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Cerebellar hypermetria associated with a selective decrease in the rate of rise of antagonist activity.

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acid intermediates is sufficient to cause a degree of
NMD equivalent to that in ZS. While correlational
analyses may provide leads, the greatest promise for the
identification of disease mechanisms lies in the study
of animal models with targeted disruption of specific
peroxisomal genes by homologous recombination. The
human bifunctional enzyme has been cloned [13], and
studies to define mutations in BFD are in progress in
our laboratory.
peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency. Proc
Natl Acad Sci USA 1987;84:2494-2496
13. Hoefler G , Forstner hl,McGuinness MC, et al. cDNA cloning
of the human peroxisomal enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme and localization
to chromosome 3q26.3-3q28: a free left A h arm is inserted in
the 3’ noncoding region. Genomics 1994;19:60-67
14. Bjorkhem I, Sisfontes L, Bostrom B, et al. Simple diagnosis
of the Zellweger syndrome by gas-liquid chromatography of
dimethylacetals. J Lipid Res 1986;27:786-791
15. Roscher A, Molzer B, Bernheimer H, et al. The cerebrohepatorenal (Zellweger) syndrome: an improved method for the
biochemical diagnosis and its potential value of prenatal detection. Pediatr Res 1985;19:930-933
This work was supported in part by March of Dimes grant 6FY
92-769 (to H. W. M.) and by National Institutes of Health grants
H D 01046 (to W. E. K.), RR 00052, RR 00722, and H D 10981.
We thank Dr V. S. Caviness for his valuable comments and support
in the preparation of this manuscript, D r J. K. Boitnott for his
review of the liver specimens, D r G. Salen for measurement of the
trihydroxycholestanoic acid levels, and D r M . R. Natowicz for mass
spectrometric analysis of urinary bile acids. The myotonic dystrophy
gene assays were performed at the Kleberg DNA Diagnostic Laboratory from the Baylor College of Medicine.
Cerebellar Hypermetria
Associated with a Selective
Decrease in the Rate of
Rrse of Antagonist Activity
M. Manto, MD,* E. Godaux, MD,?
J. jacquy, MD,$ and 1. Hildebrand, MD*
References
1. Wilson G N , Holmes KG, Custer J, et al. Zellweger syndrome:
diagnostic assays, syndrome delineation, and potential therapy.
Am J Med Genet 1986;24:69-82
2. Volpe JJ, Adams RD. Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropathol (Berl) 1972;20:175-198
3. Evrard P, Caviness VS, Prats-Vinas J, et al. The mechanism
of arrest of neuronal migration in the Zellweger malformation:
an hypothesis based upon cytoarchitectonic analysis. Acta Neuropathol (Berl) 1978;41:109-1 17
4. Watkins PA, Chen WW, Harris CJ, et al. Peroxisotnal bifunctional enzyme deficiency. J Clin Invest 1989;83:771-777
5. Evans JE, Ghosh A, Evans BA, et al. Screening techniques for
the detection of bile acid metabolism by direct injection and
micro-high performance liquid chromatography-continuous
flow/fast atom bombardment mass spectrometry. Biol Mass
Spectrom 1993;22:331-337
6. Moser AB, Rasmussen M , Naidu S, et al. Phenotype of patients
with peroxisomal disorders subdivided into 16 complementation groups. J Pediatr 1995;127:13-22
7. McGuinness MC, Moser AB, Poll-The BT, et al. Complementation analysis of patients with intact peroxisomes and impaired
peroxisomal beta-oxidation. Biochem Med Metab Biol 1993;
4W28-242
8. du Plessis AJ, Kaufmann WE, Kupsky WJ. Intrauterine-onset
myoclonic encephalopathy associated with cerebral cortical dysgenesis. J Child Neurol 1993;8:164-170
9. Watkins PA, McGuinness M C , Raymond GV, et al. Distinction between peroxisomal bifunctional enzyme and acyl-CoA
oxidase deficiency. Ann Neurol 1995;38:472-477
10. Poll-The BT, Koels F, Ogier H, et al. A new peroxisomal disorder with enlarged peroxisotnes and a specific deficiency of acylCoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J
H u m Genet 1988;42:422-434
11. Chan-Palay V, Nilaver G, Palay SL, et al. Chemical heterogeneity in cerebellar Purkinje cells: existence and coexistence of
glutamic acid decarboxylase-like and motilin-like immunoreactivities. Proc Natl Acad Sci USA 1981;78:7787-7791
12. Schram AW, Goldfischer S, van Roermund C T , et al. Human
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Classically, cerebellar hypermetria observed during fast
and accurate movements i s ascribed to a delayed onset of
the electromyographic activity of the antagonist muscle.
