Autosomal dominant striatonigral degeneration: A clinical, pathologic, and biochemical study of a new genetic disorder ROGER N. ROSENBERG, WILLIAM L. NYHAN, CAROLYN BAY, et al. Neurology 1976;26;703 DOI 10.1212/WNL.26.8.703 This information is current as of August 1, 1976
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/26/8/703.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1976 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Artlcle abstract
An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra,with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado’s disease, and Huntington’s disease.
Autosomal dominant striaton igral degeneration A ctinical, pathologic, and biochemical study of a new genetic disorder ROGER N. ROSENBERG, M.D., WILLIAM L. NYHAN, M.D., Ph.D., CAROLYN BAY, M.S., and PARKHURST SHORE, Ph.D.
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an der Eecken, Adams, and van Bogaert’ described striatonigral degeneration for the first time in 1960. Since their original report, 28 patients with this disorder have been described subsequently.*-* These patients were diagnosed clinically as having Parkinson’s disease but were unique neuropathologically in that there was bilateral degeneration of the corpus striatum and the substantia nigra, particularly the zona compacta portion. Histologically, these structures displayed marked neuronal loss. None of the reported patients had a family history of similar illness. No etiologic cause could be cited in any of these cases. Adams suggested .that a genetic factor might be invoked but could marshal1no support for this hypothesis. We describe here a family of Portuguese ancestry who
number in excess of 329 persons in eight generations who expressed a progressive neurologic syndrome, transmitted in an autosomal dominant form of inheritance. In a deceased patient the neuropathologic findings were those of striatonigral degeneration with additional abnormal findings in the dentate nucleus of the cerebellum. These patients differ clinically from previously described patients with striatonigral degeneration in that the elements of parkinsonian rigidity are minor relative to the marked degree of spasticity. In this variant of striatonigral degeneration, an autosomal dominant inheritance is clearly documented.
)y4
From the Departments of Neurology (Dr. Rosenberg) and Pharmacology (Dr. Shore),The University of Texas HealthScience Center, Southwestern Medical School at Dallas, and the Departmentof Pediatrics,The University of California School of Medicine, San Diego (Dr. Nyhan, Ms. Bay). This paper was presentedin part at the twenty-eighthannual meetingof the American Academy of Neurology, April 1976, Toronto, Canada. Received for publication February 11 , 1976. Requestsfor reprintsshould be addressedto Dr. Rosenberg,Departmentof Neurology, The University of Texas Health Science Center, Southwestem Medical School, 5323 I-larry Hines Blvd., Dallas, TX 75235.
Methods. A family meeting was attended by over 100 persons, at which neurologic examinations and genetic counseling were carried out. All of those individuals currently expressing neurologic symptoms were carefully examined neurologically. Persons considered at risk for the illness because a parent had been affected also were examined carefully. Hospital and other records were scrutinized. An autopsy was done in one patient who died of the disease, and histologic sections were available for examination. Cerebrospinalfluid was obtained from normal controls, NEUROLOGY 26: 703-714, August 1976 703
Autosomal dominant striatonigral degeneration
affected individuals, and at risk but phenotypically normal family members. Homovanillic acid was extracted and assayed according to established methods. *%*
Results. A detailed family pedigree was generated representing 329 persons in eight generations. The main segment of this family is descended from Antone Joseph, a man of Portuguese ancestry who immigrated to the United States from the Azores Islands in 1845 (figure 1). This neurologic syndrome developed in him and in at least two of his six children. The pedigree indicates that at least 51 persons descended from Antone Joseph have subsequently manifested this syndrome. Another family group with identical surnames and with identical clinical findings, also of Portuguese ancestry, are included. We believe this group represents the same clinical neurologic disorder and they appear to be related to the main family group in a generation prior to that of Antone Joseph. A total of 13 individuals of 27 at risk clearly had neurologic findings characteristic of the family illness, and 14 individuals were judged to be neurologically normal. The median age of onset of symptoms in affected family members examined was 25 years. Neurologic deficits increased progressively in all affected members and usually resulted in death from pneumonia within 15 years of onset. In several family members, the onset of neurologic symptoms was above age 40; these individuals have had slowly progressive disease for 25 years. In this series, eight affected individuals were women and five men. A statistical analysis of the incidence of affected and nonaffected offspring of affected parents was made from generations 2 through 7 from the pedigree. A total of 106 children was recorded from affected parents; disease developed in 51 and 55 remained normal. Thus, an approximate 1:1 ratio of affected to unaffected offspring of affected parents was documented, ensuring an autosomal dominant mode of inheritance. There was lack of a correlation of the sex of affected parents and the sex of affected offspring. An early neurologic symptom is a gait imbalance, which is a lurching unsteadiness of gait. Rigidity is present early in the illness and is replaced by progressive spasticity. The lower extremities progressively become stiff and spastic and are held in extension with adductor hypertonicity. Subsequently, speech becomes slow and indistinct. Vision is impaired in acuity and nystagmus is present. Patients usually remain ambulatory for 10 years after the onset of gait instability. Urinary and bowel incontinence are minimal, but some problems with the former usually develops. The intellect is preserved. On examination, the main neurologic findings were weakness of the arms and legs and spasticity of all other extremities, especially the legs. Patellar and ankle clonus were common, as were extensor toe responses to plantar stimulation. The gait was slow with a slight increase in base and lurching from side to side due to spasticity. Affected persons had no truncal titubation when seated and truncal ataxia was minimal. Pharyngeal weakness and spasticity caused difficulty with speech and swallowing. Of note were the prominence of horizontal and vertical 704 NEUROLOGY August 1976
nystagmus, the loss of fast saccade eye movements, hypermetric and hypometric saccades, and impairment of vertical gaze. Facial fasciculations, facial myokymia, and lingual fasciculations without atrophy were common and early manifestations. Cerebrospinal fluid (CSF) was assayed for homovanillic acid from 10 normal individuals, five affected family members, and one phenotypically normal but at risk family member. The mean concentration of homovanillic acid (HVA) in the CSF of 10 normal persons was 43.45 6.5 (SD) ng per milliliter within a range of 10 to 80 ng per milliliter. One at risk normal person, age 23, had 28.9 ng per milliliter. Two affected persons, ages 21 (patient 8) and 41 years (patient 4), had slightly reduced CSF levels of HVA of 21.1 ng per milliliter and 23.9 ng per milliliter, respectively. One affected person (patient 9), age 19 years, with rapidly progressive disease had a marked reduction in HVA concentration in CSF to less than 1 ng per milliliter and another affected person, age 57 (patient lo), had a low value of 4.8 ng per milliliter. The mean concentration of HVA in the CSF of the five affected persons is 15.3 4 9.9 (SD) ng per milliliter. Case 1. (MD, VI-38) This 36-year-old woman first began to have symptoms of a progressive neurologic disorder at 21 years of age. The onset was with an imbalance of gait, followed by speech difficulty. The patient’s mother had had a similar neurologic gait problem and had died of progressive disease at the age of 44 years. Similarly, the patient’s maternal grandmother had had a progressive neurologic disorder (figure 1). The patient was alert and oriented. Her intellect was intact. She had had a syncopal episode at age 31 years. The patient was seated in a wheelchair. Facial mobility and expression were reduced; visual acuity was normal, but there was a slight pallor of the optic disk. She had nystagmus on horizontal gaze and a general slowness of horizontal eye movements. Her mouth was open most of the time at rest but she was able to close it and to chew appropriately. The jaw jerk was extremely hyperactive and clonus was elicited. The pharynx moved poorly, but the gag reflex was increased. Lingual movements were slow and lateral movements impaired. The tongue was grossly fasciculating. Speech was indistinct and of a spastic dysarthric type. The motor system was abnormal, with slowness and weakness of all the extremities and marked spasticity of the lower extremities. Lead-pipe rigidity was also present, best demonstrated in the upper extremities. Her arms tended to be held in flexion and the legs and feet in extension with increased adductor tone. There was generalized hyperreflexia and bilateral extensor plantar responses. Sensory examination gave normal results. The patient was able to stand but had a marked increase in extensor tone of the legs and walked with an extremely slow spastic gait. The following laboratory tests were within normal limits: complete blood count, platelet count, urinalysis, serum sodium, potassium, chloride, bicarbonate, and pH. A technetium 99m brain scan was negative. The electroencephalogram was abnormal because of occasional short intervals of generalized 2 to 4 Hz slow wave activity, prominent anteriorly and over the right temporal region. Roentgenograms of the skull, cervical spine, and chest were normal. An intravenous pyelogram and an upper gastrointestinal barium examination were within normal limits. Cerebrospinal fluid was clear and colorless; there were no
Figure 1. Pedigree of the family showing 329 persons in eight generations with autosomal dominant striatonigral degeneration. cells; the protein was 27 and the sugar 76 mg per milliliter; and the VDRL test for syphilis was nonreactive. Diffuse lobar and bronchopneumonia developed and the patient died at 36 years of age. A postmortem examination was conducted. General autopsy findings were negative except for lobar and bronchial pneumonia, focal ulceration of the esophagus, and a small hemangioma of a vertebral body. Neuropathologic findings. The cerebral hemispheres appeared symmetrical and there were no focal lesions. The brain stem, cerebellum, and spinal cord appeared normal. Sectioning of the cerebral hemispheres in coronal fashion showed no pathologic changes. The cerebellum was sectioned in a sagittal manner and appeared grossly normal. The superior, middle, and inferior cerebellar peduncles were normal in size. The brain stem was carefully sectioned and the medullary olives and pyramidal tracts appeared normal. In particular, the pons was not atrophic. On gross examination of the substantia nigra, significant pallor was seen bilaterally throughout its extent (figure 2).
