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Autosomal dominant Lewy body parkinsonism in a four-generation family.

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Autosomal Dominant k w y Body
Parhnsonism in a Four-Generation F d y
C. H. Waters, MD, FRCP(C),” and C. A. Miller, MD”f
W e report a family with autosomal dominant parkinsonism. The propositus developed parkinsonism at a relatively
young age (45 years) and came to autopsy after a 6-year illness. She had typical features of Pdrkinson’S disease except
for an absence of rest tremor, although this was present i n other family members. A diagnosis of Lewy body parkinsonism was confirmed b y neuropathological examination. Additional pathological features included the presence of cortical Lewy bodies and anti-ubiquitin-positive neurites in the cornu Ammonis 2 and 3 (CA2-3) region of the hippocampus.
This kindred is similar both clinically and pathologically to a few previously reported pedigrees, further strengthening
recent evidence of a genetic etiology of some forms of Parkinson’s disease.
Waters CH, Miller CA. Autosomal dominant Lewy body parkinsonism in a
four-generation family. Ann Neurol 1994;35:5?-64
The etiology of Parkinson’s disease (PD) remains unknown. Environmental agents and genetic factors occurring singly or in combination have been proposed.
Many kindreds with multiple m e m b e r s with Parkinson’s disease have b e e n described, b u t only recently
have family studies included a detailed histological
evaluation. Golbe and colleagues l} described the
largest kindred, with autosomal dominant parkinsonism confirmed at autopsy in 2 of t h e affected members.
O t h e r s have reported kindreds with varying clinical
and pathological pictures; s o m e were consistent with
Lewy body parkinsonism, but others were not. We report a kindred with autosomal dominant Lewy body
Subject Evaluations
The propositus (V-2, Fig 1) was first seen at age 50 (by
C. H. We).At this evaluation, a positive family history was
obtained. The propositus and her cousins (V-3 and V - 4 )were
neurologically examined. Complete medical records were
available for the propositus’s father (IV-11, but the autopsy
was incomplete and did not include the brain. lnformation
on other members of the family was obtained from examination of family photographs, death certificates, obituaries,
home-produced videotapes, and historical information obtained from the eldest available family members. All evaluations were carried out by a single observer (C. H. W.).
Case Histories
Propositzls (V-2)
This 5 1-year-old woman developed slowness in walking and
pain in the right shoulder at age 45. One year later a diagnosis
initiated in 1986, with good benefit. However. the condition
progressed. She developed motor fluctuations and impaired
postural stabiliry. She subsequently developed “toe walking”
and suffered a significant fall (January 1989),fracturing the
left hip. Thereafter, impairment of memory developed.
When first examined at age 50 (by C. H. W.), she was
mildly responsive to Ievodopa, with improvements in tone,
walking, and peak-dose dyskinesias while on a total daily dose
of 175i700 mg of carhidopailevodopa. Magnetic resonance
images (MRIs) and computed tomography (CT) scans were
unremarkable. The patient demonstrated moderate cognitive
impairment, scoring 20!30 on the Folstein Mini-Mental State
Examination. Blood pressure was 140180 mm H g while s i r
ting and 90/70 mm Hg while standing. There were no symptoms of orthostatic hypotension, corticospinal tract involvement, or cerebellar signs. The salient neurological features
included flexion of the neck and thorax, monotone speech,
facial hypomimia, and moderate cogwheel rigidity in all four
limbs and the neck in the “off” phase. N o rest tremor was
detected. Rdpid alternating movemencs were performed
slowly. The patient walked on the toes and showed postural
instability when pulled. With levodopa, dyskinesias were evident.
Over the course of the next year, she became more confused, necessitating a reduction in carbidopailevodopa. Orthostatic hypotension persisted. She became wheelchair
bound, then bed bound, and lethargic, with poor oral intake.
She died from acute bronchopneumonia after a 6-year illness.
Postmortem examination including the brain was performed.
of PD was made and treatment with levodopa/carbidopa was
Other Farnib Members
1-1. This man wrote a letter (in che late 1800s) to his son
in America, indicating that he had to give up logging in his
40s in Scotland because he lost his balance and was “too
From the *Departments of Neurology and tPathology, University
of Southern California School of Medicine, Lo5 Angeles, CA.
Address correspondence to D r Waters, University of Southern California, 1510 San Pablo Street, Suire 615. Los Angeles, CA 90033.
Received Mar 18, 1993, and in revised form Jul 1. Accepted for
publicarion Jul 14, 1993.
