction. Altered channel characteristics
are expected to profoundly disturb the normal function of cerebral neurons.
Further studies in transgenic mice expressing mutant alleles of the CACNL1A4 gene will enable determination of the pathogenic
mechanism of SCA6.
CONCLUSIONS
Study of SCA6 by means of PET surprisingly indicated that significantly
reduced glucose uptake was present not only in the cerebellum but also in
other regions of the brain. Thus, SCA6 may not be a purely cerebellar syndrome.
Future comparison of PET findings in different subtypes of SCA may reveal
genotype-specific patterns of regional metabolic deficits in the brain, which
might sharpen the distinction between these genetically characterized forms
of SCA.
Since the submission of the manuscript, the gene causing SCA10 has also
been identified recently by Matsuura et al.53
AUTHOR INFORMATION
Accepted for publication September 29, 2000.
We gratefully acknowledge research support from grant NSC 87-2314-14-B075-021
from the National Science Council, Taipei, Taiwan, Republic of China, and
grants VGH88-352, VGH89-315, VGH89-389-10 from Veterans General Hospital–Taipei,
Taipei.
Presented as a poster at the 51st Annual Meeting of the American Academy
of Neurology, Toronto, Ontario, April 20, 1999.
We thank the families of patients with spinocerebellar ataxia whose
collaboration was essential to the present study. We would also like to thank
Michael Evans, MS, Society of Psychiatry, Taipei, for his critical reading
of this manuscript; Wen-yuan Shen, MS, for her statistical analyses; and John
Sung for his technical assistance.
From the Department of Neurology, National Yang-Ming University School
of Medicine (Dr Soong), and the Neurological Institute (Dr Soong and Mss Lu
and Lee) and PET/Cyclotron Center (Drs Liu and Wu), Veterans General Hospital–Taipei,
Taipei, Taiwan, Republic of China.
Corresponding author and reprints: Bing-wen Soong, MD, PhD, Neurological
Institute, Veterans General Hospital–Taipei, Taipei, Taiwan 112, Republic
of China (e-mail: bwsoong{at}vghtpe.gov.tw).
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