Familial juvenile parkinsonism with multiple systems degenerations

Journal of the Neurological Sciences, 1986, 72:91-101 Elsevier

91

JNS 2596

Familial Juvenile Parkinsonism with Multiple Systems Degenerations A Clinicopathological Study J.M. Mayer 1, J. Mikol 2, M. Haguenau ~, J. Dellanave 2 and B. P6pin ~ IDepartment of Neurology and 2Department of Pathology, U.E.R. Lariboisi~re-Saint Louis, H6pital Lariboisi~re, 75475 Paris Cedex I0 (France) (Received 12 April, 1985) (Received, revised 19 August, 1985) (Accepted 22 August, 1985)

SUMMARY

An unusual case of familial multisystemic degeneration is reported. Two siblings had juvenile parkinsonism, areflexia, and retinal degeneration of slow progression. The main neuropathological fmdings in case 1 were pallidoluysian, nigral, dentate, and dorsal columns degeneration. The authors draw a comparison between this case and juvenile parkinsonism, dentato-rubro-paUido-luysian atrophy, and spino-cerebellonigral degeneration.

Key words: Dentato-rubro-pallido-luysian degeneration- Familial degenerative diseases - Juvenileparkinsonism - Multisystemic degeneration - Spino-cerebello-nigral degeneration

INTRODUCTION

Our report concerns two siblings with slowly progressing juvenile parkinsonism, areflexia and retinal degeneration. A short clinical report has been presented at the Soci6t6 Fran~aise de Neurologie (P6pin et al. 1975). The neuropathological findings in case 1 were pallido-luysian, dentate, nigral, dorsal columns and dorsal roots degeneration, with less important lesions in thalamus, locus coeruleus, inferior olives and anterior horn of cervical cord. The following family is reported on account of the pattern of degeneration which has not been previously reported in juvenile parkinsonism, and the few neuropathological studies of this disease. 0022-510X/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)

92 CASE REPORTS

Case 1 (57601)

He first had difficulty in walking at age 19 because of increasing weakness and tremor of lower limbs. At age 29 he noticed hands tremor, which was not improved by Trihexyphenidyl. At age 45 walking became extremely difficult. The upper limbs tremor and rigidity were marked, and his speech became slurred. On admission at age 48 walking was almost impossible, with rigid and ataxic features. The extrapyramidal syndrome was obvious, especially bradykinesia and cogwheel rigidity, but no resting tremor was noticed, though he had a postural tremor. Speech was monotonous and his face was expressionless, with an hyperactive glabetlar reflex. A markedly decreased vibratory perception below the knees, an impaired position sense of the lower limbs, and a Romberg's sign were noted. No deep reflexes could be elicited. There was no Babinski's sign, ophthalmoplegia or nystagmus. General physical examination revealed kyphoseoliosis and thoracic flattening. CT scan, EEG and EMG were normal. Caloric stimulations showed no response of vertical ducts and left horizontal duct. Fundi were normal. There was no cataract or Kayser-Fleischer ring. ERG showed an important retinal degeneration. Routine blood studies, serum ceruleoplasmin and 24-h urine copper were normal. The patient was given L-DOPA/benserazide 500 mg/day, with dramatic improvement, especially of gait, but the daily dose was reduced because of nausea. Nevertheless, there was no evolution over the next years, until 1982 when the patient died at 56 from a pancreatic adenocarcinoma, 37 years after the onset of the disease. Case 2 (19931)