Histologically, there was an advanced loss of neurons throughout the substantia nigra and especially at its midportion (figure 2). The zona compacta of the substantia nigra was severely devoid of neurons, which were replaced by relatively dense glial proliferation. No Lewy bodies were identified. The corpus striatum showed an advanced degree of neuronal loss with replacement of glial cells (figure 3A-F). The neurons of the basal pons forming the pontocerebellar system were normal. The cerebellar cortex appeared normal (figure 4). Purkinje cells were prominent and unremarkable. The granular layer was normally dense and the molecular layer was intact. The dentate nuclei showed a loss of perhaps half of their neurons and there was a mild gliosis in that nucleus (figure 5). The anterior and lateral thalamic nuclei appeared normal without neuronal loss or reactive gliosis. The frontal cerebral cortex appeared entirely normal (figure 6). The hippocampus showed no abnormalities and Sommer’s sector was intact. The myelin content of the cerebral hemisphere, cerebellum, and brain stem were normal
NEUROLOGY August 1976 705
Autosomal dominant striatonigral degeneration
Figure 2A. Cross-section of the midbrain from patient 1 showing significant loss of melanin pigmentation in the substantia nigra bilaterally.
Figure 2B. Histologic section of the substantia nigra showing loss of neurons in the zona compacta portion. Hematoxylin and eosin, original magnification, x275.
Figure 3(A-F). (A) Cross-sectionof the corpus striatum of patient 1 showing the width of the medial segment from the ventricular surface to the internal capsule to be 2 cm. Hematoxylin and eosin, original magnification, x 10.
38. Cross-section of the corpus striatum from a control subject taken at the same level as patient 1 (A) showing the width of the medial segment from the ventricular surface to the internal capsuleto be 5 cm; thus there is severe atrophy of thecorpusstriatum present in patient 1. Hematoxylinand eosin, original magnification, x 10.
706 NEUROLOGY August 1976
3C. Histologic section of the caudate nucleus near the lateral ventricle from patient 1 showing intense neuronal loss with astrocytic replacement;there is anincrease in the number of subependymal astrocytes in the subventricular region in patient 1 compared to the control patient (V = ventricle). Hematoxylin and eosin, original magnification, x 275.
3D. Similar histologic section of the caudate nucleus as in (C) but from a control subject showing a normal neuronal density (V = ventricle). Hematoxylin and eosin, original magnification, x275.
3E. Histologic section of the putamen from patient 1 showing neuronal loss and astrocytic replacement. Hematoxylin and eosin, original magnification, x275.
3F. Histologic section of a control putamen showing a normal neuronal density in contrast to patient 1 (E). Hematoxylin and eosin, original magnification, x275.
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Figure 4. Histologic section of the cerebellar cortex showing a normal density of Purkinje, granule, and molecular layer cells. Hematoxylin and eosin, original magnification, x275.
Figure 6. Histologic section of the frontal cerebral cortex showing a normal laminar arrangement and density of neurons. Hematoxylin and eosin, original magnification, x275.
708 NEUROLOGY August 1976
Figure 5. Histologic section of the dentate nucleus of cerebellum showing moderate loss of neurons and mild gliosis. Nissl stain, original magnification, x275.
(figure 7). The inferior olives were normal in size and myelin content as were the medullary pyramids. Also, the pontocerebellar fibers, brachium conjunctivum, and spinocerebellar fibers were normally myelinated and normal in size. The corticospinal tracts appeared to be normal histologically throughout their extent. The major pathologic findings were a severe loss of neurons and glial replacement in the corpus striatum and a severe loss of neurons in the zona compacta portion of the substantia nigra. There was also a moderate loss of neurons in the dentate nucleus. Case 2. VM, VI-41 was a 39-year-old man in whom the onset of symptoms was at 30 years of age. Impairment of gait was the first symptom, and this increased in seventy to the point that he required a wheelchair from the age of 47 years. Speech and coordination also had become impaired over the past 2 years. He had had frequent cramping back and calf pains, as well as urinary frequency and urgency. Visual acuity had decreased in recent years. Dystonic and athetotic movements of the head and arms had appeared. He had had difficulty coughing and clearing secretions, and had noted dysphagia. There were marked dystonic and athetotic posturing movements of the head and anns with the head tilted to the side and flexed forward. Intellect was well preserved. There was a prosthesis in the right orbit. The left eye had a prominent nystagmus on vertical and horizontal gaze. There was a loss of the fast saccades on lateral gaze and only slow pursuit movement remained. Reflex head turning yielded the same kind of slow eye movements as did pursuit. Hypermetric and hypometric saccades occurred with pursuit eye movements. The optic disk was slightly pale and visual acuity was about 20/50. The mouth was held open most of the time. The facies appeared thin, with
Figure 7. Cross sections of (A) frontal lobe gyrus, (B) cerebellar folia and deep white matter showing the dentate nucleus, (C) midbrain, (D) pons with brachium pontis and portion of cerebellar cortex, and (E) medulla. These sections are stained for myelin and show a normal pattern and density of myelinated tracts. The brachium pontis, restiform body, subcortical white matter of cerebrum and cerebellum, and corticospinal tracts appear normal. The inferior olives are normal in size and shape. Myelin stain, x10. atrophy of the temporal muscles. There were numerous facial fasciculations and obvious mentalis muscle myokymia. The jaw jerk was strikingly increased and the muscles of mastication were weak. The speech was slow and difficult to understand. The pharynx moved poorly with voluntary phonation, and the gag reflex was markedly increased. Tongue movements were slow and the tongue fasciculated, but there was no atrophy. There was a moderate increase in tone in the arms with both rigidity and spasticity, and the legs were markedly spastic. The deep tendon reflexes were + 3 in the arms and +4 at the knees and ankle with sustained clonus and bilateral extensor plantar responses. Strength was reduced throughout to about 3/5. There was no atrophy of the extremities; occasional fasciculations were noted. Finger-to-finger and heel-to-shin movements were slightly dysmetric. His gait was broad-based and spastic, and there was increased adductor tone and legs and feet held in extension. An indwelling catheter was required because of urinary incontinence. Case 3. RB, VI-57 was a 46-year-old woman in whom the onset of neurologic symptoms was at 32 years of age with gait instability and leg numbness. A lurching, unstable gait progressed over the next 10 years, requiring a wheelchair. Impairment of speech and vision had progressed. Prominent calf pain occurred intermittently. Urinary frequency and urgency also had developed. Emotional lability and crying were prominent in recent months. Neurologic examination showed her to be diffusely weak and unable to walk. She had an expressionless face and tended to
keep her mouth open. Eye movements were slow, with horizontal nystagmus and hypermetric and hypometric saccades. Vertical gaze was impaired, but pupillary function was normal. There was slight pallor of the optic disk. Facial fasciculations and facial myokymia were present. The muscles of mastication were strong, and there was no temporal muscle atrophy. The jaw jerk was increased. Her speech was slow and inarticulate, and she had impaired voluntary pharyngeal movement and a marked increase in the gag reflex. Tongue movements were slow, with fasciculations but no atrophy. Weakness was graded 3/5, with rigidity and spasticity of the arms and marked spasticity of the legs. The reflexes were increased in the arms, and were increased in the legs with clonus. Plantar responses were extensor bilaterally. The gait was markedly spastic, and the legs and feet were held in extension and had increased adductor tone. Position and pin perception was minimally reduced in the legs and feet. There was minimal dysmetria of finger-to-finger and heel-to-shin movements. The patient was emotionally labile and easily provoked to tears and crying. She had a moderate problem with urinary frequency and continence.
Case 4. (VW, VI1-31). Neurologic symptoms had developed in this 41-year-old woman in the early 30s. A lurching, unstable gait had developed over the past 10 years, followed in the past 3 years by impairment of speech and vision. Urinary incontinence and frequency had occurred recently. The patient remained ambulatory 10years after the development of symptoms and was able to use her arms and hands well.
NEUROLOGY August 1976 709
Autosomal dominant striatonigral degeneration
On neurologic examination, she had a broad-based, lurching spastic gait without titubation. There was some pallor of the optic disks, and vertical and horizontal nystagmus were present to a moderate degree. Eye movements were slow, with hypermetric and hypometric saccades. No atrophy of facial muscles was seen, and the muscles of mastication were strong. The jaw jerk was moderately increased. Facial fasciculations were noted. Speech was slow and indistinct, she had poor voluntary pharyngeal movement. The gag reflex was markedly increased. Lingual movements were slow, and there were lingual fasciculations. The patient was strong in all muscle groups without atrophy, but the tone was moderately increased. The reflexes were 3 in the arms and 3 to 4 with unsustained clonus at the ankles. There were bilateral extensor plantar responses. Sensory examination gave normal results. Finger-to-finger and heel-to-shin testing demonstrated a minimal degree of dysmetria.
