J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from J. Neurol. Neurosurg. Psychiat., 1957, 20, 98

PROGRESSIVE FAMILIAL CHOREOATHETOSIS WITH CUTANEOUS TELANGIECTASIA BY CHARLES E. WELLS and G. MILTON SHY From the Medical Branch, National Institute of Neurological Diseases and Blindness, National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare, Bethesda, M.D., U.S.A. Progressive beginning in childhood after clasp-knife type was noted bilaterally in the upper the neonatal period is a rare clinical phenomenon and lower extremities, more marked on the left. which has been further clarified into only a small The lower extremities were strongly adducted with number of distinct clinical entities. The purpose of some scissoring. Strength was well preserved. No this communication is to direct attention to the choreo-athetotic movements were evident. Ankle incidence of this phenomenon in two sisters, each clonus was present bilaterally and the deep tendon of whom subsequently developed progressive reflexes were active and equal on the two sides. bilaterally symmetrical cutaneous telangiectasia. There were no skin lesions in any way resembling The L family is composed of healthy non-con- those in her younger sisters. Protected by copyright. sanguinous parents (ages 45 and 54 years) whose The two younger children present similar clinical only children are three girls, all of whom are affected syndromes which differ from that in the eldest. with progressive neurological disorders. The two The onset of the disorder in the two younger siblings younger siblings present a similar clinical syndrome, was at ages 5 and 7. Its inception was characterized whereas the oldest manifests a different disease by difficulty in motility in hitherto normal children. pattern. The only other known affection of the Abnormal movements of the trunk and extremities within the family is Parkinson's while at rest were then noted, followed by progressive disease which occurred in three of the paternal difficulty with speech. Two to three years after the forebears (Fig. 1). appearance of the above symptoms, cutaneous The oldest child (IV-d) appears to have a different lesions were first observed in each of the children. disorder clinically from that in the two younger. The distribution of these lesions was similar in This child, now 14 years of age, was born after a each. These were most evident below the eyes, in normal period of gestation but was cyanotic at birth. the antecubital and popliteal fossae, and over the She was not considered abnormal, however, until dorsum of the hands, forearms, legs, feet, and the after an episode of fever, diarrhoea, and lethargy anterior neck region. at 6 months of age. She has been regarded as Physical examination revealed choreo-athetosis http://jnnp.bmj.com/ retarded, both physically and mentally, since that involving the face, tongue, trunk, and extremities. time. She learned to walk only after special training Inconstant difficulties in conjugate ocular deviation and this ability has regressed within the past several in all directions was noted. A staggering gait with years. Speech has never been purposeful. Psycho- propulsive characteristics was observed, along with logical studies have shown her to be at the idiot poor coordination which was not out of proportion level. The disorder appears to be progressive. to the involuntary movements. Examinations earlier On examination* the child was very over-active in the disease by other investigators indicated that and was continually repeating stereotyped phrases. the amount of incoordination may have been exces- on October 2, 2021 by guest. She never appeared to fix her attention on any person sive in proportion to the involuntary movements or object. No nystagmus was present. Vision was then apparent. Strength was normal throughout preserved. The extremities were symmetrical and and skeletal musculature well preserved. No increase displayed no atrophy. Talipes valgus were present. or decrease in resistance to passive movement was Marked resistance to passive movement of the observed. Excepting the ocular movements and athetosis of the tongue, face, and neck, examination * We are indebted to Dr. William J. Logue of the Pennhurst State of the cranial nerves revealed no abnormality. School, Spring City, Pa., for permission to examine this patient. Sensation remained intact. The deep tendon reflexes 98 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from PROGRESSIVE FAMILIAL CHOREOATHETOSIS 99 FAMILY L.$

