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Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr -synuclein mutation.

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Clinical and Pathological Features of a
Parkinsonian Syndrome in a Family with an
Ala53Thr ␣-Synuclein Mutation
Paul J. Spira, MD, FRACP,1 David M. Sharpe, FRACP, MRCP,2 Glenda Halliday, PhD,3
Julie Cavanagh, BSc,4 and Garth A. Nicholson, PhD, FRACP4
We describe an Australian family of Greek origin with a parkinsonian syndrome and an Ala53Thr ␣-synuclein gene
mutation. Five of 9 siblings were affected, the average age of onset was 45 years, and the initial symptoms were variable,
including resting tremor, bradykinesia, and gait disturbance, as previously described in families with the same point
mutation. Affected family members responded well to levodopa, developed progressive cognitive impairment, and had a
disease duration of 5 to 16 years. Pathologic features typical of idiopathic Parkinson’s disease were found at autopsy.
However, there were several additional features not previously reported in families with this gene mutation. These
features included severe central hypoventilation, orthostatic hypotension, prominent myoclonus, and urinary incontinence. An abundance of ␣-synuclein–immunoreactive Lewy neurites were found in the brainstem pigmented nuclei,
hippocampus, and temporal neocortex. The Lewy neurites were associated with temporal lobe vacuolation. Subcortical
basal ganglia cell loss and gliosis were seen. These additional clinical and pathological features suggest that the Ala53Thr
␣-synuclein mutation can produce a more widespread disorder than found in typical idiopathic Parkinson’s disease.
Ann Neurol 2001;49:313–319
Over recent years rare genetic forms of Parkinson’s disease (PD) have provided new insights into the disorder.
The first gene mutation found to cause a parkinsonian
syndrome was the Ala53Thr mutation in ␣-synuclein.1
This mutation is rare, occurring in less than 1 in 230
PD families.2,3 There are few detailed clinical and
pathological descriptions of this form of Parkinson’s
disease. The existing reports suggest that the disease is
levodopa responsive4 and differs little from idiopathic
Parkinson’s disease, although an earlier age of onset, a
lower incidence of tremor, a more rapid course, and a
higher proportion of cases with dementia have been described.5–7 The only pathological study described
changes typical of those seen in idiopathic Parkinson’s
We report the clinical and pathological features of
an Australian family of Greek origin in which the
␣-synuclein gene mutation (Ala53Thr) was identified.
Two of the authors (Drs Sharpe and Spira) were involved in the management of 3 of the affected members over many years and thus had a longitudinal view
of the progress of the disorder. Permission for autopsy
was granted in 2 of the cases.
From the 1Institute of Neuroscience, Prince of Wales Hospital,
Randwick; 2Department of Neurology, Concord Hospital, Concord; 3Prince of Wales Medical Research Institute, Randwick; and
Department of Molecular Medicine, University of Sydney, Concord Hospital, Concord, New South Wales, Australia.
Address correspondence to Professor Nicholson, Molecular Medicine Laboratory, University of Sydney, Clinical Sciences Building,
Concord Hospital, Concord, New South Wales 2139, Australia.
Blood was collected for DNA testing with the informed consent of the subjects according to the Concord Hospital Ethics Review Committee guidelines. To preserve confidentiality
of nonexamined family members, a pedigree is not shown.
Genomic DNA was prepared from available affected family
members using standard methods. ␣-Synuclein mutation
screening was carried out as described by Polymeropoulos
and colleagues.1
In the second generation, 5 of the 9 siblings died of a
progressive movement disorder of variable duration. All
members of the first generation (described as I-1, etc) and
the second generation (II-1, etc) were born in the Peloponnesian region of Greece. There were 5 brothers in generation
II who were considered to suffer from the condition, although of these only 3 lived in Australia and were seen by
the authors. An unaffected brother was also examined at the
age of 44 while visiting Australia. He related that the features
seen in his 2 affected brothers living in Greece were the same
as seen in his Australian siblings, with progressive immobility
leading to invalidity, institutional care, and early death at
ages 55 and 58 after total illness duration of 4 and 15 years,
respectively. No details are available as to the mode of death
in either case. The father died of asthma at age 55, and the
Received Aug 8, 2000, and in revised form Sep 19. Accepted for
publication Sep 19, 2000.