+
+
Case 5. (RH, VII-I). A 44-year-old man had the onset of neurologic symptoms at 24 years of age, when a progressive staggering and lurching gait developed that produced severe disability. He was confined to a wheelchair. A severe impairment of speech articulation developed over the past 4 years and was associated with mild impairment of visual acuity and urinary frequency and urgency. The patient was intelligent. He had minimal optic disk pallor and horizontal and vertical nystagmus with impairment of vertical gaze. Eye movements were slow, with hypermetric and hypometric saccades. Pupillary function was normal. Facial muscles were atrophied and the muscles of mastication were atrophied and weak. There was a prominent jaw jerk. The patient’s speech was markedly impaired and spastic, with poor movement of pharyngeal muscles and a strikingly increased gag reflex. The tongue wasfasciculating without atrophy, and he had difficulty with rapid lingual movement. He was weak in all extremities, graded 315 with an increase in tone in his arms of both spasticity and rigidity, and severe spasticity in his legs with ankle clonus and extensor plantar responses. The patient had +3 reflexes in his arms and + 3 to 4 reflexes at the knee and ankle. The sensory examination was normal. The patient was able to walk only with help and had a lurching spastic gait with some element of rapid titubation. Finger-to-finger and heel-to-shin testing showed a moderate degree of dysmetria. Case 6. DHH, VII-4 is a 38-year-old woman in whom neurologic symptoms had developed at about the age of 25 years. Her difficulty began with a lurching imbalance of gait followed by impairment of speech and vision. She remained ambulatory but was walking with great caution to avoid falling. There was minimal urinary frequency and incontinence. She was an intelligent, articulate woman who had a broad-based, spastic, lurching gait. She had horizontal and vertical nystagmus, with impairment of vertical gaze. Eye movements were slow with hypermetric and hypometric saccades. Pupils were normal, and there was minimal optic disk pallor. The facial muscles were not atrophied, and the muscles of mastication were strong. The jaw jerk was minimally increased and she showed occasional minimal facial fasciculations. Her speech was slow and difficult to understand, with minimal impairment of pharyngeal movement but with a striking increase in the gag reflex. The strength in her arms and legs was normal, but there was a moderate increase in tone in her arms (+3) and legs with bilateral extensor plantar responses. The patient had no truncal titubation nor ataxia of gait. Urinary frequency and urgency were minimal. 710 NEUROLOGY August 1976
Case 7. DN, VII-32 was a 40-year-old woman who had the onset of neurologic symptoms at 18 years of age, with impairment of gait, progressing to a lurching, unsteady gait, and impairment of speech by 36 years of age. She continued to walk with great care, using a cane or walker. Her speech had become slow and inarticulate in the past several years, and there was a minimal impairment of visual acuity. She had noted recent urinary frequency and urgency. On neurologic examination, she was intelligent and oriented. There was minimal atrophy of the optic disk, and there was prominent horizontal and vertical nystagmus and impairment of vertical gaze. The eye movements were slow, and there were hypermetric and hypometric saccades. The patient had had an intermittent left inferior rectus palsy since early childhood. There was facial atrophy and some atrophy and weakness of muscles of mastication. The jaw jerk was moderately increased. Facial fasciculations were noted. Pharyngeal movements were slow, and there was a striking increase in the gag reflex. Lingual movements were slow, and there was no lingual atrophy, but there were prominent lingual fasciculations. The patient was minimally weak 31.5 and had minimal increase in tone in the arms and moderate increase in tone in the legs of a spastic type. The patient’s gait was spastic and lurching from side to side. The reflexes in the arms were + 3 and + 3 to 4 in the legs with unsustained clonus. The plantar responses were flexor bilaterally. There was minimal heel-to-shin and finger-to-finger dysmetria. Case 8. (KD, VII-21). This 21-year-old man had had a progressive impairment of gait since the age of 19. He had had stuttering and slight speech dysarticulation since early childhood. He had noted in the past 3 years a progressive imbalance and lurching of his gait and impairment in the clarity of his speech. He was no longer able to run or to climb stairs quickly. On neurologic examination, he had a bmad-based, lurching, spastic gait. The optic disks were normal. Visual acuity was intact. He had nystagmus of horizontal and vertical gaze and slowness of eye movement, a masking of facial expression, and a tendency to hold his mouth open. Fasciculations of the face and tongue were present without lingual atrophy. The pharynx had a slight reduction in movement, and a gag reflex was strikingly increased. The muscles of mastication were strong, but there was an increased jaw jerk. The tone in his arms was within normal limits, but there was a marked increase in tone in his legs with hyperreflexia + 3 at the knee and +4 at the ankle with unsustained clonus. Plantar response was neutral. Finger-to-nose and heel-to-shin testing were within normal limits. The sensory examination was normal. Case 9. RD, VII-22 was a 19-year-old male who had noted clumsiness of arm movements and deterioration in gait over the past 2 years and difficulty with speech over the past year. His gait was broad-based and stiff, and he had a tendency to lurch to the side. The optic fundi were normal, and there was an occasional burst of nystagmus with horizontal gaze bilaterally. He had occasional facial fasciculations. The facial muscles and muscles of mastication were strong, but there was an increased jaw jerk. The pharynx moved fairly well but the gag reflex was markedly increased. The strength in his extremities was normal, but the tone in the legs was increased. He had hyperreflexia + 3 in the arms and legs and bilateral extensor plantar responses. Finger-to-nose and heel-to-shin testing were normal, and the sensory examination was normal. His gait was stiff and slow, and he had a tendency to lurch to either side.
Case 10. PB, V-69 was a 57-year-old woman who had the onset of neurologic symptoms at age 40 years with gait impairment, followed by difficulty with speech and coordination; the disease had progressed to the point that she required a wheelchair for the past 3 years. Neurologic examination showed her to be intelligent. She had slight pallor of the optic disks, bilateral horizontal and vertical nystagmus, and impaired vertical gaze. Abduction of the eyes was incomplete bilaterally. The patient was able to converge and had normal pupillary function. She had marked facial fasciculations and facial myokymia, the muscles of mastication were normal, and there was an increased jaw jerk. Her speech was slow and spastic with decreased voluntary movement of the pharynx and a marked increase in the gag reflex. Lateral tongue movements were slow, and lingual fasciculations were prominent. Her arm strength was normal, and increased arm tone and occasional fasciculations were noted. The tone in the legs was markedly increased, and she had spasticity and hyperreflexia with ankle clonus and bilateral extensor plantar responses. Vibration and position senses were normal, and pin perception over the left foot was slightly decreased. Heel-to-shin and finger-to-nose movements were normal. The patient was able to stand with help and had a marked impairment of gait because of the spasticity. Case 11. EC, V-66 was a 70-year-old woman whose symptoms had begun with a gait impairment and speech difficulty about the age of 42 years and had been progressive over the past 30 years. The patient was in a wheelchair and had marked difficulty with hand coordination, clearing her throat, and handling secretions. Her neurologic examination showed her to be intelligent. She was able to stand but had truncal titubation and truncal ataxia. The patient had evidence of horizontal nystagmus and incomplete abduction of eye movements bilaterally. Eye movements were slow, vertical gaze was absent, and facial fasciculations were prominent. The jaw jerk was normal, but the muscles of mastication were slightly weak. Her speech was slow and spastic, and lingual fasciculations were noted, as well as impairment of tongue movements. The patient was diffusely weak; arm strength was 315 proximally and 315 distally. She had prominent fasciculations in the arms, and trace deep tendon reflexes in the upper extremities. The tone in the arms was reduced. She was able to stand with help. Leg tone was increased, of a spastic type; at rest, the tone was decreased in her legs, and she had moderate weakness about 3/5 in all groups tested. No fasciculations or atrophy were noted in the legs. The patient had trace knee reflexes, absent ankle reflexes, and bilateral extensor plantar responses. There was a mild decrease in pin perception in the legs distally. Heel-to-shin and finger-to-nose testing demonstrated a moderate degree of dysmetria. Case 12. (OH, V-72). Neurologic symptoms in this 49-year-old man began shortly after 40 years of age with an impairment of gait followed by speech impairment. At 49 years of age, he was still walking but had a spastic lurching gait. His speech was slow and somewhat indistinct, and he had a history of some deterioration in hand coordination. Neurologic examination showed that he was intelligent. He had slight disk pallor and bilateral impairment of eye abduction. He had horizontal nystagmus bilaterally and some impairment of speech, which was slow and spastic. The pharynx moved normally, but the gag reflex was increased. There were lingual fasciculations noted as well as facial fasciculations. The bulk, tone, and strength of his arms were intact and the deep tendon reflexes were slightly increased. The legs showed a moderate degree of spasticity and
increased deep tendon reflexes + 3 and extensor plantar responses bilaterally. Sensory examination gave normal results. Finger-to-finger and heel-to-shin testing showed a slight degree of dysmetria. The patient had no titubation and no truncal nor extremity ataxia.
Case 13. EA, VII-33 was a 34-year-old female at risk for the disease who was asymptomatic for any neurologic disorder. However, she had nonspecific clumsiness and a left eye esotropia since childhood. Specifically, the patient had no symptoms of difficulties with gait, vision, or speech and swallowing . The neurologic examination showed prominent horizontal nystagmus with a normal rate of extraocular movements. The patient had occasional facial fasciculations and myokymia of the mentalis muscle. The muscles of mastication were strong, but the jaw jerk was increased. The pharynx moved well and speech was normal, the gag reflex was active. The tongue was tremulous without definite fasciculations. Lingual movements were normal, and there was no lingual atrophy. The deep tendon reflexes in her arms and legs were increased 3, and there were bilateral flexor plantar responses. Finger-to-finger and heel-to-shin movements were entirely normal. She may have represented early findings of the disease.
+
In 14 other individuals the history was normal and the neurologic examination completely negative.