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14 10 9 21 17 13 8 7 10 Protected by copyright. f Affected siblings Ox9 Alive, unaffected ? Retarded older sibling 0e Parkinson's Disease ,e? Dead, unaffected FIG. 1.-Pedigree of family L. t Numbers below the figures indicate ages at present or at It-c hypertension, congestive heart failure death, when known. II-d = acute diarrhoeal disease * I-d's oldest brother developed mental retardation and Il-e = diabetes, renal abscess abnormalities of gait and speech following measles at 2-3 years 1I-f= appendicitis of age. No other neurological disorders known in her family. II-g = Parkinson's disease Causes of death, when known. 11-h = cerebrovascular accident = I-a cerebrovascular accident II- i = coronary occlusion = I-b hypertension, cerebrovascular accident II-h = rectal carcinoma I-c = uraemia Il-k = Parkinson's disease, suicide I-h = Parkinson's disease were absent while the abdominal reflexes remained months. She always appeared slightly clumsy to her active and the plantar response, downgoing. parents, but this was not considered to be of unusual Mentation in both children appeared normal. degree. At 5 years it was first noted that she had difficulty Speech was noticeably slow and indistinct, associated in holding her head steady. Within the year her parents http://jnnp.bmj.com/ with facial grimacing and respiratory irregularity. observed that she never walked slowly but always Multiple minute vascular channels which appeared to run from one spot to another. She developed blanched difficulties with balance, tending to totter from side to on pressure were present in the conjunctivae, in the side while walking, and she began to spill fluids from skin under the eyes, across the bridge of the nose, glasses. At 6 years slow, undulating movements of the in the periclavicular area, antecubital and popliteal trunk and extremities while at rest were seen, and her fossae, and on the dorsum of the forearm, hand, leg, speech became slurred and hard to understand. By 7 and foot. years, facial grimacing had made its appearance, and her The remainder of the physical examination handwriting showed deterioration. on October 2, 2021 by guest. revealed no abnormality except hepatomegaly in These difficulties have been progressive since the onset, the youngest child. Clinical pathological investiga- though the advancement appears to have been slowed during the past year. At present the child is tions revealed no abnormalities. severely disabled. Her gait is quick-stepped, with much staggering in all directions, She is able to feed and to dress herself Case Histories with much effort. She attends school where no evidence Case IV-e (Age 10 Years, 8 Months).-The birth and of any mental deterioration has been noted. early development were entirely normal. The child Within the past one or two years, many small bright began to walk at 11 months of age and to talk at 16-18 red spots which blanche on pressure have been noted in J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from

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_EA. ,of~~~~~~~l .. _o :f/. '" 01. FIG...:..2 (a, b,,c, d).-Typicalv.. skinL.t-t:lesions:.in Patient;...... IV-e.3 FIG. 3 (a. b, c. d).-Typical skin lesions in Patient IV-f. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from PROGRESSIVE FAMILIAL CHOREOATHETOSIS 101 her skin. These have developed below the eyes, across electroencephalogram showed a diffuse dysrhythmia. A the bridge of the nose, about the neck, in the antecubital serological test for was negative. Urine analysis and popliteal fossae, and over the dorsum of the forearms, revealed no significant abnormalities. Haematological hands, legs, and feet. The parents are quite certain that studies (including haematocrit, white blood cell and these were not present earlier in life. differential count, sedimentation rate, and platelet count) The past history and systemic review were unremark- were normal. The blood group was B, Rh positive. able. Studies for evaluation of liver function (alkaline phos- General physical examination was not significant phatase, cephalin flocculation, thymol turbidity, total except for the skin lesions (Fig. 2). These consisted of protein, albumin-globulin ratio, prothrombin time, serum rather localized reticular areas of telangiectasia, which bilirubin, cholesterol, bromsulphalein) were within blanched on pressure, in the bulbar conjunctivae, normal limits, as were blood