This patient, younger brother of patient 1, had a similar onset at age 24 with difficulty in walking; a few years later, there was an important upper limbs tremor and walking became nearly impossible. He was admitted at age 41 to the hospital. At physical examination, the patient could walk only with assistance; he stood with a flexed posture very suggestive of a Parkinson's disease. Resting tremor was predominant in limbs, peribuccal area and head. The upper limbs and face EMG recorded a 4/5 HZ resting tremor, characteristic of parkinsonism (Dr. N. Bathien). There was a cogwheel rigidity, a bradykinesia and a mask-like face; glabellar and jaw reflexes were overactive. No deep reflexes could be elicited. The plantar responses were flexor. No other neurological abnormalities were observed. General physical examination showed kyphoscoliosis. Fundi, EEG, EMG, serum ceruleoplasmin and 24-h urine copper were normal. All routine laboratory studies were normal except a small increase of beta- and prebetalipoproteins. Neuropsychological evaluation at age 50 showed a low intelligence level (IQ: 75) but free evaluation was impossible on account of motor disability. There was a retinal degeneration at ERG. Brainstem evoked potentials (Dr. Casteran) were normal, and visual evoked potentials were impaired in keeping with retinal degeneration. L-Dopa/benserazide was prescribed with an obvious improvement but dose was reduced to 125 mg/24 h because of nausea and choreiform movements. In December

93

LEC...

19Ol

III

1937~4 1959~)

1.3) 5

Fig. 1. Pedigree of family LEC...

1983 the patient neurological condition was stable but symptoms of congestive cardiac failure were noted. The blood pressure was 140/80 without orthostatic hypotension. ECG showed atrial tachycardia with diffuse low voltage. The father of the two patients had a history of resting tremor starting at age 73 without any other neurological problem. He was admitted in the department at age 77 because of a rapid deterioration: examination showed an important generalized resting and postural tremor, predominant at the upper limbs. The patient died of a stroke 4 years after discharge from the hospital. A niece had pes cavus but neurological examination was normal (see Pedigree, Fig. 1). PATHOLOGIC FINDINGS (Case 1, No. 14193)

The patient's death was attributed to an adenocarcinoma of pancreas, with liver extension, bileduct stenosis and lymph node metastasis (Dr. Lavergne). Macroscopic examination of the CNS revealed atrophy of midbrain and tegmenturn pontis. Atrophy was more severe in the spinal cord. There was loss of pigmentation of the substantia nigra but locus coeruleus appeared normal. Microscopic examination The sections from paraft'm, celloidin and frozen blocks were stained with hematein-eosin, trichrome de Masson, Bodian, WOlcke, Nissl and Nissl - Luxol, Mallory, Bielschowsky-Reumont and Holzer. Immunocytochemistry for GFAP was performed. Serial sections from the brainstem and cerebellum were obtained.

94

Fig. 2. a: Neuronal rarefaction and gliosis of the outer part of the globus pallidus, Celloidin - Hematetn - eosin, × 192. b: Pallor of putamino-pallidal fibers and ansa lenticularis. Celloidin - W61cke, x 3.6. u: Fibrillary gliosis mainlyin the medial part of the globus pallidus and surrounding the sub-thalamic nucleus. Holzer, × 4.8.

There was a slight myelin pallor in the corona radiata and gliosis in the 6th cortical layer. The striatum appeared normal. The globus pallidus showed a severe neuronal depletion, especially in the outer part and gliosis was predominant in the inner part (Fig. 2a). Atrophy and demyelination occurred in its afferent and efferent pathways (Fig. 2b). The lesions of the subthalamic nucleus were restricted to gliosis in the upper and lateral portion (Fig. 2c). In the thalamus there was a slight loss of neurons in the centromedian nucleus, and gliosis of the ventrolateral nucleus. In the substantia nigra, nerve cell loss was observed especially in the pars reticulata. There was a small amount of pigment free in the tissue, and reactive gliosis (Fig. 3). Nerve cell counts compared with controls showed an almost 40~o decrease. There were no Lewy bodies nor neurofibrillary tangles. Red nucleus, decussation of brachium conjonctivum, medial longitudinal fasciculus, and oculomotor nuclei were normal. The tegrnentum pontis was shrunken. In the locus coeruleus, there was only a slight gliosis; loss of pigment occurred with an increase of non-pigmented cells. In the medulla oblongata, hypertrophy and vacuolization were present in some neurons of the ventral part of the olive (Fig. 4c). Degeneration of dorsal columns was more prevalent in cuneate tract. Nuclei of the dorsal columns were gliotic. The cerebellar cortex and white matter were normal. Dentate nucleus showed a slight atrophy restricted to its dorsal and medial area, with moderate pallor of the