Discussion. This family appears to have a new genetic neurologic disorder classified as a striatonigral degeneration. It is characterized as having an autosomal dominant mode of inheritance and a regular expression of progressive neurologic deficit. Neuropathologic examination established the sites of neuronal degeneration and is consistent with the findings on neurologic examination. This variant of the striatonigral degenerations appears to be distinct from previously described patients. 1-15 Each of the previously described patients has had a sporadic or spontaneous disorder with neuronal loss and reactive gliosis in the corpus striatum and substantia nigra. The table summarizesthe neurologic findings in the present series of patients and contrasts them with those of previously reported cases of striatonigral d e g e n e r a t i ~ n . ~Previous ?~ cases have presented with parkinsonian rigidity. In the present cases, progressive spasticity, predominantly of the legs associated with patellar and ankle clonus, extensor plantar responses, and leg and foot extensor hypertonicity are much more prominent. We interpret the spasticity, a lack of inhibition or modulation of motor unit contractions, to be the main problem responsible for the gait imbalance, speech difficulty, and dysphagia. Other important early findings include gaze evoked nystagmus, slowness of eye movements, facial fasciculations and myokymia, and lingual fasciculations. These features have not been reported in the sporadic cases of striatonigraldisease. The jaw jerk and gag reflex are also exaggerated in association with hyperactive deep tendon reflexes. Our patients have had some rigidity, dystonia, or athetosis but these features were not prominent. This series of patients with striatonigral degeneration thus adds an additional phenotype t o established entities in which neuronal loss NEUROLOGY August 1976 711
Autosomal dominant striatonigral degeneration
Table 7. Summary of neurologic findings in selected cases of striatonigral degeneration
712 NEUROLOGY August 1976
and gliosis of the corpus striatum or substantia nigra occur, including Huntington’s disease, dystonia musculorum d e f o r m a n s , olivopontocerebellar degeneration, and nigrospinodentatal degeneration. It is not clear in the present cases how such diverse motor findings as athetosis, dystonia, rigidity and spasticity can be accounted for by lesions in the corpus striatum and substantia nigra. Rigidity, dystonia, and athetosis are best correlated with lesions in the striatum and substantia nigra. The occasional occurrence of minor ataxic gait and dysmetria and clumsiness are explainable on the basis o f moderate involvement of the dentatorubrothalamic system. The clinical spasticity, clonus, and extensor plantar responses were major motor abnormalities and the most problematic for a close clinicopathologic correlation. Patient 1 had no involvement of the pyramidal corticospinal tract at the level of the internal capsule, cerebral peduncles, basis of the pons, medullary pyramids, and spinal cord. Yet, this patient and others in the family had a hyperactive jaw jerk, hyperactive gag reflex, increased deep tendon reflexes, bilateral Babinski signs, and spasticity in which legs were held in extension with increased adductor hypertonicity. Several examples in the literature describe patients with extensor responses to plantar stimulation who had intact pyramidal tracts on pathological examination. This subject of clinicopathologic correlation was carefully reviewed by Nathan and Smith in 1955.19 They concluded that there was no relation between the anatomic state of the corticospinal tracts and the form of the plantar response. Woods and Schaumburg18 described an autosomal dominant neurologic disorder, nigrospinodentatal degenerationin a family of Portugueseextraction from the Azores Islands, in which rigidity and spasticity were associated with extensor responses on plantar stimulation as prominent features of the illness and in whom the pyramidal corticospinal tracts and basal ganglia were histologically normal. The major pathology in their patients was in the dentate nuclei, the spinocerebellar tracts, and the middle cerebellar peduncles. The cerebellar cortex appeared normal. Thus, nigrospinodentatal degeneration is an example of mixed rigidity and spasticity in which de-efferentation and deafferentation of the cerebellum is the apparent cause. A clear explanation of the prominent presence of spasticity in their patients is wanting. It is of interest, however, that this nigrospinodentatal degeneration occurred in an autosomal dominant manner in a family of Portuguese extraction. The clinical expression was similar to that of the present cases, but the neuropathologic findings were different. MettlerZ1J2and Rioch and Brennerz3have suggested that the striatum exerts an inhibitory modulating influence on brain stem extrapyramidal systems, such as the t e c t o s p i n a l , r u b r o s p i n a l , r e t i c u l o s p i n a l , and vestibulospinal pathways. Neuronal loss in the striatum thus might result in a release of these brain stem extrapyramidal nuclei and a clinical expression of spasticity. Similarly, a loss of an inhibitory cerebellar NEUROLOGY August 1976 713
Autosomal dominant striatonigral degeneration
influence on the extrapyramidal motor system as proposed by Henneman24 might be responsible for spasticity in nigrospinodentatal degeneration’ and olivopontocerebellar degenerationz8 in which involvement of the pyramidal corticospinal system is minimal or absent. Patient 11 in our series, a 70-year-old female had symptoms, expressed for at least 28 years, resembling Machado’s disease. This is a dominantly inherited ataxia reported in a Portuguese family from the Azores Islands in whom there is distal sensory loss and decreased deep tendon reflexes without extrapyramidal rigidity or spasticity. 2s The present patients are clearly different from those affected with Huntington’s disease in that none of our patients developed chorea or a dementia. Further, the neuropathologic findings in patient 1 included a marked selective neuronal loss in the zona compacta of the substantia nigra, which is not typical of Huntington’s disease. The cerebral cortex was entirely intact histologically in patient 1 despite advanced clinical disease, which again is not compatible with Huntington’s disease. The natural history of the disease in the present cases is a course lasting about 15 years. This is considerably longer than the average of 5 years reported in the spontaneous forms of striatonigral degeneration. Previous experience with the treatment of striatonigral degeneration has been disappointing. However, Fahn and GreenbergZ6obtained improvement in the rigidity in two patients with levodopa therapy.
It would be of great value to find a molecular marker for the disease. In a general sense such a marker is needed for all of the common autosomal dominant genetic neurologic disorders. This would greatly assist in family planning and could lead to the elimination of the disease. Genetic counseling is difficult in a disorder in which most patients have their first symptom after they have had their families. Levels of dopamine and homovanillic acid in the cerebrospinal fluid have been reported to be low in one patient with nongenetic striatonigral d e g e n e r a t i ~ nTwo .~~ of the present affected patients, 21 and 41 years of age, had slightly reduced levels of homovanillic acid in their CSF and one at risk normal person age 23 years had a normal value. It is of note that one affected patient (No. 9) had a marked reduction in his homovanillic acid concentration and one affected patient (No. 10)had a very low value. It is our hope these studies in selected patients will assist in part in family planning and potential elimination of disease. Additional homovanillic acid determinations in a larger number of affected and at risk persons are needed to determine its absolute value as a molecular marker of disease, and these studies are in progress. Acknowledgments We acknowledge the invaluable neuropathologic assistance of Dr. S. Nielsen and Dr. J Kirkpatrick. Departmentsof Pathology and Neurology, and Chief of Neuropathology at the University of Texas Southwestern Medical School. Invaluable assistance was provided by Ruth Berini, Elinor Frank, Leon Steinsapir, M.D.. Rose Marie Silva and Sister R. Curtiss. This research was supported by a grant from the National Genetics Foundation, New York, NY.
REFERENCES 1. Van der Eecken H, Adams RD, van Bogaert L: Striopallidal-nigral degeneration: An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 19:159, 1960 2. Stochdorph 0: In discussion to the paper by Van der Eecken, Adams and van Bogaert. J Neuropathol Exp Neurol 19:159, 1960 3.Adams RD, van Bogaert L, Van der Eecken H: Degenerescences nigro-striges et cerebello-nigro-striges. Psychiatr Neurol 142:219-259, 1961 4. Adams RD, van Bogaert L, Van der Eecken H: Striato-nigral degeneration. J Neuropathol Exp Neurol 23:584-608, 1964 5. Mayo GM, Barron KD: Striatonigral degeneration. J Neuropathol Exp Neurol 25172. 1966 6. Koeppen AH, Barron KD, Cox JF: Striatonigral degeneration. Acta Neuropathol 19:lO-19, 1971 7. Jellinger K, Danielczyk W: Striato-nigrale degeneration. Acta Neuropathol 10:242-257, 1968 8. Matsuyama H, Tamaoki K, Takeuchi H. et al: Two autopsy cases of severe degeneration and pigmentation of the putamen with clinical Parkinsonism. Presented at the ninth annual meeting of the Japanese Neuropathological Society. Niigata, Japan, April 1968 9. Andrews JM, Terry RD, Spataro J: Striatonigral degeneration. Clinical-pathological correlations and response to stereotaxic surgery. Arch Neurol 23:319-329, 1970 10. lzumi K, lnoue N, Shrabe T, et al: Failed levodopa therapy in striato-nigral degeneration. Lancet 1:1355, 1971 11. Takei Y, Mirra SS:Striatonigral degeneration: Aform of multiple system atrophy with clinical Parkinsonism. Prog Neuropath 2:217-251, 1973 12. Barre JA, Reys L: Syndrome Parkinsonien avec signe Babinski bilaterale. Lesion symmetrique des putamens. Rev Neurol45:966-975. 1926 13. Fleischhacker H: Afamiliare chronisch-progressive Erkrankung des mittleren Lebensaltersvom Pseudosklerosetyp.2 Ges NeurolPsychiatr 9111-22,1924 14. Borit A, Rubinstein LJ. Ulrich H: The striatonigral degenerations-Putaminal pigments and nosology. Brain 98:lOl-112. 1975 15. Naffziger HC, Shepardson HC: A new family group of hereditary and
714 NEUROLOGY August 1976
spastic ataxia-its distribution. Calif West Med 27:207-208, 1927 16. Murphy GF, Robinson D, Sharman D F The affects of tropolone on the formation of 3, 4-dihydroxyphenylacetic acid and 4-hydroxy 3-methoxyphenylacetic acid in the brain of the mouse. Br J Pharmacol 36:107-115, 1969 17. Anden NE, Roos BE, Werdinius B: On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci 2:448-458, 1963 18. Woods BT, Schaumburg HH: Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia-a unique and partially treatable clinicopathological entity. J Neurol Sci 17:149-166, 1972 19. Nathan PS, Smith MC: The Babinski response: A review and new observations. J Neurol Neurosurg Psychiatry 18:250-259, 1955 20. Waggoner RW, Lowenberg K, Speicher KG: Hereditary cerebellar ataxia. Arch Neurol Psychiatry 39570-586, 1938 21. Mettler F A Physiologic effects of bilateral and simultaneous frontal lesions in the primate. J Comp Neurol 81:105, 1944 22. Mettler FA, Ades HW, Lipman E, et al: The extrapyramidal system: An experimental demonstrationof function. Arch Neurol Psychiatry41 :984, 1939 23. Rioch DMcK, Brenner C: Experiments on the corpus striatum and rhinencephalon. J Comp Neurol 68:491, 1938 24. Henneman E: Motor functions of the brainstem and basal ganglia. In Mountcastle VB (Editor): Medical Physiology. Ed 13. 1974, vol 1, chap 26, p 687, chap 26, pp 734, 742 25. Nakano KK, Dawson DM. Spence A: Machado disease: A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology (Minneap) 22:49-55, 1972 26. Fahn S , Greenberg J: Striatonigral degeneration. Trans Am Neurol ASSOC97~275-277,1972 27. Sharpe JA, Rewcastle NB, Lloyd KG, et al: Striatonigral degeneration: Response to levodopa therapy with pathological and neurochemical correlation. J Neurol Sci 19:275-286, 1972 28. Landis OMD, Rosenberg RN, Landis SC, et al: Olivopontocerebellar degeneration: Clinical and ultrastructural abnormalities. Arch Neurol 31:295-307, 1974
Autosomal dominant striatonigral degeneration: A clinical, pathologic, and biochemical study of a new genetic disorder ROGER N. ROSENBERG, WILLIAM L. NYHAN, CAROLYN BAY, et al. Neurology 1976;26;703 DOI 10.1212/WNL.26.8.703 This information is current as of August 1, 1976 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1976 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Artlcle abstract
An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra,with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado’s disease, and Huntington’s disease.
