724
May, 1967
T h e Journal of P E D I A T R I C S
Familial benign chorea with intention
tremor: A clinical entity
Three cases of familial chorea and associated intention tremor in two families are
presented. In each affected person of the two families, the movement disorder began
in the first two decades of life and has continued unchanged, in some cases into
adulthood. The mode of inheritance appears to be autosomal dominant with
incomplete penetrance. The hereditary nature of the disorder and the lack of
associated mental deterioration and seizures differentiate it from other described
forms of chorea. A possible pathophysiologic basis [or this condition is discussed.
Jonathan H. Pincus, M.D., and Abe Chutorian, M.D.
N E W H A V E N , CONN.~ AND N E W YORK, N. Y.
NONPROGRESSIVE
f a m i l i a l chorea, unassociated w i t h intellectual d e t e r i o r a t i o n or
epilepsy, has n o t b e e n clearly described as a
clinical entity. R e c e n t l y t w o families w i t h
such a disorder h a v e b e e n seen.
CASE REPORTS
Case 1. A 13-year-old Caucasian schoolgirl
was seen in the Pediatric Clinic of the Y a l e New Haven Hospital for evaluation of clumsiness.
Three years prior to examination a deterioration
in her handwriting associated with "emotional
lability" was noted; there was a "tremor" of the
hands which became worse when she was upset.
There was no history of progression or resolution
of this symptom which was felt by the school
authorities to be a manifestation of an emotional
disorder. As part of the evaluation at a Child
Guidance Clinic, psychological tests were done,
and these included the Wechsler Intelligence
Scale for Children, Rorschach, Thematic ApSupported in part by Grant 5T1 NB 5030 from
the National Institutes of Health, United States
Public Health Service.
Address: Yale University School of Medicine,
New Haven, Conn.
Vol. 70, No. 5, pp. 724-729
perception Test, and the Bender-Gestalt Test.
A normal pattern was revealed on the verbal
tests, as well as a full scale I.Q. of 108, but on
some of the subtests requiring writing and drawing she performed badly. No evidence of an
organic disorder of intellect was present, but the
suspicion of a movement disorder was raised and
she was referred for neurological evaluation.
The child, the eldest of five children, was the
product of a normal pregnancy and delivery.
Her growth and development were within normal
limits, and she had never been seriously ill. There
was no history of joint pains, encephalitis, or
rash.
She was a healthy-appearing, prepnbertal girl.
No abnormality was found on general physical
examination other than choreatic movements,
mainly of hands and fingers, but also of shoulders,
arms, and legs. Although she was cooperative,
she was unable to remain quiet. She could neither
maintain protrusion of the tongue nor maintain
steady pressure of grip; she pronated the arms
when holding them above the head, and had
"spooning" of the outstretched fingers.
A very slight intention tremor was apparent
on finger-to-nose testing. Heel-to-shin testing, as
Volume 70
Number 5
Familial benign chorea with intention tremor
well as stance and t a n d e m gait, were normal.
There were no abnormalities of the cranial
nerves, and muscle strength was well preserved.
The muscle tone was somewhat diminished. Deep
tendon reflexes were symmetrical and brisk; the
knee jerks tended to be "hung up." Plantar responses were flexor.
Laboratory data were not abnormal. These
included: complete blood count, sedimentation
rate, urinalysis, blood serology, and antistreptolysin titer. The serum content of electrolytes,
calcium, phosphorus, alkaline phosphatase, and
ceruloplasmin was normal, as was the electrophoretic pattern of the serum proteins. Three lupus erythematosus (L. E.) cell preparations were
negative. Urine chromatography for amino acids
and sugars was normal; Normal flora were grown
from nose and throat cultures. Roentgenograms
of the skull and chest were normal, as were
an electrocardiogram and electroencephalogram.
No abnormalities of optic fieIds, fundus, lens, or
cornea were noted. A handwriting sample was
obtained, and the patient was started on chlorpromazine 10 rag. three times per day. Her movement disorder was somewhat improved on this
regimen, and a handwriting sample was obtained
two weeks later (Fig. 1 ).