95

Fig. 3. a: Section of the locus niger showing predominant neuronal rarefaction in the pars reticulata, b: Normal locus niger. Celloidin - Nissl, x 15.3.

adjacent hilus (Fig. 4a). Its thickness was 0.3 mm for the dorsal folium, 0.5 mm for the ventral. The number of dentate nerve cells was reduced by one-third in the dorsomedial area, in the upper part of the nucleus (Fig. 4b). Spinal cord was very atrophic. There was a marked degeneration of the dorsal columns. Demyelination of the dorsal roots was evident. At cervical level degeneration predominated in the cuneate tracts. Nerve cell loss was present in anteromedial nucleus of the ventral horns. A slight demyelination occurred in anterior roots (Fig. 5a). Clarke's

96

Fig. 4. a: Atrophy of the upper dorsal part of the nucleus dentatus. Celloidin - W61cke, × 4.8. b: Higher power view showing chromatolysis and disappearance of the neurons of the nucleus dentatus. Celloidin Kliiver - Barrera, x 208. c: Hypertrophic and vacuolar degeneration of the ventral part of the inferior olive. Paraffin - Bodian, × 270.

Fig. 5. Horizontal section of the spinal cord at the level of C7 and Th 12. Pallor and shrinkage in posterior roots and posterior columns. The demyelinisation predominates in fasciculus cuneatus and in the middle part of the thoracic fasciculus gracilis. Cello/din - W61cke, × 9.6.

97 column and n. intermediolateralis were normal (Fig. 5b). There was a slight nerve cell loss in the lumber ganglia showing interstitial sclerosis. No inclusions were seen in the roots of the cauda equina. The eyeballs were not available for examination. DISCUSSION Both patients had parkinsonism of early onset and slow progression. The elder had a rigid and bradykinetic form; tremor was prominent in the younger. There was no consanguinity. The father had parkinsonism of late onset and a niece had pes cavus. The mode of inheritance of this disease appears to be autosomal dominant with variable expression. The most prevalent pathologic features in case 1 were dentato-pallidoluysian, nigral and spinal degenerations. Most of the classical extra-pyramidal diseases can be easily ruled out. No data relevant to progressive supra-nuclear palsy (PSP) were seen in our case (Chavany et al. 1951; Steele et al. 1964; Dubas et al. 1983). Pathologic findings were different from those of striatonigral degeneration (Adams et al. 1961), Hallervorden-Spatz disease (Jankovic et al. 1985), parkinson-dementia syndrome of the third decade (Mata et al. 1983), familial central and peripheral nervous system disease (Tom6 et al. 1985). We are therefore confronted with a disorder combining features of three diseases: juvenile parkinsonism, dentato-rubro-pallido-luysian atrophy, and spino-cerebellonigral degeneration. Juvenile parkinsonism (JP) has a clinical definition and is characterized by an idiopathic parkinsonism beginning before the age of 40 (Yokochi 1984), with unusual manifestations such as pseudobulbarism (van Bogaert 1930), spastic paraplegia (Davison 1954), lack of rigidity (van Bogaert 1930), head's tremor (Martin et al. 1971), ophthalmoplegia and peripheral neuropathy (Van der Wiel and Staal 1981), marked diurnal fluctuation of symptoms (Yamamura et al. 1973). In Japan, 10~o of patients with idiopathic parkinsonism are considered as JP, 5 being familial (Yokochi et al. 1984). The clinical picture of JP differs from that of Parkinson's disease, with a slower progression, more symmetrical symptoms, tendency to dystonic posture and action tremor and immediate and dyskinetic response to L-Dopa therapy. JP does not seem to be an unvarying group: Hunt's patient 2 was f'n'st diagnosed as dyssynergia cerebellaris myoclonica, then JP and at last pallido-pyramidal disease (Davison 1954). The pathological features usually differ from those of idiopathic parkinsonism. The neuronal rarefaction extends to several structures and no Lewy bodies are observed except in Yokochi's case 2. The dissimilarities between Parkinson's disease and JP may be related to different mechanisms, some investigators suspecting a primary striatal dysfunction (Naidu et al. 1978; Yokochi et al. 1984). The pallidal degenerations have been classified by Van Bogaert (1946) and Jellinger (1969) in 4 groups: (1) pure pallidal degeneration, (2) pallido-luysian atrophy, (3) pallidal degeneration extended to the striatum or substantia nigra, and (4) combined degeneration of the paUido-luysian system with other system degenerations. The