Autosomal dominant striaton igral degeneration A ctinical, pathologic, and biochemical study of a new genetic disorder ROGER N. ROSENBERG, M.D., WILLIAM L. NYHAN, M.D., Ph.D., CAROLYN BAY, M.S., and PARKHURST SHORE, Ph.D.
V
an der Eecken, Adams, and van Bogaert’ described striatonigral degeneration for the first time in 1960. Since their original report, 28 patients with this disorder have been described subsequently.*-* These patients were diagnosed clinically as having Parkinson’s disease but were unique neuropathologically in that there was bilateral degeneration of the corpus striatum and the substantia nigra, particularly the zona compacta portion. Histologically, these structures displayed marked neuronal loss. None of the reported patients had a family history of similar illness. No etiologic cause could be cited in any of these cases. Adams suggested .that a genetic factor might be invoked but could marshal1no support for this hypothesis. We describe here a family of Portuguese ancestry who
number in excess of 329 persons in eight generations who expressed a progressive neurologic syndrome, transmitted in an autosomal dominant form of inheritance. In a deceased patient the neuropathologic findings were those of striatonigral degeneration with additional abnormal findings in the dentate nucleus of the cerebellum. These patients differ clinically from previously described patients with striatonigral degeneration in that the elements of parkinsonian rigidity are minor relative to the marked degree of spasticity. In this variant of striatonigral degeneration, an autosomal dominant inheritance is clearly documented.
)y4
From the Departments of Neurology (Dr. Rosenberg) and Pharmacology (Dr. Shore),The University of Texas HealthScience Center, Southwestern Medical School at Dallas, and the Departmentof Pediatrics,The University of California School of Medicine, San Diego (Dr. Nyhan, Ms. Bay). This paper was presentedin part at the twenty-eighthannual meetingof the American Academy of Neurology, April 1976, Toronto, Canada. Received for publication February 11 , 1976. Requestsfor reprintsshould be addressedto Dr. Rosenberg,Departmentof Neurology, The University of Texas Health Science Center, Southwestem Medical School, 5323 I-larry Hines Blvd., Dallas, TX 75235.
Methods. A family meeting was attended by over 100 persons, at which neurologic examinations and genetic counseling were carried out. All of those individuals currently expressing neurologic symptoms were carefully examined neurologically. Persons considered at risk for the illness because a parent had been affected also were examined carefully. Hospital and other records were scrutinized. An autopsy was done in one patient who died of the disease, and histologic sections were available for examination. Cerebrospinalfluid was obtained from normal controls, NEUROLOGY 26: 703-714, August 1976 703
Autosomal dominant striatonigral degeneration
affected individuals, and at risk but phenotypically normal family members. Homovanillic acid was extracted and assayed according to established methods. *%*
Results. A detailed family pedigree was generated representing 329 persons in eight generations. The main segment of this family is descended from Antone Joseph, a man of Portuguese ancestry who immigrated to the United States from the Azores Islands in 1845 (figure 1). This neurologic syndrome developed in him and in at least two of his six children. The pedigree indicates that at least 51 persons descended from Antone Joseph have subsequently manifested this syndrome. Another family group with identical surnames and with identical clinical findings, also of Portuguese ancestry, are included. We believe this group represents the same clinical neurologic disorder and they appear to be related to the main family group in a generation prior to that of Antone Joseph. A total of 13 individuals of 27 at risk clearly had neurologic findings characteristic of the family illness, and 14 individuals were judged to be neurologically normal. The median age of onset of symptoms in affected family members examined was 25 years. Neurologic deficits increased progressively in all affected members and usually resulted in death from pneumonia within 15 years of onset. In several family members, the onset of neurologic symptoms was above age 40; these individuals have had slowly progressive disease for 25 years. In this series, eight affected individuals were women and five men. A statistical analysis of the incidence of affected and nonaffected offspring of affected parents was made from generations 2 through 7 from the pedigree. A total of 106 children was recorded from affected parents; disease developed in 51 and 55 remained normal. Thus, an approximate 1:1 ratio of affected to unaffected offspring of affected parents was documented, ensuring an autosomal dominant mode of inheritance. There was lack of a correlation of the sex of affected parents and the sex of affected offspring. An early neurologic symptom is a gait imbalance, which is a lurching unsteadiness of gait. Rigidity is present early in the illness and is replaced by progressive spasticity. The lower extremities progressively become stiff and spastic and are held in extension with adductor hypertonicity. Subsequently, speech becomes slow and indistinct. Vision is impaired in acuity and nystagmus is present. Patients usually remain ambulatory for 10 years after the onset of gait instability. Urinary and bowel incontinence are minimal, but some problems with the former usually develops. The intellect is preserved. On examination, the main neurologic findings were weakness of the arms and legs and spasticity of all other extremities, especially the legs. Patellar and ankle clonus were common, as were extensor toe responses to plantar stimulation. The gait was slow with a slight increase in base and lurching from side to side due to spasticity. Affected persons had no truncal titubation when seated and truncal ataxia was minimal. Pharyngeal weakness and spasticity caused difficulty with speech and swallowing. Of note were the prominence of horizontal and vertical 704 NEUROLOGY August 1976
nystagmus, the loss of fast saccade eye movements, hypermetric and hypometric saccades, and impairment of vertical gaze. Facial fasciculations, facial myokymia, and lingual fasciculations without atrophy were common and early manifestations. Cerebrospinal fluid (CSF) was assayed for homovanillic acid from 10 normal individuals, five affected family members, and one phenotypically normal but at risk family member. The mean concentration of homovanillic acid (HVA) in the CSF of 10 normal persons was 43.45 6.5 (SD) ng per milliliter within a range of 10 to 80 ng per milliliter. One at risk normal person, age 23, had 28.9 ng per milliliter. Two affected persons, ages 21 (patient 8) and 41 years (patient 4), had slightly reduced CSF levels of HVA of 21.1 ng per milliliter and 23.9 ng per milliliter, respectively. One affected person (patient 9), age 19 years, with rapidly progressive disease had a marked reduction in HVA concentration in CSF to less than 1 ng per milliliter and another affected person, age 57 (patient lo), had a low value of 4.8 ng per milliliter. The mean concentration of HVA in the CSF of the five affected persons is 15.3 4 9.9 (SD) ng per milliliter. Case 1. (MD, VI-38) This 36-year-old woman first began to have symptoms of a progressive neurologic disorder at 21 years of age. The onset was with an imbalance of gait, followed by speech difficulty. The patient’s mother had had a similar neurologic gait problem and had died of progressive disease at the age of 44 years. Similarly, the patient’s maternal grandmother had had a progressive neurologic disorder (figure 1). The patient was alert and oriented. Her intellect was intact. She had had a syncopal episode at age 31 years. The patient was seated in a wheelchair. Facial mobility and expression were reduced; visual acuity was normal, but there was a slight pallor of the optic disk. She had nystagmus on horizontal gaze and a general slowness of horizontal eye movements. Her mouth was open most of the time at rest but she was able to close it and to chew appropriately. The jaw jerk was extremely hyperactive and clonus was elicited. The pharynx moved poorly, but the gag reflex was increased. Lingual movements were slow and lateral movements impaired. The tongue was grossly fasciculating. Speech was indistinct and of a spastic dysarthric type. The motor system was abnormal, with slowness and weakness of all the extremities and marked spasticity of the lower extremities. Lead-pipe rigidity was also present, best demonstrated in the upper extremities. Her arms tended to be held in flexion and the legs and feet in extension with increased adductor tone. There was generalized hyperreflexia and bilateral extensor plantar responses. Sensory examination gave normal results. The patient was able to stand but had a marked increase in extensor tone of the legs and walked with an extremely slow spastic gait. The following laboratory tests were within normal limits: complete blood count, platelet count, urinalysis, serum sodium, potassium, chloride, bicarbonate, and pH. A technetium 99m brain scan was negative. The electroencephalogram was abnormal because of occasional short intervals of generalized 2 to 4 Hz slow wave activity, prominent anteriorly and over the right temporal region. Roentgenograms of the skull, cervical spine, and chest were normal. An intravenous pyelogram and an upper gastrointestinal barium examination were within normal limits. Cerebrospinal fluid was clear and colorless; there were no
Figure 1. Pedigree of the family showing 329 persons in eight generations with autosomal dominant striatonigral degeneration. cells; the protein was 27 and the sugar 76 mg per milliliter; and the VDRL test for syphilis was nonreactive. Diffuse lobar and bronchopneumonia developed and the patient died at 36 years of age. A postmortem examination was conducted. General autopsy findings were negative except for lobar and bronchial pneumonia, focal ulceration of the esophagus, and a small hemangioma of a vertebral body. Neuropathologic findings. The cerebral hemispheres appeared symmetrical and there were no focal lesions. The brain stem, cerebellum, and spinal cord appeared normal. Sectioning of the cerebral hemispheres in coronal fashion showed no pathologic changes. The cerebellum was sectioned in a sagittal manner and appeared grossly normal. The superior, middle, and inferior cerebellar peduncles were normal in size. The brain stem was carefully sectioned and the medullary olives and pyramidal tracts appeared normal. In particular, the pons was not atrophic. On gross examination of the substantia nigra, significant pallor was seen bilaterally throughout its extent (figure 2).