We describe here 3 patients presenting a late-onset cerebellar degeneration and exhibiting a hypermetria during
their fast and accurate movements in spite of a normal
onset latency of the antagonist activity. Hypermetria was
found to be due to a slower rate of rise of the antagonist
activity.
Manto M, Godaux E, Jacquy J, Hildebrand J.
Cerebellar hypermetria associated with a selective
decrease in the rate of rise of antagonist activity.
Ann Neurol 1996;39:271-274
Hypermetria consists of a movement overshooting the
target when a patient attempts to perform fast and accurate movements. It is a classic sign of a lesion in the
cerebellum or in the cerebellar connections [I-41. In
healthy subjects, such movements are launched by a
burst of electromyographic (EMG) activity in the agonist muscle and braked by a burst of EMG activity in
the antagonist muscle [4-71. The major EMG abnor-
From the *Department of Neurology, H6pital Erasme, Bruxelles;
?Department of Neurophysiology, Faculty of Medicine, University
of Mons, Mons; and the $Department of Neurology, H6pital Civil
de Charleroi, Charleroi, Belgium.
Received Jul 18, 1995, and in revised form Sep 26. Accepted for
publication Sep 28, 1995.
Address correspondence to Prof Godaux, University of Mons, Place
du Parc, 20, 7000 Mons, Belgium.
Copyright 0 1996 by the American Neurological Association
271
mality associated with cerebellar hypermetria is a delayed onset of the antagonist activity [4,81.
We describe here another mechanism of cerebellar
hypermetria where the antagonist activity (the braking
force) starts at a normal latency after the onse: of the
agonist activity, but develops roo slowly to stop the
movement on time.
Subjects and Methods
Patients and Healthy Subjects
Three patients (3 men 48, 56 and 57 years old) presenting a
late-onset cerebellar degeneration were studied. Their family
history was unremarkable. The length of illness was 3 years
for Patient 1 and 2 years for Patients 2 and 3. The patients
were taking no medication. Neurological examination
showed cerebellar signs without any other neurological signs.
None of the patients had postural hypotension or urinary
incontinence. Brain magnetic resonance imaging (MRI) revealed isolated cerebellar atrophy in all 3 patients. This atrophy involved both cerebellar hemispheres and vermis in the
3 patients. Meanwhile, it was severe in the vermal and paravermal structures. Results of laboratory tests (complete blood
cell counts; liver and renal function rests; visual, brainstem
auditory, and somatosensory evoked potentials; serum levels
of vitamins B,,, E, and folic acid; and studies of thyroid
function) were normal. An extensive search for an occult
malignancy and serum and cerebrospinal fluid (CSF) antiPurkinje cell antibodies were negative. External urethral
sphincter EMG analysis was normal in the 3 patients.
Results of wrist flexion recordings in the 3 patients were
compared with those obtained in 9 healthy subjects (mean
age, 55 years; range, 36-79 years).
muscle may vary as a function of electrode position. The
activity of each muscle under examination was calibrated by
asking the patient to develop an isometric contraction against
a load that was intended to stretch the muscle. Calibration
for both agonist and antagonist activities was obtained by
loading the wrist with 200 gm using a pulley. For both the
agonist and the antagonist muscle, 15 rectified EMG activities developed during a I-second period of isometric contraction were averaged. The 1-second duration area extending
from the zero-potential line to the trace of the EMG activity
defined the calibration activity (measured in microvolts . second). For each muscle activity, the ratio of the corresponding
integrated EMG activity (expressed in microvolts second)
and of the calibration activity (measured in microvolts . second) of this muscle was computed. These ratios were expressed in arbitrary units (a.u.). To check the reliability of
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15
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5
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EMG
AGO
EMG
AGO
EMG
ANTA
-
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&
Kinematic and Electromyographic Recoiodirzg
The methodology for motion analysis was, for its major part,
previously described [9, 101. Briefly, each patient was asked
to make fast and accurate goal-directed wrist movements
with his fingers extended. In response to a “go” signal, horizontal wrist flexion had to be made toward a target located
15 degrees away from the scart position. Movement was recorded with a Selspot I1 system (Selcom). One infrared lightemitting diode (LED) was attached to the forefinger. Two
cameras, each fitted with a photodetector unit, recorded the
two-dimensional positioning of the LED. The activity of the
flexor carpi radialis (agonist muscle) and of the extensor carpi
radialis (antagonist muscle) was recorded by surface electrodes. EMG signals were differentially amplified, filtered
(2,000 X, 30-8,000 Hz), and full-wave rectified. For both
the agonist and the antagonist muscle, 12 full-wave rectified
EMGs were averaged (Pathfinder I, Nocolet Instrument,
Madison, WI) after aligning them to the moment when the
finger crossed a light beam received by a photoelectric cell
located 4 degrees away from the initial position.