98 associated degeneration of the dentate nucleus and its projections have lead to the description of a dentato-rubro-pallido-luysian atrophy (DRPLA). Our case has to be included in this last group with the restriction of the integrity of the red nucleus. The first cases of DRPLA have been reported by Verhaart (1940), Van Bogaert (1946), Smith et al. (1958) and Neumann (1959); more recently, Japanese authors have observed some familial or sporadic cases; Gray et al. (1981; 1985) have reported the association of pallido-luyso-nigral atrophy with amyotrophic lateral sclerosis. A clinical heterogeneity exists in a greater degree in DRPLA than in other multisystemic degenerations. Early (Naito and Oyanagi 1982), middle-life (Verhaart 1940) or late onset (Smith et al. 1958) are possible. Familial, mainly autosomal dominant forms coexist with sporadic cases. The main symptomatology is a disturbance of motor function. Cerebellar syndromes, hemiballismus, choreic syndromes, myoclonus epilepsy have been described (Andr6 - Van Leeuwen and Van Bogaert 1947; Verhaart 1940; Titeca and Van Bogaert 1945; Iizuka et al. 1984). At the opposite our cases were characterized by an akinetic and rigid symptomatology. Many associated symptoms have been reported: dementia (Van Bogaert 1946; Hasaerts 1957, Goto et al. 1982; Naito and Oyanagi 1982), pyramidal signs (Andr6 - Van Leeuwen and Van Bogaert 1947; Mizutani et al. 1983), oculomotor disturbances (Verhaart 1940; Smith et al. 1958; Maeshiro et al. 1980) and amyotrophy (Hasaerts 1957). Although clinicopathological correlations are uncertain one may assume that motor disturbances in DRPLA arise from dentate and pallido-luysian lesions. One of the most important functions of the cerebellar nuclei is to hold a limb's (and eyes') position, especially after a fast movement (Kornhuber 1974). In primates, lesions of the dentate and interpositi nuclei result in cerebellar ataxia and intentional and sometimes postural tremor (Verdi6 1975). It is therefore possible that dentate nucleus atrophy was responsible for postural tremor in our case. The prominent degenerative changes in pallidum and substantia nigra of our case probably account for the hypokinetic-rigid symptomatology. Clinical data provide evidence of a functional separation of pallidal segments. Involvement of external (GPe) or internal (GPi) segments usually leads to different movement disorders but experimental lesions of the globus pallidus produce hypokinetic syndromes. The difficulties of clinicopathological correlations have to be emphasized. The spinal cord involvement in our case makes it close to the spino-cerebellar degenerations, where lesions may spread to the dentate nuclei and basal ganglia (Boudin et al. 1972). Spino-cerebello-nigral degeneration (SCND) is a term used by Ropper (1983) for inherited cases displaying features of both Friedreich ataxia (FA) and parkinsonism. To our knowledge, only two anatomical cases have been reported by Biemond and Sinnege (1955) and Weir and Fan (1981). Castaigne et al. (1961) have reported a clinical case combining features of parkinsonism and FA, with a familial occurrence. Our case is distinct from SCND because of the integrity of the spinocerebellar tracts. Other parkinsonian syndromes of sporadic or familial occurrence disclose multisystemic degenerations with a spinal cord involvement. Ferguson-Critchley syndrome (Ferguson and Critchley 1929; Brown 1975), in addition to the parkinsonian features,