Histologically, there was an advanced loss of neurons throughout the substantia nigra and especially at its midportion (figure 2). The zona compacta of the substantia nigra was severely devoid of neurons, which were replaced by relatively dense glial proliferation. No Lewy bodies were identified. The corpus striatum showed an advanced degree of neuronal loss with replacement of glial cells (figure 3A-F). The neurons of the basal pons forming the pontocerebellar system were normal. The cerebellar cortex appeared normal (figure 4). Purkinje cells were prominent and unremarkable. The granular layer was normally dense and the molecular layer was intact. The dentate nuclei showed a loss of perhaps half of their neurons and there was a mild gliosis in that nucleus (figure 5). The anterior and lateral thalamic nuclei appeared normal without neuronal loss or reactive gliosis. The frontal cerebral cortex appeared entirely normal (figure 6). The hippocampus showed no abnormalities and Sommer’s sector was intact. The myelin content of the cerebral hemisphere, cerebellum, and brain stem were normal
NEUROLOGY August 1976 705
Autosomal dominant striatonigral degeneration
Figure 2A. Cross-section of the midbrain from patient 1 showing significant loss of melanin pigmentation in the substantia nigra bilaterally.
Figure 2B. Histologic section of the substantia nigra showing loss of neurons in the zona compacta portion. Hematoxylin and eosin, original magnification, x275.
Figure 3(A-F). (A) Cross-sectionof the corpus striatum of patient 1 showing the width of the medial segment from the ventricular surface to the internal capsule to be 2 cm. Hematoxylin and eosin, original magnification, x 10.
38. Cross-section of the corpus striatum from a control subject taken at the same level as patient 1 (A) showing the width of the medial segment from the ventricular surface to the internal capsuleto be 5 cm; thus there is severe atrophy of thecorpusstriatum present in patient 1. Hematoxylinand eosin, original magnification, x 10.
706 NEUROLOGY August 1976
3C. Histologic section of the caudate nucleus near the lateral ventricle from patient 1 showing intense neuronal loss with astrocytic replacement;there is anincrease in the number of subependymal astrocytes in the subventricular region in patient 1 compared to the control patient (V = ventricle). Hematoxylin and eosin, original magnification, x 275.
3D. Similar histologic section of the caudate nucleus as in (C) but from a control subject showing a normal neuronal density (V = ventricle). Hematoxylin and eosin, original magnification, x275.
3E. Histologic section of the putamen from patient 1 showing neuronal loss and astrocytic replacement. Hematoxylin and eosin, original magnification, x275.
3F. Histologic section of a control putamen showing a normal neuronal density in contrast to patient 1 (E). Hematoxylin and eosin, original magnification, x275.
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Figure 4. Histologic section of the cerebellar cortex showing a normal density of Purkinje, granule, and molecular layer cells. Hematoxylin and eosin, original magnification, x275.
Figure 6. Histologic section of the frontal cerebral cortex showing a normal laminar arrangement and density of neurons. Hematoxylin and eosin, original magnification, x275.
708 NEUROLOGY August 1976
Figure 5. Histologic section of the dentate nucleus of cerebellum showing moderate loss of neurons and mild gliosis. Nissl stain, original magnification, x275.
(figure 7). The inferior olives were normal in size and myelin content as were the medullary pyramids. Also, the pontocerebellar fibers, brachium conjunctivum, and spinocerebellar fibers were normally myelinated and normal in size. The corticospinal tracts appeared to be normal histologically throughout their extent. The major pathologic findings were a severe loss of neurons and glial replacement in the corpus striatum and a severe loss of neurons in the zona compacta portion of the substantia nigra. There was also a moderate loss of neurons in the dentate nucleus. Case 2. VM, VI-41 was a 39-year-old man in whom the onset of symptoms was at 30 years of age. Impairment of gait was the first symptom, and this increased in seventy to the point that he required a wheelchair from the age of 47 years. Speech and coordination also had become impaired over the past 2 years. He had had frequent cramping back and calf pains, as well as urinary frequency and urgency. Visual acuity had decreased in recent years. Dystonic and athetotic movements of the head and arms had appeared. He had had difficulty coughing and clearing secretions, and had noted dysphagia. There were marked dystonic and athetotic posturing movements of the head and anns with the head tilted to the side and flexed forward. Intellect was well preserved. There was a prosthesis in the right orbit. The left eye had a prominent nystagmus on vertical and horizontal gaze. There was a loss of the fast saccades on lateral gaze and only slow pursuit movement remained. Reflex head turning yielded the same kind of slow eye movements as did pursuit. Hypermetric and hypometric saccades occurred with pursuit eye movements. The optic disk was slightly pale and visual acuity was about 20/50. The mouth was held open most of the time. The facies appeared thin, with
Figure 7. Cross sections of (A) frontal lobe gyrus, (B) cerebellar folia and deep white matter showing the dentate nucleus, (C) midbrain, (D) pons with brachium pontis and portion of cerebellar cortex, and (E) medulla. These sections are stained for myelin and show a normal pattern and density of myelinated tracts. The brachium pontis, restiform body, subcortical white matter of cerebrum and cerebellum, and corticospinal tracts appear normal. The inferior olives are normal in size and shape. Myelin stain, x10. atrophy of the temporal muscles. There were numerous facial fasciculations and obvious mentalis muscle myokymia. The jaw jerk was strikingly increased and the muscles of mastication were weak. The speech was slow and difficult to understand. The pharynx moved poorly with voluntary phonation, and the gag reflex was markedly increased. Tongue movements were slow and the tongue fasciculated, but there was no atrophy. There was a moderate increase in tone in the arms with both rigidity and spasticity, and the legs were markedly spastic. The deep tendon reflexes were + 3 in the arms and +4 at the knees and ankle with sustained clonus and bilateral extensor plantar responses. Strength was reduced throughout to about 3/5. There was no atrophy of the extremities; occasional fasciculations were noted. Finger-to-finger and heel-to-shin movements were slightly dysmetric. His gait was broad-based and spastic, and there was increased adductor tone and legs and feet held in extension. An indwelling catheter was required because of urinary incontinence. Case 3. RB, VI-57 was a 46-year-old woman in whom the onset of neurologic symptoms was at 32 years of age with gait instability and leg numbness. A lurching, unstable gait progressed over the next 10 years, requiring a wheelchair. Impairment of speech and vision had progressed. Prominent calf pain occurred intermittently. Urinary frequency and urgency also had developed. Emotional lability and crying were prominent in recent months. Neurologic examination showed her to be diffusely weak and unable to walk. She had an expressionless face and tended to
keep her mouth open. Eye movements were slow, with horizontal nystagmus and hypermetric and hypometric saccades. Vertical gaze was impaired, but pupillary function was normal. There was slight pallor of the optic disk. Facial fasciculations and facial myokymia were present. The muscles of mastication were strong, and there was no temporal muscle atrophy. The jaw jerk was increased. Her speech was slow and inarticulate, and she had impaired voluntary pharyngeal movement and a marked increase in the gag reflex. Tongue movements were slow, with fasciculations but no atrophy. Weakness was graded 3/5, with rigidity and spasticity of the arms and marked spasticity of the legs. The reflexes were increased in the arms, and were increased in the legs with clonus. Plantar responses were extensor bilaterally. The gait was markedly spastic, and the legs and feet were held in extension and had increased adductor tone. Position and pin perception was minimally reduced in the legs and feet. There was minimal dysmetria of finger-to-finger and heel-to-shin movements. The patient was emotionally labile and easily provoked to tears and crying. She had a moderate problem with urinary frequency and continence.
Case 4. (VW, VI1-31). Neurologic symptoms had developed in this 41-year-old woman in the early 30s. A lurching, unstable gait had developed over the past 10 years, followed in the past 3 years by impairment of speech and vision. Urinary incontinence and frequency had occurred recently. The patient remained ambulatory 10years after the development of symptoms and was able to use her arms and hands well.
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Autosomal dominant striatonigral degeneration
On neurologic examination, she had a broad-based, lurching spastic gait without titubation. There was some pallor of the optic disks, and vertical and horizontal nystagmus were present to a moderate degree. Eye movements were slow, with hypermetric and hypometric saccades. No atrophy of facial muscles was seen, and the muscles of mastication were strong. The jaw jerk was moderately increased. Facial fasciculations were noted. Speech was slow and indistinct, she had poor voluntary pharyngeal movement. The gag reflex was markedly increased. Lingual movements were slow, and there were lingual fasciculations. The patient was strong in all muscle groups without atrophy, but the tone was moderately increased. The reflexes were 3 in the arms and 3 to 4 with unsustained clonus at the ankles. There were bilateral extensor plantar responses. Sensory examination gave normal results. Finger-to-finger and heel-to-shin testing demonstrated a minimal degree of dysmetria.
