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Autosomal dominant motor system degeneration in a black family.

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17. Velasco ME, Dahl D, Roessniann V, Gambetti P: Immunohis-
tochemical localization of glial fibrillary acidic protein in human
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18. Vogl SE: Acute leukemia complicating treatment of glioblastoma muitiforme. Cancer 41:333-336, 1978
13 Wakamarsu T, Matsuo T, Kawano S, Teramoto S, Matsumma H:
Extracranial metastasis of intracranial tumor: review of literature
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review of I 2 cases. Ann Neurol 8:605-608, 1980
Autosomal Dominant
Motor System
Degeneration in
a Black Family
plegias as well as lid retraction have been reported in all
three types of the disease ( I , 2, 8, 91. Most patients
described were members of four families with origins
in the Azorean Islands (I, 8, 91. Subsequently, a number of families in the Azores were found to have similar symptoms { 11. One non-Portuguese black family
has been described with clinical findings similar to
those in type I1 ADMSD { S ] . A Japanese family was
reported recently 1121. W e describe a second black
family with roots in the West Indies and a clinical picture similar t o that in type I ADMSD.
Case Report
Joanna A. Cooper, MD," Tsutomu Nakada, MD,"
Robert T. Knight, MD,* and Robert P. Friedland, MDV
Autosomal dominant motor system degeneration has
been described primarily i n Portuguese families from
the Azorean Islands. The symptoms include various
combinations of ataxia, pyramidal and extrapyramidal
signs, appendicular dystonias, tics, ophthalmoplegias,
and peripheral neuropathies with amyotrophy. O n e nonPortuguese, non-Azorean black family has been described previously; this report describes a second such
family affected by autosomal dominant motor system degeneration.
Cooper JA, Nakada T, Knight RT, Friedland RP
Autosomal dominant motor system degeneration in
a black family Ann Neurol 14 585-587, 1983
Autosomal dominant motor system degeneration
(ADMSD) affects primarily families of AzoreanPortuguese ancestry 11, 2, 7-9, 111. At present three
phenotypes of ADMSD have been described: type I
begins at a young age (second to third decades) with
primarily extrapyramidal and pyramidal manifestations;
type I1 is dominated by pyramidal and cerebellar
findings and starts later in life (fourth to sixth decades);
type I11 begins late (fifth to seventh decades) and the
patients primarily exhibit ataxia and peripheral neuropathy with prominent distal amyotrophy. OphthalmoFrom the *Departmen[ of Neurology, University of California,
Davis, Veterans Administration Medical Center, Martinez, CA
94553, and the tDonner Laboratory, University of California,
Berkeley, CA 94720.
Received Jan 31, 1983, and in revised form Mar 23, 1983. Accepted
for publication Mar 25, 1983.
Address reprint requests to D r Cooper, University of California,
Davis, Veterans Administration Medical Center, 150 Muir Rd, Martinez, CA 94553.
The propositus presented at the age of 3 1 years. H e was well
until the age of 23 years, when he developed gait difficulties,
dysarthria, and impaired mental function. Neurological examination revealed a reduction in memory functions,
difficulties with calculations and spelling, poor comprehension of complicated tasks or written text and concrete thinking. His eye movements were slow, with severe limitation in
spontaneous lateral movements and upgaze. The doll's eyes
maneuver improved his lateral movements and upgaze, indicating a supranuclear component. Lid retraction was present.
Gaze nystagmus was elicited bilaterally at 15 to 25 degrees,
and optokinetic nystagmus was present bilaterally. He had
mild difficulties in swallowing, a spastic dysarthria, and mild
facial and tongue weakness, and drooled on occasion. Facial
grimacing without tics was observed. There was bilateral
spasticity with a marked gait abnormality. The deep tendon
reflexes were symmetrically hyperactive, with clonus and extensor plantar responses bilaterally. Appendicular dystonia
with spooning of the hands was noted. Sensation was intact,
as was cerebellar function. Computed tomographic scan
showed a slight prominence of the primary fissure of the
cerebellar vermis but was otherwise normal. Visual, auditory,
and somatosensory evoked responses were normal, as were
an electroencephalogram, an electromyogram, and nerve
conduction velocity study. A chest roentgenogram, an electrocardiogram, complete blood count, electrolytes, muscle
and serum liver enzymes, serum creatinine and blood urea
nitrogen, serum amino acid electrophoresis, serum arylsulfatase A, serum copper, serum ceruloplasmin, serum phytanic
acid, and cerebrospinal fluid all were normal. Fibroblast cultures done from a skin biopsy specimen showed equivocal
protein pattern abnormalities.
