Familial benign chorea with intention tremor: A clinical entity

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 REFERENCES 1. Paradise, J. L.: Sydenham's chorea without evidence of rheumatic fever--report of its association with the Henoch-SchSnleln syndrome, and with systemic lupus erythematosus and review of the literature, New England J. Med. 263: 625, 1960. 2. Lessor, M. H., and Bywaters, E. G.: The duration of chorea, Brit. M. J. h 1520, 1956. 3. Parker, A. M., and Lipschutz, E. W.: An unusual case of Sydenham's chorea of prolonged duration, New York State J. Med. 58: 2834, 1958. 4. Jervis, G. A.: Huntington's chorea in childhood, Arch. Neurol. 9: 244, 1963. 5. Bittenbender, J. B., and Quadfasel, F. A.: Rigid and akinetic forms of Huntington's chorea, Arch. Neurol. 7: 275, 1962. 6. Mount, L. A., and Reback, S.: Familial paroxysmal choreoathetosis, Arch. Neurol. & Psychiat. 44: 481, 1940. 7. Pryles, C. V., Livingston, S., and Ford, F. R.: Familial paroxysmal choreoathetosis of Mount and Reback; study of second family in which this condition is found in association with epilepsy, Pediatrics 9: 44, 1952. 8. Williams, J., and Stevens, H.: Familial paroxysmal choreoathetosis, Pediatrics 31: 656, 1963. 9. Lance, J. W.: Sporadic and familial varieties of tonic seizures, J. Neurol. Neurosurg. & Psychiat. 26: 51, 1963. 10. Larsson, T., and Si6gren, T.: Essential tremor - - a clinical and population study, Acta psychiat, et neurolog, scandinav. (Suppl. 144) 36: 1, 1960. 10a. Ford, F. R.: Diseases of the nervous system in infancy, childhood, and adolescence, ed. 5, Springfield, Ill., 1966, Charles C Thomas, p. 299. 11. Velander, F. G. H.: Nrftlighetsstudier inom tvenne sl~ikter med. heredit~ir tremor, Nord. reed. tidskr. 3: 102, 1931. 12. Brown, J. B.: The anatomic basis of cerebellar symptoms, Proc. Staff Meet. Mayo. Clinic 19; 169, 1944. 13. Carrea, R. M. E., and Mettler, F. A.: Physiologic consequences following extensive removal of the cerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate, J. Comp. Neurol. 87: 169, 1947. 14. Cooper, I. S.: Heredofamilial tremor abolition by chemothalamectomy, Arch. Neurol. 7: 129, 1962. 15. Crosby, E. C., Humphrey, T., and Lauer, E. W.: Correlative anatomy of the nervous system, New York, 1962, The Macmillan Company. 16. Carrea, R. M. E., and Mettler, F. A.: Functions of the primate brachium conjunctivum and related structures, J. Comp. Neurol. 102: 151, 1955. 17. Cooper, I. S., Bergmann, L. L., and Caracalos, Ao: Anatomic verification of the lesion Volume 70 Number 5 Familial benign chorea with intention tremor which abolishes parkinsonian tremor and rigidity, Neurology 13: 779, 1963. 18. Dierssen, G., Gionio, G. G., and Cooper, I. S.: Participation of ipsilateral hemisphere lesions in the pathology of hemiehorea and hemiballismus, Neurology 11: 894, 1961. 19. Carpenter, M., and Brittin, G. M.: Subthalamic hyperkinesia in rhesus monkey: Effects of 729 secondary lesions in red nucleus and brachium conjunctivum, J. Neurophysiol. 21: 400, 1958. 20. Mettler, F. A.: The experimental anatomicophysiologic approach to the study of diseases of the basal ganglia, J. Neuropath. & Exper. Neurol. 14: 115, 1955. 21. Denny-Brown, D.: The basal ganglia and their relation to disorders of movement, New York, 1962, Oxford University Press.