99 include pyramidal, cerebellar and sensory disturbances, supra-nuclear ophthalmoplegia and micturition and mood disorders. The anatomical data are consistent with FA but the age of onset is later than in FA and the inheritance is autosomal dominant. Staal et al. (1983) have reported a similar case, the mode of inheritance of which was probably autosomal recessive; there was no ataxia, in spite of the cerebellar degeneration. Recondo's case 2 (1964)had a sporadic disease; a multisystemic degeneration involving substantia nigra, pons, oculomotor pathways, dentate nuclei, and dorsal columns was reported. In other instances, involvement of the lower motor neuron with a marked degeneration of anterior horn is prominent (B6nard et al. 1952; Biemond and Beck 1955; Moffie 1961; Brait etal. 1973; Serratrice et al, 1983). Among them, Serratrice et al.'s case deserves special mention because of the unusual combination of a chronic spinal muscular atrophy with pallidonigral degeneration. Juvenile Joseph's disease is an example of a familial multisystemic degeneration including pyramidal and extrapyramidal signs and a progressive external ophthalmoplegia. Dentato-pallido-luysian and degeneration of dorsal columns and posterior roots have been recently described (Sachdev et al. 1982), but the other degenerative changes and clinical picture differed from ours. CONCLUSION We report here an heredo-degenerative disorder not previously described, which appears related to juvenile parkinsonism, dentato-rubro-pallido-luysian atrophy, and spino-cerebello-nigral degeneration. Although a metabolic deficiency is highly suspected in multi-systemic degenerations, no positive evidence of this aetiology has yet been produced. ACKNOWLEDGEMENTS The authors thank Drs. A. Lavergne and K. Dellagi who have studied general pathology and Dr. J.L. Raggueneau for editing this manuscript; they are indebted for her capable technical assistance to Mrs. C. Letellier. REFERENCES Adams, R., L. Van Bogaert and H. Van der Eecken(1961) Deg6n6rescencesnigrostri6eset c6r6bello-nigrostri6es, Psychiat. Neurol. (Basel), 142: 219-259. Andr6-Van Leeuwen,M. and L. Van Bogaert(1949)Hereditaryataxia with optic atrophyof the retro-bulbar type and latent pallido-luysianatrophy, Brain, 72: 340-363. B6nard, R., A. Grossiord,J. Gruner and A. Hoppeler(1952)Sur une formeparticuli/~rede maladiefamiliale du syst6menerveux,apparent6eaux maladies de Friedreichet de Charcot-Marie - Deux observations anatomo-cliniques,Rev. Neurol. (Paris), 86: 800-818. Biemond,A. and W. Beck(1955) Neural muscle atrophy with degenerationof the substantia nigra, Confin. Neurol., 15: 142-153. BiemondA. and J. L. Sinnege(1955)Tabes of Friedreichwith degenerationof the substantia nigra, a special type of hereditary parkinsonism, Confin. NeuroL, 15: 129-142.