© 2001 Wiley-Liss, Inc.
mother was bed bound for years following a postpartum
event before dying in Greece at age 50. Six offspring of the
affected Australian members were examined by the authors at
a time when they were all aged between 15 and 28. None
exhibited any evidence of movement disorder.
␣-Synuclein sequencing revealed a single base pair change
at nucleotide 209, changing guanine (G) to adenine (A), resulting in an alanine (Ala) to threonine (Thr) substitution at
the amino acid codon 53 in exon 4 (Ala53Thr) in the three
affected brothers, as previously described for the Contursi
pedigree.1 Four siblings were unaffected (aged 59, 52, 47,
and 47).
Neuropathological Methods
Consent for autopsy was obtained for 2 of the affected members (II-5 and II-6), and the brains were examined after 14
days of fixation in 15% neutral buffered formalin. The
brains were sectioned at approximately 3-mm intervals in the
coronal (cerebrum) or transverse (brainstem) planes using a
rotary slicer. The cerebellum was sectioned sagittally and
then parasagitally. All brain surfaces were examined for macroscopic evidence of pathologic conditions. Microscopic examination was performed on 10-␮m paraffin sections of the
precentral gyrus (Brodmann area 4), frontal cortex (area 9),
temporal cortex (area 20), parietal cortex (area 39), occipital
cortex (areas 17 and 18), cingulate cortex (area 24), hippocampus (at the level of the lateral geniculate nucleus),
amygdala, anterior and posterior basal ganglia (including the
basal forebrain), diencephalon, midbrain, pons, medulla oblongata, cerebellar vermis, and lateral lobe (including the
dentate nucleus). A series of sections from each block was
stained for hematoxylin-eosin, modified Bielschowsky silver,
and tau II (T5530, Sigma, St. Louis, MO, diluted 1:10,000),
ubiquitin (Z0458, Dako, Glostrup, Denmark, diluted
1:200), ␣synuclein (18 – 0215, Zymed, San Francisco, CA,
diluted 1:200), and glial fibrillary acidic protein (Z334,
Dako, diluted 1:750) immunohistochemical studies. Peroxidase visualization was used for the immunohistochemical
studies, and cresyl violet was used as a counterstain.
Detailed Case Reports
Patient II-6 presented at age 42 with generalized slowing,
decreased left arm swing, and bradykinesia (Table). There
were no eye movement abnormalities, pyramidal signs, or
resting tremor. He was on prazosin for hypertension but had
no history of other significant illnesses. Levodopa and
benserazide were introduced slowly. Eventually a moderate
response was obtained at 1,000 mg/day and 100 mg/day,
respectively. Bromocriptine 10 mg/day was added and slowly
increased with little benefit. At his best, after 2 years he
walked with a good stride but had difficulty with balance. At
this time, foot dyskinesia and end-of-dose failure commenced. Four years after onset, he had bilateral upper limb
rigidity but no tremor, walked without arm swinging, and
turned by numbers. He was somnolent and cognitively slow,
with a short attention span. Blood gas determinations revealed central hypoventilation (see Table).
He often fell asleep at the table, being found by his family
with his face in his plate. He had frequent urinary incontinence, which was not explained by his mobility problems.
He displayed postural hypotension, which was not corrected
with the withdrawal of prazosin. An episode of delirium was
improved by a reduction in his levodopa dose from 900 to
600 mg/day. He had progressive difficulties with activities of
daily living due to both bradykinesia and excessive daytime
somnolence. Sleep studies 12 months prior to death revealed
frequent arousals, with multiple underlying mini-myoclonus
on electromyogram (EMG; see Table). In the months before
Table. Summary of Clinical Features
Age at onset (yr)
Duration (yr)
Eye movements
Pyramidal signs
Levodopa response
Long-term response
Dyskinesia, end-of-dose failure
Decreased upgaze
Postural hypotension
Bladder involvement
Excessive daytime tiredness
Respiratory status
Frequent arousals, snores;
awake PO2 74, asleep 64;
awake pCO2 50, asleep 64;
Mini-myoclonus on electromyogram
pCO2 51;
Frequent later
Dyskinesia, end-of-dose
Snores, frequent apnea;
PO2 62;
pCO2 64;
A “good” response means as good as expected in sporadic Parkinson’s disease.