The family pedigree IS snown in the Figure. The family
origins could be traced back to the West Indies. It is believed
that there is Irish ancestry in the proband's maternal grandfather's line. We could not elicit a history of Azorean, Portuguese, Angolan, or Mozambikian connection. Two of the
proband's siblings were affected by the disease. An older
brother had experienced onset of similar symptoms at age 28,
and a younger sister had become symptomatic at age 18. This
sibling also had facial tics. There were two unaffected siblings. The mother and both her sisters reportedly had been ill
with similar manifestations, with onset in their early twenties;
all three had died of cachexia in the fifth decade. The maternal grandmother and great grandfather reportedly had suffered similar symptoms and died in their early forties with
severe spasticity and dementia. No postmortem examinations
b t oD46
2 5
0 D39
2 0
were performed. Seven living children of affected members
are presently all under age 20 and asymptomatic.
This family demonstrates an autosomal dominant pattern of inheritance for motor system degeneration
characterized by pyramidal and extrapyramidal signs
along with supranuclear gaze palsies and dementia. The
symptoms in this family are almost identical to type I
ADMSD. Although supranuclear gaze palsies, dementia, and extrapyramidal signs are characteristic of progressive supranuclear palsy [ 131, the pattern of autosoma1 dominant inheritance and the early onset of the
disease eliminates that consideration. Other hereditary
ataxias such as olivopontocerebellar atrophy and cerebellar parenchymal degeneration, in which inheritance
is often dominant, are characterized primarily by gait
and limb ataxia with or without pyramidal and extrapyramidal signs, sensory loss, and dementia [3, 4 , 6 , 141.
Dystonia is a rare symptom, despite abnormalities
found in the basal ganglia postmortem 13, 61.
Ophthalmoplegias, slow or “viscous” eye movements, lid retraction, abnormalities of gaze nystagmus,
abnormalities of saccadic eye movements, and abnormal optokinetic nystagmus have been described in patients with ADMSD [2]. A supranuclear pattern of
gaze palsy, however, has not been reported in the previously described patients with ADMSD.
Dementia has not been characterized to be among
the prominent features of ADMSD, and the members
of the previously described black family were reported
to have relatively preserved mental function [ 5 ] . It has
been suggested, however, that ADMSD and Huntington’s disease represent allelic mutations of the same
dominantly inherited regulatory gene { 101. Indeed, the
same class of protein abnormalities has been found in
Family pedzgree. The urroui repreJmts the prohand. (0= q r ut
onset of jymptorm; D = age at deuth.)
brains of patients with ADMSD and Huntington’s disease, although in different sites: frontal cortex and corpus striatum are involved in Huntington’s disease,
whereas the cerebellum and corpus striatum show
pathological changes in ADMSD [lo]. The prominence of dementia in the present case provides some
clinical evidence of overlap of symptoms in these two
1. Coutinho P, Andrade C: Autosomal dominant system degeneration in Portuguese families o f the Azores Islands. Neurology
(NY) 28:703-709, 1978
2. Dawson DM, Feudo P, Zubick E M , et al. Electro-ocult)graphic
findings in Machado-Joseph disease. Neurology tNY) 12: 1 L’L1276, 1982
3. Greenfield JG: The Spino-cerebellar Dcgencrations. Oxford,
Blackwell Scientific Publications, 1 0 5 4
4. Harding AE: The clinical features and classification of the late
onser autosomal dominant cerebellar ataxias. Brain 105: 1-18,
5 . Healton EB, Brust JCM, Kerr DL, et al: Presumably Azorean
disease in a presumably non-Portuguese family. Neurology
( N Y ) 30:1084-1089, 1980
6. Konigsmark BW, Weiner LP. The olivoporitoccrebcllar atrophies: a review. Medicine 4 9 2 2 7 - 2 4 1 , 19’0
7 . Nakano KK, Dawson DM, Spence A: Machaclo disease: a hereditary ataxia in Portuguese emigrants t o Massachusetts. Neilrology (Minneap) 22:49-55, 1972
8. Romanul FCA, Fowler HL, Radrany J. et al. Azorean disease ( i f
the nervous system. N Engl J McJ 296:1505- 1508, lo7’
9. Rosenberg R N , Nyhan WL: Joseph’s disease: an autosomal
dominant neurological disease in the Portuguese of the United
States and the Azores Islands. Aclv Neurol 21:31-57, 19’8
10 Rosenberg R N , Ivy N, Kirkpatrick J , et al: Joseph disease anJ
Huntington disease: protein patterns in hhroblasts and hrairi.