+
+
Case 5. (RH, VII-I). A 44-year-old man had the onset of neurologic symptoms at 24 years of age, when a progressive staggering and lurching gait developed that produced severe disability. He was confined to a wheelchair. A severe impairment of speech articulation developed over the past 4 years and was associated with mild impairment of visual acuity and urinary frequency and urgency. The patient was intelligent. He had minimal optic disk pallor and horizontal and vertical nystagmus with impairment of vertical gaze. Eye movements were slow, with hypermetric and hypometric saccades. Pupillary function was normal. Facial muscles were atrophied and the muscles of mastication were atrophied and weak. There was a prominent jaw jerk. The patient’s speech was markedly impaired and spastic, with poor movement of pharyngeal muscles and a strikingly increased gag reflex. The tongue wasfasciculating without atrophy, and he had difficulty with rapid lingual movement. He was weak in all extremities, graded 315 with an increase in tone in his arms of both spasticity and rigidity, and severe spasticity in his legs with ankle clonus and extensor plantar responses. The patient had +3 reflexes in his arms and + 3 to 4 reflexes at the knee and ankle. The sensory examination was normal. The patient was able to walk only with help and had a lurching spastic gait with some element of rapid titubation. Finger-to-finger and heel-to-shin testing showed a moderate degree of dysmetria. Case 6. DHH, VII-4 is a 38-year-old woman in whom neurologic symptoms had developed at about the age of 25 years. Her difficulty began with a lurching imbalance of gait followed by impairment of speech and vision. She remained ambulatory but was walking with great caution to avoid falling. There was minimal urinary frequency and incontinence. She was an intelligent, articulate woman who had a broad-based, spastic, lurching gait. She had horizontal and vertical nystagmus, with impairment of vertical gaze. Eye movements were slow with hypermetric and hypometric saccades. Pupils were normal, and there was minimal optic disk pallor. The facial muscles were not atrophied, and the muscles of mastication were strong. The jaw jerk was minimally increased and she showed occasional minimal facial fasciculations. Her speech was slow and difficult to understand, with minimal impairment of pharyngeal movement but with a striking increase in the gag reflex. The strength in her arms and legs was normal, but there was a moderate increase in tone in her arms (+3) and legs with bilateral extensor plantar responses. The patient had no truncal titubation nor ataxia of gait. Urinary frequency and urgency were minimal. 710 NEUROLOGY August 1976
Case 7. DN, VII-32 was a 40-year-old woman who had the onset of neurologic symptoms at 18 years of age, with impairment of gait, progressing to a lurching, unsteady gait, and impairment of speech by 36 years of age. She continued to walk with great care, using a cane or walker. Her speech had become slow and inarticulate in the past several years, and there was a minimal impairment of visual acuity. She had noted recent urinary frequency and urgency. On neurologic examination, she was intelligent and oriented. There was minimal atrophy of the optic disk, and there was prominent horizontal and vertical nystagmus and impairment of vertical gaze. The eye movements were slow, and there were hypermetric and hypometric saccades. The patient had had an intermittent left inferior rectus palsy since early childhood. There was facial atrophy and some atrophy and weakness of muscles of mastication. The jaw jerk was moderately increased. Facial fasciculations were noted. Pharyngeal movements were slow, and there was a striking increase in the gag reflex. Lingual movements were slow, and there was no lingual atrophy, but there were prominent lingual fasciculations. The patient was minimally weak 31.5 and had minimal increase in tone in the arms and moderate increase in tone in the legs of a spastic type. The patient’s gait was spastic and lurching from side to side. The reflexes in the arms were + 3 and + 3 to 4 in the legs with unsustained clonus. The plantar responses were flexor bilaterally. There was minimal heel-to-shin and finger-to-finger dysmetria. Case 8. (KD, VII-21). This 21-year-old man had had a progressive impairment of gait since the age of 19. He had had stuttering and slight speech dysarticulation since early childhood. He had noted in the past 3 years a progressive imbalance and lurching of his gait and impairment in the clarity of his speech. He was no longer able to run or to climb stairs quickly. On neurologic examination, he had a bmad-based, lurching, spastic gait. The optic disks were normal. Visual acuity was intact. He had nystagmus of horizontal and vertical gaze and slowness of eye movement, a masking of facial expression, and a tendency to hold his mouth open. Fasciculations of the face and tongue were present without lingual atrophy. The pharynx had a slight reduction in movement, and a gag reflex was strikingly increased. The muscles of mastication were strong, but there was an increased jaw jerk. The tone in his arms was within normal limits, but there was a marked increase in tone in his legs with hyperreflexia + 3 at the knee and +4 at the ankle with unsustained clonus. Plantar response was neutral. Finger-to-nose and heel-to-shin testing were within normal limits. The sensory examination was normal. Case 9. RD, VII-22 was a 19-year-old male who had noted clumsiness of arm movements and deterioration in gait over the past 2 years and difficulty with speech over the past year. His gait was broad-based and stiff, and he had a tendency to lurch to the side. The optic fundi were normal, and there was an occasional burst of nystagmus with horizontal gaze bilaterally. He had occasional facial fasciculations. The facial muscles and muscles of mastication were strong, but there was an increased jaw jerk. The pharynx moved fairly well but the gag reflex was markedly increased. The strength in his extremities was normal, but the tone in the legs was increased. He had hyperreflexia + 3 in the arms and legs and bilateral extensor plantar responses. Finger-to-nose and heel-to-shin testing were normal, and the sensory examination was normal. His gait was stiff and slow, and he had a tendency to lurch to either side.
Case 10. PB, V-69 was a 57-year-old woman who had the onset of neurologic symptoms at age 40 years with gait impairment, followed by difficulty with speech and coordination; the disease had progressed to the point that she required a wheelchair for the past 3 years. Neurologic examination showed her to be intelligent. She had slight pallor of the optic disks, bilateral horizontal and vertical nystagmus, and impaired vertical gaze. Abduction of the eyes was incomplete bilaterally. The patient was able to converge and had normal pupillary function. She had marked facial fasciculations and facial myokymia, the muscles of mastication were normal, and there was an increased jaw jerk. Her speech was slow and spastic with decreased voluntary movement of the pharynx and a marked increase in the gag reflex. Lateral tongue movements were slow, and lingual fasciculations were prominent. Her arm strength was normal, and increased arm tone and occasional fasciculations were noted. The tone in the legs was markedly increased, and she had spasticity and hyperreflexia with ankle clonus and bilateral extensor plantar responses. Vibration and position senses were normal, and pin perception over the left foot was slightly decreased. Heel-to-shin and finger-to-nose movements were normal. The patient was able to stand with help and had a marked impairment of gait because of the spasticity. Case 11. EC, V-66 was a 70-year-old woman whose symptoms had begun with a gait impairment and speech difficulty about the age of 42 years and had been progressive over the past 30 years. The patient was in a wheelchair and had marked difficulty with hand coordination, clearing her throat, and handling secretions. Her neurologic examination showed her to be intelligent. She was able to stand but had truncal titubation and truncal ataxia. The patient had evidence of horizontal nystagmus and incomplete abduction of eye movements bilaterally. Eye movements were slow, vertical gaze was absent, and facial fasciculations were prominent. The jaw jerk was normal, but the muscles of mastication were slightly weak. Her speech was slow and spastic, and lingual fasciculations were noted, as well as impairment of tongue movements. The patient was diffusely weak; arm strength was 315 proximally and 315 distally. She had prominent fasciculations in the arms, and trace deep tendon reflexes in the upper extremities. The tone in the arms was reduced. She was able to stand with help. Leg tone was increased, of a spastic type; at rest, the tone was decreased in her legs, and she had moderate weakness about 3/5 in all groups tested. No fasciculations or atrophy were noted in the legs. The patient had trace knee reflexes, absent ankle reflexes, and bilateral extensor plantar responses. There was a mild decrease in pin perception in the legs distally. Heel-to-shin and finger-to-nose testing demonstrated a moderate degree of dysmetria. Case 12. (OH, V-72). Neurologic symptoms in this 49-year-old man began shortly after 40 years of age with an impairment of gait followed by speech impairment. At 49 years of age, he was still walking but had a spastic lurching gait. His speech was slow and somewhat indistinct, and he had a history of some deterioration in hand coordination. Neurologic examination showed that he was intelligent. He had slight disk pallor and bilateral impairment of eye abduction. He had horizontal nystagmus bilaterally and some impairment of speech, which was slow and spastic. The pharynx moved normally, but the gag reflex was increased. There were lingual fasciculations noted as well as facial fasciculations. The bulk, tone, and strength of his arms were intact and the deep tendon reflexes were slightly increased. The legs showed a moderate degree of spasticity and
increased deep tendon reflexes + 3 and extensor plantar responses bilaterally. Sensory examination gave normal results. Finger-to-finger and heel-to-shin testing showed a slight degree of dysmetria. The patient had no titubation and no truncal nor extremity ataxia.
Case 13. EA, VII-33 was a 34-year-old female at risk for the disease who was asymptomatic for any neurologic disorder. However, she had nonspecific clumsiness and a left eye esotropia since childhood. Specifically, the patient had no symptoms of difficulties with gait, vision, or speech and swallowing . The neurologic examination showed prominent horizontal nystagmus with a normal rate of extraocular movements. The patient had occasional facial fasciculations and myokymia of the mentalis muscle. The muscles of mastication were strong, but the jaw jerk was increased. The pharynx moved well and speech was normal, the gag reflex was active. The tongue was tremulous without definite fasciculations. Lingual movements were normal, and there was no lingual atrophy. The deep tendon reflexes in her arms and legs were increased 3, and there were bilateral flexor plantar responses. Finger-to-finger and heel-to-shin movements were entirely normal. She may have represented early findings of the disease.
+
In 14 other individuals the history was normal and the neurologic examination completely negative.