urea nitrogen and fasting beneath the eyes, over the bridge of the nose, the anterior blood sugar. Studies for evidence of hepatolenticular and upper chest, in the antecubital and popliteal fossae, degeneration (total urinary amino-acids, urinary copper, and over the dorsum of the forearms, hands, legs, and serum copper, ceruloplasmin, serum uric acid) were feet. Dr. Eugene Van Scott, consultant in dermatology, negative. In addition, specific quantitative and qualitative observed that these lesions did not resemble those seen urinary amino-acid and sugar studies disclosed no in the Osler-Rendu-Weber syndrome, Sturge-Weber- abnormalities. Spinal fluid examination showed normal Dimitri syndrome, or von Hippel-Lindau syndrome. cells, protein, globulin, and a normal colloidal gold curve. No Kayser-Fleischer ring could be seen either by naked eye or slit-lamp examination. The spleen and the Case IV-f (Age 9 years, 6 Months).-The birth and liver were not enlarged. early development were entirely normal. The child On neurological examination the patient was intelligent began to walk and to talk at the usual ages and never and alert. Psychological studies revealed an average to displayed any clumsiness. She was considered to be high average range of intellectual function. Cranial entirely normal until approximately 7 years of age when nerve examination showed limitation of upward con- her parents noted her to have difficulty with balance jugate gaze. Lateral conjugate gaze was at times limited, while walking. This staggering increased in severity and Protected by copyright. with some nystagmoid jerks. Occasionally dysconjugate her steps became much quicker than previously. In- lateral movements were seen. There was a slight right voluntary movements then appeared, taking the form esotropia. The face was somewhat mask-like and was of quick, non-repetitive, asymmetrical jerks involving a contorted by frequent grimaces. The tongue was involved part ofa segment or a segment ofthe extremities associated in almost continuous athetoid movements. Speech was with slow undulating movements of the extremities and slurred and sometimes " mushy ", associated with dis- the trunk. The quick components of the abnormal move- turbances in the rhythm of respiration. At rest the trunk ments were more prominent than they were in her older and head swayed continuously but irregularly in all sister. Shortly thereafter her speech became slurred and directions. All four extremities were involved in the difficult to understand. flowing, undulating involuntary movements which were Progression of the symptoms has been somewhat faster asymmetrical at a given time but approximately equal in this child than in her older sibling. At present she on the two sides. These slow movements were occasion- has much difficulty with walking. She can feed herself ally interrupted by quick single movements causing but can only partially dress herself. She attends school momentary displacement of the part involved, for where her scholarship is poor but with no suggestion of example, the finger or shoulder. On standing, she could mental deterioration since the onset of the illness. maintain balance only with the feet separated widely Within the past .year skin lesions of exactly the same apart. Walking was of a propulsive character with much nature and distribution as those present in her older sister staggering, the legs being thrown out wildly at the sides, have appeared. http://jnnp.bmj.com/ the upper extremities being abducted into strangely The past history is unremarkable except for the presence contorted postures in an effort to maintain balance. of a left esotropia of several years duration. The systemic The muscles were well developed and without apparent review was negative. . Tone appeared normal within the limits On examination of the skin, lesions of exactly the same imposed on the examination by the involuntary move- type as are present in her older sister were noted (Fig. 3). ments. Fine finger movements were slightly slowed These were present in precisely the same distribution, while rapid rhythmic movements were markedly so. though of less severity. The liver was palpable 1 cm. Associated movements occurred in the contralateral below the costal and not right margin; it was smooth on October 2, 2021 by guest. extremity on voluntary contraction of the homolateral tender. No Kaiser-Fleischer ring could be seen either limb. Finger-to-nose, point-to-point, and heel-to-shin directly or on