There was no family history of rheumatic
fever, mental retardation, insanity, or epilepsy,
nor was there known consanguinity. The patient's
father had a "tremor" of his hands which made
his "fingers j u m p " and his "hands shake." This
was accentuated during activities such as drinking from a cup or glass. This was said to have
begun at about the age of 12 years and to have
continued without change into adulthood. As he
was working in another city, and the family was
preparing to join him, it was impossible to arrange an examination.
Case 2. A 19-year-old paternal uncle of the
girl, with a similar disorder beginning at 10 years
of age, was seen in the Neurology Clinic of the
Yale-New Haven Hospital. A student at a busi-
B
Fig. 1. Handwriting specimen of patient described
in case 1: A, before drug therapy. B, two weeks
after therapy with ehlorpromazine was begun.
725
ness school, he had graduated from high school
at age 18 with a B average, and had been active
in sports, lettering in soccer. However, he had
been declared 4-F by the Army as a result of
the tremor. He was found to have an intention
tremor of both hands which was worsened by
voluntary activity. There was no past pointing,
rebound phenomena, or ataxia. Stance and gait
were normal. There were choreatic movements
of the fingers and hands with a positive "pronator sign." The remainder of the neurological
and physical examinations was within normal
limits. Unfortunately, he refused to allow any
laboratory studies to be done.
Case 3. An eight-year-old Caucasian schoolboy was seen at the Columbia Presbyterian Medical Center for evaluation of a movement disorder
of six years' duration. At the age of two years,
involuntary movements were first noted by his
mother. These were intermittent at first, occurring at intervals of several hours, but within
several months the movements were occurring
continuously, disappearing only during sleep. The
movements consisted of a brief jerking of the
head to the right or left, or of either shoulder
or upper extremity, less frequently of the lower
extremities. There was no characteristic pattern
to these movements and they could not be voluntarily prevented or reproduced. They were
aggravated by anxiety and were only slight when
the child was preoccupied. They interfered with
coordinated voluntary acts and distorted the
child's penmanship from the time he learned to
write, at the age of five years. There had been
no progression in severity or frequency of the
movements after the first year of disability.
The child was the product of an uncomplicated full-term gestation. There was an uneventful labor and delivery. The neonatal course
was normal, and developmental milestones were
reached at the usual times. His attention span
had always been good, he was in an advanced
group in the third grade, and he socialized well
with his peers. There was no history of convulsions, encephalitis, or rheumatic disorders. Several members of the family were said to be affected by an identical disorder which was not
progressive in nature and had not involved intellectual faculties (Fig. 2). The father, mother,
and brother of the patient were examined and
found not to be affected. Unfortunately, because
of intrafamily antagonisms, none of the affected
members consented to submit to examination.
The patient was alert, well developed, and
cooperative. The physical examination was un-
7 2 6 Pincus and Chutorian
312[7
.......
;
~
~ - a f f e c t e d female
I i - affected male
Fig. 2. Family of patient described in case 3: I,
Patient (Case 3), see text; 2, 31 years of age,
clinically unaffected; 3, 55 years of age, onset
at 13 years; 4, 52 years of age, onset "in youth";
5, 17 years of age, onset at 2 years; 6, died at
70 years of age, age at onset unknown; 7, no details known.