Copyright 0 1994 by the American Neurological Association
frequent falls. At the end. she was mentally impaired with
loss of memory and was bed bound for several months. Information was obtained from her children and was confirmed
by photographs.
IV-3. At the time of writing, this woman, born on May 24,
1916,was unaffected, by her own report at age 76 (telephone
report; she refused examination).
Fig 1. Pedigree. Arrow represents propositus. Numbers below
symbols veprrsent age at death.
V-1. At the time of writing, this woman, age 54, was unaffected, by her own report and by home videotape (reviewed
by C. H . W.1.
shaky” to jump from log to log. N o further information is
V-3. This man, age 49, had completely normal findings on
1-2. No information is available.
V-4. This woman, age 38, had completely normal findings
11-1. This man, born in 1847, died in 1922 and was thought
(by the family) to have had PD.
11-2. This woman, born in 1855, carried a diagnosis of PD
(by the family) and died in 1897 at the age of 42. She was
too disabled to raise her children.
111-1. This man was born in April 1874 and carried a diagnosis of P D (by family report). H e worked as a carpenter
and married but had no children. The age of death is unknown, but he was still alive by a census report of 1900.
111-2. This woman, born in 1875, was unaffected and raised
her younger siblings because her mother (11-2) was disabled
with PD. She married and had children; her daughter-in-law
(since deceased) was the source of much information.
111-3. This woman, born in
carried a diagnosis (by
her family) of PL), but died at a much younger age (age 20
in 18y7) than other family members.
111-4. This woman was born on October 1, 1879. Her children were placed in a children’s home in Stanton, Iowa, as
she was too disabled to care for them. She had been described by family members as “stooped” and died on July
20, 1922, at the age of43. She was placed in a “poor farm,”
described by the family as a facility where indigent, sick people go to die. No medical records are available.
111-5. This man, born in 1892, died in 1953.
I\’-1. This man, born on June 28, 1910, developed rest
tremor of the right arm, cogwheel rigidity, slow speech, festinating gait, and decreased facial expressivity at age .36.He
died on November 14, 1353 at age 4 3 following a I-month
admission for severe PD. He became progressively more
lethargic and died. A postmortem examination did not include a brain examination.
1V-2. This woman, born on March 22, 1915, died at the
age of 49 years after a 7-year illiiess characterized by a pill
rolling tremor, decreased facial expression, stooping of posture, and shuffling gait with walking on the toes. She had
60 Annals of Neurology
Vol 35
No 1 January 1994
neurological examination.
on neurological examination.
V-5. This man was not examined but was reported by his
mother to be unaffected, at age 43.
Postmortem Study
On gross inspection at autopsy, there was diffuse pallor
of the substantia nigra. There was no cerebral atrophy.
Tissue blocks (1 cm3) were obtained 5 hours postmortem and fixed in 10%:neutral buffered formalin, p H
7.0 (EM Sciences, Gibbstown, PA) and embedded in
paraffin. Samples included the superior frontal gyrus,
superior and middle cemporal gyri, inferior parietal
lobule, cingulate gyrus, hippocampus at the level of the
lateral geniculate nucleus, mesencephalon, amygdaloid
nucleus, nucleus basalis of Meynert, basal ganglia at
the level of the head of the caudate nucleus, rostral
pons including the locus ceruleus, and medulla at the
level of the inferior olivary nuclei.
The topographic distribution of neuronal degeneration was consistent with PD. As shown in Figure 2A,
hemacoxylin and eosin-stained sections (8 pm) of mesencephalon revealed marked loss of neurons and extraneuronal pigment deposits in [he zona compacta and
zona reticularis of the substantia nigra. There were one
to three Lewy bodies within the cytoplasm of a few
remaining neurons. In all sites, the Lewy bodies were
atypical with a homogeneous, lightly eosinophilic matrix (Figs 2A-2C). Some had a narrow, stain-free clear
haio surrounding the inclusion (Fig 2B). None had the
deeply eosinophilic central cores, concentric lamellae,
and clear peripheral halo of Lewy bodies in idiopathic
PD .