The EMG activities were quantified by integrating EMG
activity over the acceleratory phase of the movement for the
agonist muscle or over the deceleratory phase of the movement for the antagonist muscle [I 11. Since we also wanted
to compare the EMG activities recorded in the 3 patients
with those recorded in healthy subjects, calibration became
a critical factor. Indeed, the recorded EMG activity of each
272 Annals of Neurology
Vol 39 No 2
February 1996
40 rnsec
, I
Y
20 msec
100 msec
Y
100 msec
= 20 a.u.
A
B
I ,
30 msec
u
100 msec
d-L
43 msec
Y
100 msec
C
D
Kinematic and electromyographic (EMG) features of fat and
accurate wrist flexion movements made by a healthy subject
(A) and by Patient 1 (B) and the agonist (AGO) (flexor
carpi radialis) and antagonist (ANTA) (extensor carpi radi(A, B)
alis) EMG activities in Patients 2 and 3 (C, 0).
Each top panel correspond to the superimposition of the individual records of position f . r I 2 jexion movements (target distance, 15 degrees). The middle and bottom panels
correspond to the averages of the fill-rectified EMG activities
associated with these 12 movements. Su faces of EMG activities are calibrated in arbitray units (a,..).
Comparison of the Kinematic and Electromyographic (EMG) Parameters of the Fast and Accurate Movernents Performed
by Health Subjects and by Our 3 Cevebellar Patients
Cerebellar function examinationh
Mean movement amplitudes (degrees)
Onset latencies of antagonist EMG activity
(msec)‘
Integrated agonist EMG activities”
Integrated antagonist EMG activitiesc
Rates of rise of agonist EMG activity‘
Rates of rise of antagonist EMG activityg
~
~~
Heal thy
Subjects
(n = 9)Z
Healthy Subject
Presented in Fig
Patient 1
Patient 2
Patient 3
15.6 2 0.9
41.0 f 11.0
15.3
40
T3A1H1D2
19.0
28
T2A3HOD 1
18.3
30
T2A2HODO
19.1
43
75.1
80.2
12.1
12.6
85.5
89.7
12.8
13.2
79.8
57.5
12.7
2.9
2 9.3
5 11.0
2 0.9
t 0.7
87.5
83.2
63.5
61
12.1
3.0
11.8
3.2
~~
’Values are mean i SD (n = 9).
bT = tremor; A = ataxia (stance/gait); H = hypotonia; D = dysarthria. Rating of clinical symptoms: 0 = normal, 1--4 = mild to severe
disturbance.
‘Values are measured from the onset of agonist EMG activity.
“Calibrated agonist EMG activity expressed in arbitrary units.
‘Calibrated antagonist EMG activity expressed in arbitrary units.
‘Rate of rise of the agonist EMG activity assessed by the measurement of 430 and expressed in arbitrary units.
‘Rate of rise of the antagonist EMG activity assessed by the measurement of 4 3 0 and expressed in arbitrary units.
this procedure, we computed the ratios described above on
3 successive days in 6 control subjects. The variation from
day to day never exceeded 3% either for the agonist or for
the antagonist muscle.
The rate at which both agonist and antagonist activities
rose was assessed by calculating the area under the calibrated
EMG curve for the first 30 msec after the onset of the EMG
activity (430) according to the method described by Gottlieb
and associates [ 1 11.