100 Bogaert, L. Van (1930) Contribution clinique et anatomique ~. l'6tude de la paralysie agitante juvdnile primitive, Rev. Neurol. (Paris), 2: 315-326. Bogaert, L. Van (1946) Aspects cliniques et pathologiques des atrophies pallidales et pallido-luysiennes progressives, J. Neurol. Neurosurg. Psychiat., 9: 125-157. Boudin, G., A. Grossiord, A. Guillard, J. Mikol and P. Lacert (1972) Maladie de Friedreich avec atteintes syst~matis6es sus-m6dullaires, Rev. Neurol. (Paris), 127: 441-456. Brait, K., S. Fahn and G.A. Schwartz (1973) Sporadic and familial parkinsonism and motor neuron disease, Neurology, 23: 990-1002. Brown, J.W. (1975) Hereditary spastic paraplegia with ocular and extrapyramidal symptoms (Ferguson-Critchley syndrome). In: P.J. Vinken and G.W. Bruyn, (Eds.), Handbook of Clinical Neurology. Vol. 22, Part H (System Disorders and Atrophies), North-Holland Publishing Comp., Amsterdam. pp. 433-443. Castaigne, P., J. Cambier, H. P. Cathala and P. Augustin (1961 ) Association chez plusieurs malades d'une m~me fratrie d'une maladie de Friedreich et d'un syndrome parkinsonien, Rev. Neurol. (Parts), 105: 452-453. Chavany, J. A., L. Van Bogaert and S. Godlewski (1951) Sur un syndrome de rigidit6/t pr6dominance axiale avec perturbation des automatismes oculo-palp~braux d'origine enc6phalitique, Presse Mdd., 59: 958-962. Davison, C. (1954) Pallido-pyramidal disease, J. Neuropath. Exp. Neurol., 13: 50-59. Dubas, F,, F. Gray and R. Escourolle (1983) Maladie de Steele-Richardson-Olszewski sans ophtalmopl6gie - - Six cas anatomo-cliniques, Rev. Neurol. (Paris), 139: 407-416. Ferguson F. and M. Critchley (1929) A clinical study of an heredo-familial disease ressembling disseminated sclerosis, Brain, 52: 203-225. Goto, I., S. Tobimatsu, M. Ohta, S. Hosokawa, H. Shibasaki and Y. Kwoiwa (1982) Dentatorubropallidoluysian degeneration - - Clinical, neuroophthalmologic, biochemical and pathologic studies on autosomal dominant form, Neurology, 32: 1395-1399. Gray, F., C. De Baecque, M. Serdaru and R. Escourolle (1981) Pallido-luyso-nigral atrophy and amyotrophic lateral sclerosis, Acta Neuropath., (Suppl.) VIII: 348-351. Gray, F., J. F., Eizenbaum, R. Gherardi, J.D. Degos and J. Poirier (1985) Luysio-pallido-nigral atrophy and amyotrophic lateral sclerosis, Acta Neuropath. (Berl.), 66: 78-82. Hasaerts, R. (1957) Sur une d~g6n~rescence optico-cochl6o-dentel~e avec extension strio-thatamique des abiotrophies, Encdphale, 46:81-107. lizuka, R., K. Hirayama and K. Maehara (1984) Dentato-rubro-pallido-luysian atrophy - - A clinicopathological study, J. Neurol. Neurosurg. Psychiat., 47: 1288-1298. Jankovic, J., J.B. Kirkpatrick, K.A. Blomquist, P.J. Langlais and E.D. Bird (1985) Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism, Neurology, 35: 227-234. Jellinger, K. (1969) Degenerations and exogenous lesions of the pallidum and striatum. In: P.J. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 6 (Diseases of the Basal Ganglia), North-Holland Publishing Comp., Amsterdam, pp. 632-693. Kornhuber, H.H. (1974) Cerebral cortex, cerebellum and basal g a n g l i a - An introduction to their motor functions. In: F.O. Schmitt and F.G. Warden (Eds.), The Neurosciences - - lllrd Study Program, The MIT Press, Cambridge, pp. 267-280. Maeshiro, H., Y. Kato, S. Nakamura, H. Hosaki and H. Matsuyama (1980) An unclassified case of degenerative disease of the central nervous system, with reference to 'Hereditary Pallidal and Dentate System Atrophy (Oyanagi)', Psychiat. Neurol. Jpn., 82: 234-248. Martin, W. E., J. A. Resch and A.B. Baker (1971) Juvenile parkinsonism, Arch. NeuroL (Chic.), 25: 494-500. Mata, M., K. Dorovini-Zis, M. Wilson and A. Young (1983) New form of familial Parkinson-dementia syndrome - - Clinical and pathologic findings, Neurology, 33: 1439-1443. Mizutani, T., M. Oda, H. Abe, S. Fuduka, H. Oikawa and K. Kosaka (1983) Hereditary multisystemic degeneration with unusual combination of cerebellipetal, dentato-rubral, and nigro-subthalamopallidal degenerations, Clin. Neuropath., 2: 147-155. Moffie, D. (1961) Familial occurrence of neural muscle atrophy (Tooth-Charcot-Marie), combined with cerebral atrophy and parkinsonism, Psychiat. Neurol. Neurochir., 64: 381-391. Naidu, S., L. I. Wolfson and N. S. Sharpless (1978) Juvenile parkinsonism-- A patient with possible primary striatal dysfunction, Ann. Neurol., 3: 453-455. Naito, H. and S. Oyanagi, (1982) Familial myoclonus epilepsy and choreoathetosis - - Hereditary dentatorubral-pallidoluysian atrophy, Neurology, 32: 798-807. Neumann, M. (1959) Combined degeneration of globus pallidus and dentate nucleus and their projections, Neurology, 9: 430-438.