remarkable except for that of the nervous system. Frequent, multifocal choreiform jerks of the
head, neck, and of the proximal and distal upper
and lower extremities were noted. These spared
the lower extremities to the extent that there
was no functional disturbance of gait. Grimacing
was not evident. On attempting to perform some
manuevers, anxiety became evident, and the jerks
were at times repetitive in rapid series with gross
interference with intentional movement. A moderately severe intention tremor of both upper
extremities was present on finger-to-object maneuvers in addition to the sudden jerks which took
one or the other extremity off course dramatically
and suddenly. This intention tremor was not
evident in the lower extremities on heel-to-kneeto-shin maneuvers, which were disturbed only by
an occasional choreatic jerk. Rapid alternating
movements were welI performed, except for interference by intermittent choreatic jerks. Muscle
tone was normal, and no drift of any extremity
occurred on maintenance of posture. Stance was
normal with the eyes open or shut. Muscle power
was fully intact. The deep tendon reflexes were
brisk and equal, and the plantar responses were
The ]ournal of Pediatrics
May 1967
flexor. All modalities of sensation were intact,
as were the cranial nerves. Laboratory investigation revealed no abnormalities. The tests included complete blood count, determinations of
blood sugar, urea nitrogen, calcium, phosphorous,
serum enzymes, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic
transaminase (SGPT), and roentgenograms of
the skull and chest. The electroencephalograms
showed a normal resting record. Moderate slowing and moderate number of medium to high
voltage spikes appeared in a general distribution
during hyperventilation. The spinal fluid was
under normal pressure. There were no cells and
the protein value was normal as were those of
lactic dehydrogenase, phosphohexoisomerase, and
gamma globulin.
The child was started on chlorpromazine 10
mg. three times daily, and the dose was advanced
in 10 rag. increments daily to a maximum of
40 rag. three times daily. On examination the
child appeared lethargic and dulled, and was
noted to have worsened with respect to his intention tremor, though the choreatic jerks were
rare and isolated rather than repetitive. The dose
of chlorpromazine was gradually tapered to 100
mg. daily; there were restoration of alertness,
maintenance of marked improvement in frequency
and severity of chorea, and marked diminution
of intention tremor on periodic follow-up examinations. Specimens of writing were obtained
repeatedly at intervals of several weeks before
and after therapy (Fig. 3).
DISCUSSION
C h o r e a in the first two decades of life
m a y be a manifestation of one of several
diseases. S y d e n h a m ' s chorea, which m a y be
associated with r h e u m a t i c fever a n d other
disorders, 1 is a c o m m o n cause. Perinatal brain
injury, encephalitis, vascular disease, hypoparathyroidism, and, rarely, b r a i n t u m o r are
also to be considered. Drugs, especially the
phenothiazines, m a y p r o d u c e a choreatic disorder. T h e r e is no evidence that the patients
described here h a d any of these disorders,
a n d the family history is i n c o m p a t i b l e with
most of them. T h e r e is a higher incidence of
S y d e n h a m ' s chorea in relatives of an affected
individual t h a n in the general population,
but it is a self-limited disorder a n d an a t t a c k
seldom lasts Ionger than several m o n t h s . I n
a review of 206 attacks of S y d e n h a m ' s chorea
Volume 70
Number 5
Familial benign chorea with intention tremor
A
= rio
Fig. 3. Handwriting specimens from case 3: A,
before drug therapy B, several weeks after therapy
with chlorpromazine was begun.
in 170 patients, Lessof and Bywaters 2 found
a mean duration of 19 weeks with a range
of one to 117 weeks; rarely, it may be permanent, a
Familial chorea must always suggest Huntington's chorea but this seems unlikely in the
cases presented because of the benign course.
Often when Huntington's chorea begins before 15 years of age it is characterized more
by seizures, intellectual deterioration, and
rigidity, than by chorea. 4' s Also, it tends to
be more rapidly progressive than the forms
with onset in adulthood.
Familial paroxysmal choreoathetosis 6s and
other tonic seizures 9 cannot be seriously considered in the differential diagnosis because
of the lack of paroxysmal attacks of chorea
and the absence of seizures in the cases presented here. Similarly, paramyoclonus multiplex l~ may in its early stages be difficult to
distinguish from benign chorea. However,
the progressive course with intellectual deterioration, associated massive jerks of trunk,
head, and neck, and characteristic electroencephalographic abnormalities help to differentiate the two conditions.
The tremor, which was a constant feature
of the three cases presented above, was similar to that seen in patients with essential
(familial) tremor; for it was absent at rest,
was brought out by use of the involved limb,
and was more prominent in the upper extremities. Essential tremor is a benign, often
inherited disorder, studied intensively by
Larsson and Sj6gren, 1~ who found neither
choreatie movements in 81 clinically examined cases, nor such a complication in
the 129 other cases which they reviewed,
727
according to their records. However, under
the title "Hereditary Tremor," Velander 1~ described two families in Northern Sweden
who were affected with a disorder of movement characterized as "chorea-like" with
prominent involvement of the tongue. The
tremulousness in some members of the families was markedly increased by movements.