Results
The Figure compares the agonist and antagonist EMG
activities associated with fast and accurate wrist flexion
movements performed by a healthy subject and by all
3 patients. The most striking difference was a marked
decrease in the rate of rise of the antagonist activity
(compare the bottom traces of Figs B, C, and D with
that of Fig A). Moreover, the first and second agonist
EMG bursts were not clearly demarcated in the 3 patients (compare the middle traces of Figs B, C, and D
with that of Fig A). Contrasting with the movements
of the healthy subject, which were accurate (their mean
amplitude was 15.3 degrees, see Fig A), the movements
of the 3 patients were hypermetric (the mean amplitude was 19.0 degrees for Patient 1 [see Fig B], 18.3
degrees for Patient 2 [not illustrated], and 19.1 degrees
for Patient 3 [not illustrated]).
The Table compares the individual values of the kinematic and EMG parameters measured in the 3 patients with those recorded in a group (n = 9) of
healthy subjects. For each of the 3 patients, the mean
movement amplitude was higher than the upper limit
of the 95% confidence interval of the normal values,
while the rate of rise (430) of the antagonist activity
was below the lower limit of the 95% confidence inter-
val of the normal values. By contrast, for each of the
3 patients, the integrated EMG agonist and antagonist
activities, the latency of the onset of the antagonist activity, and the rate of rise of the agonist activity were within
the 95% confidence interval of the normal values.
Discussion
The major EMG abnormality associated with cerebellar
hypermetria repeatedly has been found to be a delayed
onset of the braking activity of the antagonist muscle
[4, 8, 12, 131. We here report another type of unsuitability between the launching force (agonist activity)
and the braking force (antagonist activity) also resulting
in a hypermetria. The 3 patients described were able
to develop a correct rate of rise of the agonist muscle
(the launching force) and the timing of the agonistantagonist activities was normal. However, they were
unable to develop a normal rate of rise of the antagonist activity (the braking force). As a result, an imbalance between the agonist and the antagonist EMG activities emerged and the patients overshot the aimed
target. Moreover, failure of the agonist EMG to pause
briefly at the end of the acceleratory phase of movement might also play a significant role in the genesis
of hypermetria. Since the vermal and paravermal parts
of the cerebellum were more seriously damaged in our
patients, it is possible that regional differences in cerebellar degeneration might account for different types
of cerebellar hypermetria. Our findings could also explain the observation of Holmes, who described a decreased tone of the antagonist activity in cerebellar patients [ 1-31.
In two previous studies, we demonstrated that while
a healthy subject was able to increase both agonist and
Brief Communication: Manto et al: A New Mechanism of Cerebellar Hypermetria
273
antagonist activity when an inertial mass was added to
the moving hand, patients with a cerebellar disease
could increase appropriately their agonist but not their
antagonist activity [9, 101. This suggested that the cerebellum was involved not only in tht: computation of
the onset latency of the antagonist activity, but also in
the preprogrammation of the intensity of the antagonist muscle. The present findings suggest that the cerebellum contributes to the genesis of a normal rate of
rise of the antagonist activity in the basal condition
(no load addition) and that the computation of the
rate of rise of the antagonist muscle rnay be selectively
altered in some cerebellar patients. Tlherefore, we suggest that the rate of rise of the antagonist muscle is a
parameter of ballistic movements that should be measured in patien ts exhibiting cerebellar hypermetria.
Our results lead LIS to suggest that one of the functions of the cerebellum is tu tune the shape of the antagonist activity during fast and accurate movements.
Flament and Hore [8, 141, studying fast and accurate
elbow flexion movements in monkeys, observed that
cooling the dentate nucleus resulted in a less-abrupt
onset of the agonist activity. However, discrepancy between our findings on wrist movements and the observations on elbow movements could be due to differences in the involved inertias.
This study was supported by a grant from the I’hilippe and Th6rkse
Lefkbvre’s Fund. Mario Manro was supported by a grant from the
Erasme Fundation.
We arc gratefill to Christiane Busson for secrctarial assistance and
to Bernard Foucart for taking care of the elecironic equipment.
274 Annals of Neurology
Vol 39
No 2
February 1336
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3. Holmes G. The cerebellum of man. The Hughlings Jackson
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4. Gilman S, Bloedel JR, Lechtenberg I<. Disorders of the cerehellum. Contemporary neurology series, vol 2 1. Philadelphia:
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5. Meinck H M , Benecke R, Meyer W , er al. Human ballistic
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