slit-lamp examination. tests were performed poorly, with much overshooting On neurological examination the patient was mentally and undershooting; to dissociate this disability from the clear and alert. Psychological studies revealed a function involuntary movements was impossible. at the lower limits of the average range. The cranial No sensory abnormalities were demonstrated. Deep nerve examination showed a left esotropia, some limita- tendon reflexes were not elicited. Superficial abdominal tion of upward gaze, and intermittent limitations in reflexes were active and equal. Plantar responses were lateral conjugate gaze in either direction with occasional downgoing. dysconjugate movements. Expressive facial movements Skull radiographs revealed no abnormalities. The were reduced and there were frequent grimaces. The J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from 102 CHARLES E. WELLS AND G. MILTON SHY tongue showed continuous athetoid movements. Speech extrapyramidal system, (2) a toxic disorder of the was slow and slurred and was associated with respiratory extrapyramidal system, (3) a progressive disorder irregularities. of the The child could maintain herself in the standing extrapyramidal system. position with the heels held together. While standing A post-encephalitic disorder must certainly be or sitting the head and trunk swayed markedly. Two considered in the eldest sibling. Since the abnor- types of abnormal movements of the extremities could mality was first noted following an infectious process, be distinguished. The first consisted of irregular, asym- a post- abnormality is possible in this metrical quick movements which were non-repetitive in child; if, however, all three siblings are considered, the same muscle groups, involved either single or entire there is strong argument against such an origin. muscle groups, and might or might not cause segmental The questionable aetiological in the eldest displacement. The second consisted of slow, irregular, episode non-repetitive, asymmetrical flowing movements, most antedated the neonatal period of either of the two severe in the fingers and hands. When walking, she younger children. No history of antecedent infec- threw her feet out in an awkward manner and tottered tion could be obtained in these younger children, from side to side, while the arms were abducted in and furthermore the onset of their neurological strange postures in a partially effectual effort to maintain involveme-nt was separated by over two years. balance. Lastly, the likelihood of an identical syndrome No evidence of muscular atrophy or weakness was following encephalitis in two afflicted members of a found. There was a question of minimal increase in tone, family would be distinctly unusual. evaluation being quite difficult due to the constancy of the abnormal movements. Fine movements were con- The likelihood of this being a toxic disorder is siderably slowed. Attempts at rapid rhythmic movements slight in view of its onset at widely separated periods. resulted in decomposition of the usual movement pattern. We were unable to obtain a history of exposure to Point-to-point, finger-to-nose, and heel-to-shin tests were either carbon monoxide or manganese. ill performed, with much overshooting and undershooting Progressive disorders involving the basal gangliaProtected by copyright. which could not be dissociated from the abnormal have been described by Creutzfeldt (1920) and Jakob movements in the examination. reviewed de No sensory abnormalities were observed. Deep tendon (1921) (recently by Ajuriaguerra, reflexes were not elicited. Superficial abdominal reflexes Hecaen, Layani, and Sadoun, 1953; Lhermitte, were active and equal on the two sides, and plantar Cornil, and Quesnel, 1920; Lhermitte and McAlpine, responses were downgoing. 1926; and Ross, 1955). The onset in each of these The same laboratory examinations were performed in disorders was reported to be in adult life. To our this patient as in her older sister. No further abnormalities knowledge such disorders have not been observed were uncovered in any of these studies. in children. There remains for diagnostic consideration only Discussion a group of rare progressive disorders of infancy and The onset of athetosis at the ages of 5 and 7 childhood in which the extrapyramidal system may removes from diagnostic consideration the largest be involved: (1) Hepatolenticular degeneration, group of involuntary movements of childhood, i.e., (2) progressive