While some were "imbeciles," the author
stresses that, in general, they were remarkable
for an absence of psychiatric disorders and
for longevity. This disorder became symptomatic in some patients as early as the second
or third decades and was apparently transmitted as an autosomal dominant. These
cases of Velander may well have been suffering from a disorder similar to the one presented, but this is uncertain from the available data.
Though the underlying pathophysiology of
this condition is unknown, speculations may
be of some interest. Essential familial tremor
has been attributed to involvement of the
dentate nucleus of the cerebellum or the
brachium conjunctivuin. 12 Evidence supporting this assumption consists to a great extent
of experiments in which intention tremor
has followed the placement of lesions in the
dentate nucleus and brachium conjunctivum
in primates, la Fibers leaving the dentate
nucleus project upward through the brachium conjunctivum, decussafing near the
red nucleus. Some fibers end in the red
nucleus while others end in the lateral ventral nucleus of the thalamus. Cooper 14 has
reported that lesions in the region of the
lateral ventral nucleus can abolish familial
intention tremor; he has speculated that intention tremor may result from thalamic influences on cerebellar-cortical pathways.
Chorea, on the other hand, is considered
to be the result of an interruption or imbalance of certain neurone arcs which relate
various inhibitory systems with active motor
pathways. These systems include important
connections of the caudate, globus pallidus,
and the rostral end of the ventral nuclear
group of the dorsal thalamus with the motor
pathways of the cortex2 ~
In this formulation, the neurone chains
728
Pincus and Chutorian
involved in the p r o d u c t i o n of intention tremor a n d chorea are distinct, a n d perhaps this
fact underlies the clinical observation t h a t
essential t r e m o r a n d chorea a r e rarely associated. 1~ C e r t a i n lesions~ however, along the
p a t h of outflow from the dentate nucleus
have been shown to p r o d u c e hyperkinetic disorders other t h a n t r e m o r a n d ataxia a n d m a y
be of some significance in explaining the
association of chorea a n d tremor described
here. C a r r e a a n d M e ttler 16 p r o d u c e d transitory choreiform activity in monkeys by placing lesions in the b r a c h i u m c o n j u n c t i v u m
bilaterally. U n i l a t e r a l lesions of the: ventrolateral thalamus a n d subthalamic nuclei of
manlZ, as a n d monkeys 19 m a y sometimes produce choreatic movements a n d hemiballismus. T h e hyperkinesia in such cases is considered to result from the release of inhibiting influences on the globus pallidus. T h e
use a n d m e a n i n g of the term " c h o r e a " to
describe this hyperkinesia is disputed. M e t tler 2~ believes t h a t ballism, chorea, a n d
athetosis form a spectrum of choreoid activity, a view which differs f u n d a m e n t a l l y from
t h a t of Denny-Brown 21 who draws a n absolute distinction between choreoathetosis and
hemiballismus. Should the "chorea" resulting from lesions of the dentate outflow system be related to the chorea described in the
cases presented here, it would be possible
to conceive of a lesion in this system which
produces faulty m o d e r a t i o n of the d e n t a t e
outflow on one h a n d a n d of the afferent
supply to the globus pallidus on the other,
thereby creating the clinical combination of
intention t r e m o r a n d chorea.
SUMMARY
A familial, benign e x t r a p y r a m i d a l disorder
which consists of chorea a n d intention tremor is described. Its onset is ordinarily in the
first two decades of life, a n d it continues unchanged into adulthood. I t is unassociated
with intellectual deterioration or seizures,
and is a p p a r e n t l y transmitted as an autosomal d o m i n a n t with varying penetrance. I t
is believed t h a t this is the first r e p o r t delineating such an entity.
The Journal o[ Pediatrics
May 1967
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Familial benign chorea with intention tremor
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729
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