Neurology ( N Y ) 31:1003-1014, 1981
586 Annals of Neuroiogy Vol 14 No 5 November 1083
11. Sachdev HS, Forno LS: Joseph disease: a multisystem degenerative disorder of the nervous system. Neurology ( N Y ) 32:192195, 1982
12. Sakai T, Ohta M, lshino H: Joseph disease in a non-Portuguese
family. Neurology (NY) 33:74-80, 1983
13. Steele JC: Progressive supranuclear palsy. Brain 95:693-704,
14. Stumpf DA: Friedreich’s ataxia and other inherited ataxias. In
Tyler HR, Dawson DM (eds): Current Neurology. Boston,
Houghton Mifflin, 1978
External Ophthalmoplegia,
Alpha and Spindle Coma
in Imipramine Overdose:
Case Report and Review
of the Literature
subjects have been reported in whom these EEG
changes occurred as a consequence of drug overdose
IS, 6, 91. An absence of oculovestibular reflexes in a
comatose patient appearing soon after a hypoxic event
usually implies a grave prognosis [ 151. Oculovestibular
reflexes may be suppressed, however, by anxiolytic,
most sedative, and antidepressive drugs [lo, 12, 15,
161. Only five subjects poisoned by tricyclic drugs have
been described since the first report [12]. EEGs and
brainstem auditory evoked potentials (BAEPs) were
not obtained in these six previous patients. Me describe an adolescent with imipramine overdose in
whom seizures developed, respiratory arrest progressed to coma, and abnormalities of oculovestibular
reflexes occurred. Serial EEGs and BAEPs closely related to measurements of drug levels showed the rapid
evolution of an alpha-coma pattern into a spindle-coma
one, with latency delays in BAEPs and both EEGs and
BAEPs returning to normal as the patient recovered.
Stefan-M. Pulst, MD, and C. T Lombroso, MD, PhD
Case Report
A 13-year-old boy with imipramine overdose developed
seizures, respiratory arrest, and coma. Abnormalities of
oculovestibular reflexes, electroencephalograms, and
brainstem auditory evoked potentials were monitored i n
relation to measurements of d r u g levels. A n alpha-coma
electroencephalographic pattern evolved into one
evidencing spindle coma and eventually into a normal
pattern. Prolonged brainstem auditory evoked potentials also normalized as coma and oculocephalic reflex
abnormalities resolved. In spite of the history that suggested hypoxic damage, the absence of reflex eye movements in a comatose patient a n d the presence of alphaand spindle-coma electroencephalographic patterns,
even with prolonged brainstem auditory evoked potentials, are not reliable prognostic indicators i n tricyclic
drug overdose.
Pulst S-M, Lombroso CT. External ophthalmoplegia,
alpha and spindle coma in imipramine overdose
case report and review of the literature
Ann Neurol 14.587-590, 1983
Electroencephalographic (EEG) patterns described in
alpha coma or in spindle coma have been shown to
occur mainly following diffuse hypoxic-ischemic brain
damage, brainstem infarctions, or head trauma. Few
From the Seizure Unit and Division of Neurophysiology, Department of Neurology, Children’s Hospital Medical Center, and the
Department of Neurology, Harvdrd Medical School, Boston, M A
Received Dec 7, 1982, and in revised form Apr
for publication Apr 12, 1983.
4,1983. Accepted
Address reprint requests to Dr Lombroso, Seizure Unit, Children’s
Hospital Medical Center, Boston, MA 02 1 15.
A 13-year-old boy was admitted to the hospital after ingestion of approximately 1,000 mg of imipramine. O n the same
day the patient had a generalized tonic-clonic seizure. At
another hospital he had required intubation after a respiratory arrest. Arterial blood gas measurements showed partial
pressures of 52 for oxygen and 39 for carbon dioxide, and a
p H of 7.05, a scenario suaestive of an anoxic insult. O n
admission to the Children’s Hospital Medical Center, he had
another seizure. A toxic screen revealed a serum imipramine
level of 1,021 pdcc (therapeutic level, 150 pglcc) and desipramine level of 420 pg/cc (therapeutic level, 100 pglcc). An
EEG showed an invariant pattern of 10 to 1 2 Hz rhythms,
with anterior predominance unreactive to stimuli (Fig 1).O n
the third hospital day the patient was still comatose.
Oculocephalic reflexes were absent. Ice-water irrigation produced dysconjugate abduction of the ipsilateral eye only. An
EEG taken then showed random or sequential 0.5 to 2 Hz
delta waves, on which spindles at 10 to 12 Hz were superimposed, with some reactivity to stimuli (Fig 2). BAEPs to 60
decibel HL click stimulation showed a bilateral delay of conduction time between waves I1 and V outside of the normal
mean plus 3 standard deviations (Fig 3). The imipramine
levels were unchanged. O n the sixth hospital day the imipramine level had dropped to 40 and the desipramine level to
181 pg/cc. The boy showed fluctuating alertness with periods
of lucidity alternating with brief episodes of agitation and
mild confusion. There was nystagmus on gaze in all directions, and finger-to-nose testing showed mild dysmetria. An
EEG now showed well-developed 9 Hz (30 to 50 pV)alpha
rhythms posteriorly that blocked to eye opening. Anteriorly,
low-voltage beta activity was mixed with 4 to 5 Hz theta
activity. BAEP conduction times were now normal when the
left ear was stimulated, whereas a very mild delay persisted
between waves I1 and V when the right ear was stimulated.
Two days later the patient was fully recovered and the
neurological examination showed no abnormalities. Followup EEG and BAEP testing two weeks after discharge also
revealed no abnormalities.
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autosomal, black, motor, dominantly, degeneration, family, system
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