101 P6pin, B., M. Haguenau and C. Job (1975) Affection h6r6do-d6g6nerative avec s6miologie extra-pyramidale pr6dominante, Rev. Neurol. (Paris), 131:294-297. Recondo, J. De (1964) Sur Quelques Cas Anatomo-cliniques d'Atrophies C~r~belleuses Associ~es ~ des D~g~n~rescences Syst~matis~es (Cordons Post~rieurs, Voies d'Association, Syst~me Pallido-nigrique) avec une Digression sur les Modalit~s de la Paralysie des Mouvements Conjugu~s Oculaires, Medical Thesis Paris. Ropper A.J. (1983) Case records of the Massachussets General Hospital, N. Engl. J. Med., 308 (1983) 1406-1414. Sachdev H., L. S. Forno and C.A. Kane (1982) Joseph's disease - - A multi-system degenerative disorder of the nervous system, Neurology, 32: 192-195. Serratrice, G., M. Toga, and J.F. Pellissier (1983) Chronic spinal muscular atrophy and pallido-nigral degeneration: report of a case, Neurology, 33: 306-310. Smith, J.K., V.A. Gonda and N. Malamud (1958) Unusual form of cerebellar ataxia combining dentatorubral and paUido-luysian degeneration, Neurology, 8: 205-209. Staal, A., S.Z. Stefanko, F. G. I. Jennekens, L. H. Penning de Vries-Bos and J. Van Gijn (1983) Autosomal recessive spino-olivo-cerebellar degeneration without ataxia, 3. Neurol. Neurosurg. Psychiat., 46: 648-652. Steele, J.C., J. C. Richardson and J. Olszewski (1964) Progressive supranuclear palsy - - A heterogeneous degeneration involving the brain stem, basal ganglia, and cerebellum, with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia, Arch. Neurol. (Chic.), 10: 333-359. Titeca, J. and L. Van B ogaert (1946) Heredo-degenerative hemiballismus - - A contribution to the question of primary atrophy of the corpus Luysi, Brain, 69: 251-263. Tom6, F.M.S., P. Brunet, M. Fardeau, F. Hentati and J. Reix (1985) Familial disease affecting the central and peripheral nervous systems characterized by cytoplasmic inclusions in peripheral nerves, blood capillaries and satellite cells of muscle, Acta Neuropath. (Berl.), In press. Verdi6, J.C. (1975) - Le Noyau Dentel~ - Donn~es Fondamentales - Analyse de 50 Cas de Dentatotomies, St~r~otaxiques, Medical Thesis, Toulouse. Verhaart, W.J.C. (1940) An unclassified degenerative disease of the central nervous system, Arch. Neurol. Psychiat., 44: 1262-1270. Weir, R. and K. Fan (1981) Spinocerebellar degeneration with parkinsonian features - - A clinical and pathological report, Ann. Neurol., 9: 87-89. Wiel, H.L. Van der and A. Staal (1981) External ophthalmoplegia, juvenile parkinsonism and axonal polyneuropathy in 2 siblings, Clin. Neurol. Neurosurg., 83: 247-252. Yamamura, Y., I. Sobue, K. Ando, M. lida, T. Yanagi and C. Kono (1973) Paralysis agitans of early onset with marked diurnal fluctuation of symptoms, Neurology, 23: 239-244. Yokochi, M., H. Narabayashi, R. Iizuka and T. Nagatsu (1984) Juvenile parkinsonism - - Some clinical, pharmacological, and neuropathological aspects. In: R.G. Hassler and J. F. Christ (Eds.), Advances in Neurology. Vol. 40. (Parkinson-specific Motor and Mental Disorders), Raven Press, New York, pp. 407-413.