With rabbit polyclonal serum specific for anti-ubiquitin (LJBQ) (1: 200 dilution) immunoperoxidase staining (ABC method, Vector Laboratories, Burlingame,
CA), the Lewy bodies were very faintly and diffusely
immunoreactive. A few showed more intense, focal
staining (Fig 2D). Hyaline bodies, nonreactive with
anti-UBQ, were occasionally seen in the adjacent neu-
F i g 2. MeJencephulon: substantia nigra. (AIAt low magnifiutioti. there is marked depletion of pigmented neuruiu o/ the par.,
comnpacta. A remaining neuron contuim a Leu 7 bod), (,arrow)
i x 0011).(B)A [urge. homoReneously stained. intrucjtop/usniic
Leuy body occtdpies the c y ~ p l m.
u ~diJplai i n g the nicileu~lateralfy. A nawou, clear halo .riirrounds the incku.rion i x 2.040).
i<;) A multilobulated inclii~ion utith focal area.! v f . inrreased &tisity i3- seen within the neuivnal qytop1aJ.m amid granulei
ne~romelunin pigment. (Hernatoxylin und eosin. x 2.6411.i ( D , I n
thir Jeitiori reacted with unti-ubiquitiii. a Leu3 body on-upin
most of the iytopla.r.rtnand S ~ O U J J,foial inmunoreactiiiry within
thr inilzision (arrow).,x 2.64O.i
ropil (not shown). The locus ceruleus also showed
striking neuronal loss and a few of the Lewy bodies.
There was also marked loss of pigmented neurons but
no Lewy bodies in the medulla in the region of the
dorsal motor nucleus of the tenth cranial nerve.
In the CAZ-3 region of the hippocampus, hematoxylin and eosin-stained sections showed a slightly disordered, “windswept” appearance of neurons, with
randomly oriented apical dendrites. Anti-UBQ immunocytochemistry revealed a few positive and enlarged
neurites traversing the CA2-3 pyramidal layer (Fig 3).
Pyramidal neurons in this region showed granulovacuolar degeneration (not shown).
Waters and Miller: Famild Autosomdl Dornir~ant Lewy Body PD
F i g 3. Hippocumpus. In the CA2-3 region. ~ i e u r i l edemeh
reuct i r e u'ith anti-tihiquitin traverre the nruropil arZjaieiit t o the pyramidal neurons. (Immunoperoxiilase. x 1.060.)
Neurons in the subiculum of the hippocampus and
deeper layers ( 5 and 6) of the entorhinal cortex contained moderate numbers of intracytoplasmic Lewy
bodies, also without central cores or surrounding halos.
Lewy bodies were strongly and uniformly immunoreactive with anti-UBQ. There was moderate spongiform
change in the surrounding neuropil.
In the cerebrum, the frontal, parietal, and temporal
association cortices and the cingulate gyrus were
sparsely populated with Lewy bodies, particularly in
small and medium-size nonpyramidal neurons in layers
3, 5 , and 6 (Fig 4). Sections of the amygdaloid nucleus
and nucleus basalis of Meynert also revealed intraneuronal Lewy bodies accompanied by a diffuse reduction
of neurons. Affected regions showed astrogliosis.
Neocortical and hippocampal sections, stained by a
modified Bielschowsky method or by thioflavin S, revealed very sparsely distributed, primitive plaques only
in the frontal cortex and rare neurofibrillary tangles
in the entorhinal cortex. No abnormal neurites were
detected in the hippocampus, including the CA2-3 region.
This family exhibited hereditary parkinsonism transmitted in a mendelian autosomal dominant pattern.
The clinical and pathological findings are most comparable with a subtype of PD. It has been suggested that
Lewy body disease includes a spectrum of clinicopatho-
62 Annals of Neurology Vol 33 No 1 January 1994
F i g 4. Cerebral cortex. tAi In la.yer 5 . one n e u ~ o nrorituins a
Leuy body inclusion (arrow) that 2s di,$fusrh inirnunoreuctit'e
with anti-ubiquitin. Mild spongi f om t~aczrolizationof the nruropil is also seen. IBi In another.field at higher magnzfiration.
a similar. strongly immunoreartizv inclusion displaces the nruronal nucleus laterally. (Immunoperoxidase. x 2.640.)
logical entities encompassing PD and diffuse Lewy
body disease (DLBD) {21. The pathological criteria that
distinguish PD from DLBD rest primarily in the relative numbers of cerebral cortical Lewy bodies, and the
presence of abnormal UBQ-positive neurites in the
CA2-3 region of the hippocampus [3}.
Our diagnosis is based on the clinical findings of PD
as well as the presence of neuronal degeneration and
Lewy bodies in the brainstem catecholaminergic nuclei,
the hippocampus, and neocortex. The presence of
Lewy bodies in portions of the limbic system, including
the amygdala, and in small nonpyramidal neurons of
deeper neocortical layers plus the presence of antiUBQ-positive neurites in CA2-3 of the hippocampus
represent a novel neuropathological combination.