Discussion. This family appears to have a new genetic neurologic disorder classified as a striatonigral degeneration. It is characterized as having an autosomal dominant mode of inheritance and a regular expression of progressive neurologic deficit. Neuropathologic examination established the sites of neuronal degeneration and is consistent with the findings on neurologic examination. This variant of the striatonigral degenerations appears to be distinct from previously described patients. 1-15 Each of the previously described patients has had a sporadic or spontaneous disorder with neuronal loss and reactive gliosis in the corpus striatum and substantia nigra. The table summarizesthe neurologic findings in the present series of patients and contrasts them with those of previously reported cases of striatonigral d e g e n e r a t i ~ n . ~Previous ?~ cases have presented with parkinsonian rigidity. In the present cases, progressive spasticity, predominantly of the legs associated with patellar and ankle clonus, extensor plantar responses, and leg and foot extensor hypertonicity are much more prominent. We interpret the spasticity, a lack of inhibition or modulation of motor unit contractions, to be the main problem responsible for the gait imbalance, speech difficulty, and dysphagia. Other important early findings include gaze evoked nystagmus, slowness of eye movements, facial fasciculations and myokymia, and lingual fasciculations. These features have not been reported in the sporadic cases of striatonigraldisease. The jaw jerk and gag reflex are also exaggerated in association with hyperactive deep tendon reflexes. Our patients have had some rigidity, dystonia, or athetosis but these features were not prominent. This series of patients with striatonigral degeneration thus adds an additional phenotype t o established entities in which neuronal loss NEUROLOGY August 1976 711
Autosomal dominant striatonigral degeneration
Table 7. Summary of neurologic findings in selected cases of striatonigral degeneration
712 NEUROLOGY August 1976
and gliosis of the corpus striatum or substantia nigra occur, including Huntington’s disease, dystonia musculorum d e f o r m a n s , olivopontocerebellar degeneration, and nigrospinodentatal degeneration. It is not clear in the present cases how such diverse motor findings as athetosis, dystonia, rigidity and spasticity can be accounted for by lesions in the corpus striatum and substantia nigra. Rigidity, dystonia, and athetosis are best correlated with lesions in the striatum and substantia nigra. The occasional occurrence of minor ataxic gait and dysmetria and clumsiness are explainable on the basis o f moderate involvement of the dentatorubrothalamic system. The clinical spasticity, clonus, and extensor plantar responses were major motor abnormalities and the most problematic for a close clinicopathologic correlation. Patient 1 had no involvement of the pyramidal corticospinal tract at the level of the internal capsule, cerebral peduncles, basis of the pons, medullary pyramids, and spinal cord. Yet, this patient and others in the family had a hyperactive jaw jerk, hyperactive gag reflex, increased deep tendon reflexes, bilateral Babinski signs, and spasticity in which legs were held in extension with increased adductor hypertonicity. Several examples in the literature describe patients with extensor responses to plantar stimulation who had intact pyramidal tracts on pathological examination. This subject of clinicopathologic correlation was carefully reviewed by Nathan and Smith in 1955.19 They concluded that there was no relation between the anatomic state of the corticospinal tracts and the form of the plantar response. Woods and Schaumburg18 described an autosomal dominant neurologic disorder, nigrospinodentatal degenerationin a family of Portugueseextraction from the Azores Islands, in which rigidity and spasticity were associated with extensor responses on plantar stimulation as prominent features of the illness and in whom the pyramidal corticospinal tracts and basal ganglia were histologically normal. The major pathology in their patients was in the dentate nuclei, the spinocerebellar tracts, and the middle cerebellar peduncles. The cerebellar cortex appeared normal. Thus, nigrospinodentatal degeneration is an example of mixed rigidity and spasticity in which de-efferentation and deafferentation of the cerebellum is the apparent cause. A clear explanation of the prominent presence of spasticity in their patients is wanting. It is of interest, however, that this nigrospinodentatal degeneration occurred in an autosomal dominant manner in a family of Portuguese extraction. The clinical expression was similar to that of the present cases, but the neuropathologic findings were different. MettlerZ1J2and Rioch and Brennerz3have suggested that the striatum exerts an inhibitory modulating influence on brain stem extrapyramidal systems, such as the t e c t o s p i n a l , r u b r o s p i n a l , r e t i c u l o s p i n a l , and vestibulospinal pathways. Neuronal loss in the striatum thus might result in a release of these brain stem extrapyramidal nuclei and a clinical expression of spasticity. Similarly, a loss of an inhibitory cerebellar NEUROLOGY August 1976 713
Autosomal dominant striatonigral degeneration
influence on the extrapyramidal motor system as proposed by Henneman24 might be responsible for spasticity in nigrospinodentatal degeneration’ and olivopontocerebellar degenerationz8 in which involvement of the pyramidal corticospinal system is minimal or absent. Patient 11 in our series, a 70-year-old female had symptoms, expressed for at least 28 years, resembling Machado’s disease. This is a dominantly inherited ataxia reported in a Portuguese family from the Azores Islands in whom there is distal sensory loss and decreased deep tendon reflexes without extrapyramidal rigidity or spasticity. 2s The present patients are clearly different from those affected with Huntington’s disease in that none of our patients developed chorea or a dementia. Further, the neuropathologic findings in patient 1 included a marked selective neuronal loss in the zona compacta of the substantia nigra, which is not typical of Huntington’s disease. The cerebral cortex was entirely intact histologically in patient 1 despite advanced clinical disease, which again is not compatible with Huntington’s disease. The natural history of the disease in the present cases is a course lasting about 15 years. This is considerably longer than the average of 5 years reported in the spontaneous forms of striatonigral degeneration. Previous experience with the treatment of striatonigral degeneration has been disappointing. However, Fahn and GreenbergZ6obtained improvement in the rigidity in two patients with levodopa therapy.
It would be of great value to find a molecular marker for the disease. In a general sense such a marker is needed for all of the common autosomal dominant genetic neurologic disorders. This would greatly assist in family planning and could lead to the elimination of the disease. Genetic counseling is difficult in a disorder in which most patients have their first symptom after they have had their families. Levels of dopamine and homovanillic acid in the cerebrospinal fluid have been reported to be low in one patient with nongenetic striatonigral d e g e n e r a t i ~ nTwo .~~ of the present affected patients, 21 and 41 years of age, had slightly reduced levels of homovanillic acid in their CSF and one at risk normal person age 23 years had a normal value. It is of note that one affected patient (No. 9) had a marked reduction in his homovanillic acid concentration and one affected patient (No. 10)had a very low value. It is our hope these studies in selected patients will assist in part in family planning and potential elimination of disease. Additional homovanillic acid determinations in a larger number of affected and at risk persons are needed to determine its absolute value as a molecular marker of disease, and these studies are in progress. Acknowledgments We acknowledge the invaluable neuropathologic assistance of Dr. S. Nielsen and Dr. J Kirkpatrick. Departmentsof Pathology and Neurology, and Chief of Neuropathology at the University of Texas Southwestern Medical School. Invaluable assistance was provided by Ruth Berini, Elinor Frank, Leon Steinsapir, M.D.. Rose Marie Silva and Sister R. Curtiss. This research was supported by a grant from the National Genetics Foundation, New York, NY.
REFERENCES 1. Van der Eecken H, Adams RD, van Bogaert L: Striopallidal-nigral degeneration: An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 19:159, 1960 2. Stochdorph 0: In discussion to the paper by Van der Eecken, Adams and van Bogaert. J Neuropathol Exp Neurol 19:159, 1960 3.Adams RD, van Bogaert L, Van der Eecken H: Degenerescences nigro-striges et cerebello-nigro-striges. Psychiatr Neurol 142:219-259, 1961 4. Adams RD, van Bogaert L, Van der Eecken H: Striato-nigral degeneration. J Neuropathol Exp Neurol 23:584-608, 1964 5. Mayo GM, Barron KD: Striatonigral degeneration. J Neuropathol Exp Neurol 25172. 1966 6. Koeppen AH, Barron KD, Cox JF: Striatonigral degeneration. Acta Neuropathol 19:lO-19, 1971 7. Jellinger K, Danielczyk W: Striato-nigrale degeneration. Acta Neuropathol 10:242-257, 1968 8. Matsuyama H, Tamaoki K, Takeuchi H. et al: Two autopsy cases of severe degeneration and pigmentation of the putamen with clinical Parkinsonism. Presented at the ninth annual meeting of the Japanese Neuropathological Society. Niigata, Japan, April 1968 9. Andrews JM, Terry RD, Spataro J: Striatonigral degeneration. Clinical-pathological correlations and response to stereotaxic surgery. Arch Neurol 23:319-329, 1970 10. lzumi K, lnoue N, Shrabe T, et al: Failed levodopa therapy in striato-nigral degeneration. Lancet 1:1355, 1971 11. Takei Y, Mirra SS:Striatonigral degeneration: Aform of multiple system atrophy with clinical Parkinsonism. Prog Neuropath 2:217-251, 1973 12. Barre JA, Reys L: Syndrome Parkinsonien avec signe Babinski bilaterale. Lesion symmetrique des putamens. Rev Neurol45:966-975. 1926 13. Fleischhacker H: Afamiliare chronisch-progressive Erkrankung des mittleren Lebensaltersvom Pseudosklerosetyp.2 Ges NeurolPsychiatr 9111-22,1924 14. Borit A, Rubinstein LJ. Ulrich H: The striatonigral degenerations-Putaminal pigments and nosology. Brain 98:lOl-112. 1975 15. Naffziger HC, Shepardson HC: A new family group of hereditary and
714 NEUROLOGY August 1976
spastic ataxia-its distribution. Calif West Med 27:207-208, 1927 16. Murphy GF, Robinson D, Sharman D F The affects of tropolone on the formation of 3, 4-dihydroxyphenylacetic acid and 4-hydroxy 3-methoxyphenylacetic acid in the brain of the mouse. Br J Pharmacol 36:107-115, 1969 17. Anden NE, Roos BE, Werdinius B: On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci 2:448-458, 1963 18. Woods BT, Schaumburg HH: Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia-a unique and partially treatable clinicopathological entity. J Neurol Sci 17:149-166, 1972 19. Nathan PS, Smith MC: The Babinski response: A review and new observations. J Neurol Neurosurg Psychiatry 18:250-259, 1955 20. Waggoner RW, Lowenberg K, Speicher KG: Hereditary cerebellar ataxia. Arch Neurol Psychiatry 39570-586, 1938 21. Mettler F A Physiologic effects of bilateral and simultaneous frontal lesions in the primate. J Comp Neurol 81:105, 1944 22. Mettler FA, Ades HW, Lipman E, et al: The extrapyramidal system: An experimental demonstrationof function. Arch Neurol Psychiatry41 :984, 1939 23. Rioch DMcK, Brenner C: Experiments on the corpus striatum and rhinencephalon. J Comp Neurol 68:491, 1938 24. Henneman E: Motor functions of the brainstem and basal ganglia. In Mountcastle VB (Editor): Medical Physiology. Ed 13. 1974, vol 1, chap 26, p 687, chap 26, pp 734, 742 25. Nakano KK, Dawson DM. Spence A: Machado disease: A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology (Minneap) 22:49-55, 1972 26. Fahn S , Greenberg J: Striatonigral degeneration. Trans Am Neurol ASSOC97~275-277,1972 27. Sharpe JA, Rewcastle NB, Lloyd KG, et al: Striatonigral degeneration: Response to levodopa therapy with pathological and neurochemical correlation. J Neurol Sci 19:275-286, 1972 28. Landis OMD, Rosenberg RN, Landis SC, et al: Olivopontocerebellar degeneration: Clinical and ultrastructural abnormalities. Arch Neurol 31:295-307, 1974
Autosomal dominant striatonigral degeneration: A clinical, pathologic, and biochemical study of a new genetic disorder ROGER N. ROSENBERG, WILLIAM L. NYHAN, CAROLYN BAY, et al. Neurology 1976;26;703 DOI 10.1212/WNL.26.8.703 This information is current as of August 1, 1976 Updated Information & Services
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