atrophy of the globus pallidus, those which occur on or about the neonatal period (3) musculorum deformans, (4) Pelizaeus- (double athetosis, cerebral , and ). Merzbacher disease, (5) Hallervorden-Spatz disease, The duration of the illness, its steady progression, and (6) status dysmyelinatus. The clinical charac- http://jnnp.bmj.com/ and the absence of such as teristics which distinguish these disorders are listed arthralgia, subcutaneous nodules, cardiovascular in Table I. disease, and elevated sedimentation rate, also make The most common progressive degenerative dis- the choreo-athetosis associated with rheumatic fever order of the extrapyramidal system in childhood is unlikely. hepatolenticular degeneration (Wilson, 1912). Within Therefore from a diagnostic standpoint we are the past decade, abnormalities in copper and protein confronted with a progressive degenerative disorder metabolism and in amino-acid excretion have been of the nervous system occurring in three siblings described in this disorder (Uzman and Denny- on October 2, 2021 by guest. and characterized in two by choreo-athetosis and Brown, 1948; Cartwright, Hodges, Gubler, Mahoney, cutaneous telangiectasia. We have been unable to Daum, Wintrobe, and Bean, 1954; Bush, Mahoneyv find such a syndrome previously described. If one Markowitz, Gubler, Cartwright, and Wintrobe, assumes that these two processes (choreo-athetosis 1955). All such studies (serum copper, urinary and cutaneous telangiectasia) are unrelated and that copper, serum ceruloplasmin, urinary amino-acids) two concurrently progressive disorders are present, were within normal limits in these two patients. then several diagnostic possibilities must be con- This would appear effectively to rule out a diagnosis sidered: (1) A post-encephalitic disorder of the of hepatolenticular degeneration in our two patients. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from PROGRESSIVE FAMILIAL CHOREOATHETOSIS 103 TABLE I PROGRESSIVE EXTRAPYRAMIDAL DISORDERS OF CHILDHOOD Hepato- Progressive Dystonia Syndrome Lenticular Atrophy of Musculorum Pelizaeus-Peiau- Hallervorden-Hlevre- StatusSau Degeneration Globus Pallidus Deformans Merzbacher Spatz Dysmyelinatus Onset Ilst-4th decade 6-30 years 5-15 years Infancy Childhood Infancy Duration Moderate oderate Long Long Moderate Moderate (2-20 years) (10-20 years (to 52 years) (death at (death at .______16-27 years) 10-20 years) Mental Power ? Preserved Preserved Preserved Demented ± ? Neurological J u v e n i I e Prolonged con- Nystagmus Rigidity Rigidity Picture Choreoathetosis Parkinson's tractions of Rigidity Pareses Athetosis Wing beating disease axial muscles Incoordination Slowed speech Rigidity Pareses Contractions Mask-like facies Choreoathetosis K-F ring Slowed speech Cirrhosis movement Pyramidal signs Transmitted Familial S o m e t i m e s R a r e I y Sex linked Familial Sporadic familial familial Pathology Nerve cell loss Degeneration Status marma- Demyelination Iron deposition Demyelination i n b a s a 1 of nerve cells ratus. De- with islands in globus of striopal- ganglia and in globus generation of preserved pallidus, sub- lidal, thala- cortex. Wide- pallidus. of nerve cells myelin. Rela- stantia nigra, mopallidal, spread gliosis in b a s a I tive sparing of and vascular pallidoluy- ganglia cortex walls o f sial and H(l) basal ganglia tracts Clinical Pathology Amino-aciduria 9 9 9 9 9

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The absence of tremor and rigidity in our two mental deterioration, rigidity, paresis, and pyramidal patients makes unlikely the diagnosis of progressive signs. Such a diagnosis, however, could not be atrophy of the globus pallidus (juvenile ruled out definitely for the eldest child. agitans) (Hunt, 1917; Denny-Brown, 1946). Hallervorden and Spatz (1922) described a Many clinical patterns have in the past been placed progressive disorder with onset in childhood in- within the dystonia musculorum deformans category. volving five female siblings, characterized by If one accepts Herz' (1944) criterion for the diagnosis spasticity, paresis, and contractions of the extremities of dystonia musculorum deformans, based on clinical associated with mental deterioration and choreo- and pathological studies, then prolonged contrac- athetosis. Against such a diagnosis in our two tions of the axial musculature are prerequisite for patients is the absence of paresis, contractures, and the diagnosis. This criterion was not satisfied by spasticity and