These findings overlap in part with the type B form of
DLBD where only modest numbers of cortical L e y
bodies are present [4].
The type B or transitional form of DLBD and the
brainstem form (type C) are consistent with what we
recognize clinically as classic PD 141. Dickson and associates 131 examined 5 PD patients and found no neurites in CA2-3 and sparse parahippocampal Lewy bodies. Conversely, their study of 45 patients with DLBD
showed neurires in CA2-3, comparable to our observations, but also abundant parahippocampal Lewy bodies
and senile plaques in the frontal cortex, features not
seen in our patient.
The pathological changes described in our patient
are identical to those found in 2 patients with PD who
responded poorly to levodopa C21. Corifirmation of
cortical Lewy bodies in all patients with PD observed
by Hughes and coworkers [ 5 ] suggests that this finding
in our patient is still quite consistent with PD.
The atypical Lewy bodies seen in all sites in our
patient contrast with the typical form found in the
brainstem of sporadic P D patients. Although these inclusions were identical in topographic distribution to
PD, the absence of a defined, strongly UBQ-reactive
core and peripheral clear halo suggests subtle histological differences among these diseases, particularly the
familial forms. The Table outlines the various descriptions of familial parkinsonism where Lewy bodies have
been shown. Our patient most closely resembles both
clinically and pathologically the descriptions by Golbe
and colleagues [I} and Muenter and associates 191.
Atypical Lewy bodies seen in our patient were also
found in the brainstem by Golbc and colleagues [ 11
and Purdy and coworkers [ 8 } , as well as in the cortex
by Kosaka and coworkers 111, 12). As with our patient, the other familial parkinsonisms that most resemble PD show a malignant course, an early onset, and a
somewhat atypical pathology. Other recently described
farnilies r l 3 , 14) represent new syndromes unlike our
Lewy body parkinsonism.
Inherited parkinsonisms that resemble P D have renewed interest in the genetics of this disorder [151.
Johnson and coauthors [ 161 reanalyzed the original
twin studies of PD and concluded that the low monozygotic concordance rate could still be compatible with
a genetic contribution. More recently, “F-dopa positron emission tomography studies of P D twins showed
a decrease in the putaminal “F-dopa uptake in a significant proportion of both monozygotic and dizygotic
convins, suggesting that concordance for P D is much
greater than previously thought { 171.
Maraganore and associates { 181 studied 20 families
collected from a London clinic in which P D could be
ascertained in the proband and at least one other affected relative. Subjects with familial PD were clinically indistinguishable from those with sporadic PD.
This report was further strengthened by a recent study
by Latzarini and coworkers [19} of 40 multiplex fami-
Clinical Features
No rest tremor
Nigral neurorial loss
Atypical Lewy bodies
Cortical Lewy bodies
Present report
Rest tremor in other family members
No rest tremor in any member
Nigral neuroiial loss
Atypical Lewy bodies
Cortical Lewp bodies n o t documented
Hypoventilation parkinsonism (rare rest tremor)
Nigrdl neurorial loss
Atypical Lewy bodies in brainstem
Cortical Lewy bodies n o t ciocumented
Nigral neurorial loss
Atypical Lewy bodies not documented
Lewy bodies in brainstem
Cortical Lcwy bodies (limbic)
Nigral neuronal loss
Pare Lewy bodies
Ballooned neurons (atypical Lewy bodies?
in brainstem and cortex)
Waters and Miller: Familial hutosomal Dominant Lewy Body PD
lies. In both studies, segregation ratios, transmission
pattern, and sex ratios were consistent with autosomal
dominant inheritance with reduced penetrance. Our
clinicopathological family study contribu tes to the
growing evidence that some types of PD have a strong
genetic component. We believe that multiple-case kindreds of PD are much more apparent than previously
realized. Such kindreds provide the opportunity for
further genetic studies and possibly DNA linkage analysis to clarify the genetic etiology of PD.
This project was supported in part by the National Institute of Mental Health (to C. A. M., ROl-MH?9145). National Institute of
Aging ( t o C. A. M., PjO AG051421, and National Parkinson Foundation (to C. H. W.).
The authors wish to acknowledge Lou hlallory and Jeanette Espinosa
fur manuscript preparation, Kristen Hollen for expert technical assistance, D r Roger Duvoisin for his helpful advice, and Dr Dennis
Dickson, Albert Einstein College of Medicine, for antiubiquitin serum.
Presented in parr at the 10th Annual International Symposium on
Parkinson’s Disease, Tokyo, October LX, 1991.
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