the presence of well preserved mental our patients. Furthermore the familial occurrence faculties. of dystonia musculorum deformans is rare. Status dysmyelinatus (Vogt and Vogt, 1920, http://jnnp.bmj.com/ In 1885 Pelizaeus reported a progressive neuro- abstracted at length by Winkelman, 1923) is an logical disorder involving five members of a single extremely rare disorder characterized by the onset family. In 1910 Merzbacher presented a further in infancy of progressive rigidity and athetosis. It report on the same family in which 14 members of has been reported associated with convulsions (the four generations were afflicted, 12 being males and Vogts' first case) and with dystonia (Alexander's two females, together with the pathological findings second case, 1942). It has not been reported to

in one case. The disease characteristically appeared occur familially. The late onset, absence of rigidity, on October 2, 2021 by guest. in the male and was transmitted by the female. and familial nature of the disease in our patients Symptoms were usually first noted at about 3 months argue against this diagnostic possibility. of age, though onset at 43 years has been reported Thus, even if the presence of two concomitantly (Lowenberg and Hill, 1933). Its occurrence in progressive disorders is accepted, it is difficult to females and its non-familial incidence have also place the neurological involvement with certainty been recorded (Scheftel, 1931; Lowenberg and Hill, within any of the previously defined entities. If, 1933). Nevertheless, a diagnosis of Pelizaeus- on the other hand, the premise of two independent Merzbacher disease in our two patients would appear processes in these two patients is rejected, then the unlikely, due to its late onset and the absence of question must arise as to the nature of the disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.20.2.98 on 1 May 1957. Downloaded from 104 CHARLES E. WELLS AND G. MILTON SHY which is manifested by progressive choreo-athetosis REFERENCES associated with cutaneous telangiectasia. Neurolo- Ajuriaguerra, J. de, Hecaen, H., Layani, F., and Sadoun, R. (1953). Rev. neurol. (Paris), 89, 81. gically, these two patients present definite evidence Alexander, L. (1942). Res, Publ. Ass. nerv. ment. Dis., 21, 334. Bush, J. A., Mahoney, J. P., Markowitz, H., Gubler, C. J., Cartwright, of disease involving the extrapyramidal system, G. E., and Wintrobe, M. M. (1955). J. clin. Invest., 34, 1766. together with dorsal root or peripheral nerve in- Cartwright, G. E., Hodges, R. E., Gubler, C. J., Mahoney, J. P., Daum, K., Wintrobe, M. M., and Bean, W. B. (1954). Ibid., volvement (absent deep tendon reflexes), and possibly 33, 1487. Creutzfeldt, H. G. (1920). Z. ges. Neurol. Psychiat., 57, 1. cerebellar involvement (suggested by the early Denny-Brown, D. (1946). Diseases of the Basal Ganglia and Sub- though now impossible to determine thalamic Nuclei. Oxford University Press, New York. (Re- printed from Oxford Loose-Leaf Medicine.) accurately due to the frequency of involuntary Hallervorden, J., and Spatz, H. (1922). Z. ges. Neurol. Psychiat., 79, 254. movements). We have no further relevant in- Herz, E. (1944). Arch. Neurol. Psychiat. (Chicago), 51, 319. formation concerning the possible pathogenesis of Hunt, J. R. (1917). Brain, 40, 58. Jakob, A. (1921). Z. ges. Neurol. Psychiat., 64, 147. this disorder, and carotid arteriograms were declined. Lhermitte, J., Cornil, L., and Quesnel (1920). Rev. neurol. (Paris), 27, 262. and McAlpine, D. (1926). Brain, 49, 157. Summary Lowenberg, K., and Hill, T. S. (1933). Arch. Neurol. Psychiat. The case histories of two sisters evincing a syn- (Chicago), 29, 1232. Merzbacher, L. (1910). Z. ges. Neurol. Psychiat., 3, 1. drome with onset in childhood of progressive Pelizaeus, F. (1885). Arch. Psychiat. Nervenkr., 16, 698. Ross, R. T. (1955). Canad. med. Ass. J., 73, 17. choreoathetosis associated with similar symmetrical Scheftel, Y. (1931). J. nerv. ment. Dis., 74, 175. are Uzman, L., and Denny-Brown, D. (1948). Amer. J. med. Sci., 215, cutaneous telangiectasia presented. The clinical 599. pattern of this syndrome does not fit clearly into Vogt, C., and Vogt, 0. (1920). J. Psychol. Neurol., 25, 627 (Erganzung- sheft 3. any of the previously defined diseases of childhood. Wilson, S. A. K. (1912). Brain, 34, 295. Its aetiology is unknown. Winkelman (1923). Arch. Neurol. Psychiat. (Chicago), 10, 563. Protected by copyright. http://jnnp.bmj.com/ on October 2, 2021 by guest.