Annals of Neurology
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he died, he spent most of his time sleeping, although, when
motivated, he was able to walk half a kilometer, but with
falls. The drowsiness did not respond to trials of dexamphetamine 10 mg/day, methysergide 2 mg/day, or selegiline 10
mg/day. He died unexpectedly at the age of 47 while alone
at home.
Postmortem examination revealed mild portal hypertension, cirrhosis, and mild hypertrophy of myocardial fibers,
with no evidence of ischemic change. The pulmonary examination revealed acute changes consisting of parenchymal
edema and congestion, suggesting a respiratory mode of
death. In addition, there were changes of emphysema and
pulmonary hypertension.
Macroscopic examination of the brain revealed depigmentation of the substantia nigra and the locus ceruleus. Microscopically, these brainstem regions exhibited severe cell loss
and gliosis, with Lewy bodies in many of the remaining neurons (Fig A). ␣-Synuclein– and ubiquitin-positive Lewy neurites were extremely prominent in these regions. Mild cell
loss was also seen in the dorsal motor nucleus of the vagus
Fig. Representative photomicrographs of the pathological features of the disease. (A) Hematoxylin-eosin–stained section of the midbrain substantia nigra of patient II-6. Scale in inset ⫽ 50 ␮m. There was severe depigmentation of the substantia nigra (arrowheads), with few pigmented neurons remaining (arrows). Lewy body pathologic features were found in remaining pigmented neurons. (B) ␣-Synuclein immunohistochemical study of the midbrain substantia nigra in patient II-5. Immunoreactive Lewy neurites
were concentrated in the substantia nigra. (C) ␣-Synuclein immunohistochemical study of the anterior cingulate cortex in patient
II-6. Scale equivalent to E. The upper cortical layers undergoing neurodegeneration contained weakly immunoreactive neurons. (D)
Silver-stained section of the hippocampus in patient II-5 showing the absence of neurons in the CA2 and CA3 region. Scale equivalent to A. (E) ␣-Synuclein immunostaining in the hippocampal CA2 and CA3 region in patient II-6. The region of severe neurodegeneration contained a high density of abnormal immunoreactive Lewy neurites. (F) Hematoxylin-eosin–stained section of the entorhinal cortex in patient II-6. Scale equivalent to G. There was considerable spongiosis in the lower layers of the cortex. wm ⫽
white matter. (G) Ubiquitin immunohistochemical study of the entorhinal cortex in patient II-6. Enlarged Lewy neurites were consistently associated with vacuolation in the lower layers of the entorhinal cortex. wm ⫽ white matter.
Spira et al: Clinical and Pathological Description of ␣-Synuclein Gene Mutation
nerve. These findings fulfill current consensus criteria for the
diagnosis of PD.9
In addition to the classic neuropathologic features of PD,
cortical neuritic pathologic conditions were extensive, although their distribution was restricted to the deeper cortical
layers. These neuritic changes were notable in all cortical
areas examined but were most pronounced in the medial
temporal regions, where they were associated with significant tissue vacuolation (Fig F, G) similar to that seen in
Creutzfeldt-Jakob disease. Each tissue vacuole was associated
with an ␣-synuclein– and ubiquitin-positive Lewy neurite. In
the hippocampus, the CA2 and CA3 regions were sclerotic,
with severe cell loss and gliosis (Fig C, E). There was no
evidence of cortical intracytoplasmic neuronal inclusions
or neuritic or diffuse plaques, although pale-staining
␣-synuclein–positive neurons were seen in the cortical layers
above the aggregations of Lewy neurites (Fig C). There was a
marked gliosis throughout the cortex, white matter, and
basal ganglia but no deposition of ␣-synuclein or ubiquitin
within the glial cells. White matter arterioles had thickened
vessel walls, hemosiderin, and cellular infiltrates and enlarged
perivascular spaces.
Patient II-5 presented at age 46 with progressive bradykinesia
and rigidity (see Table). There were no pyramidal signs or
resting tremor (see Table). He demonstrated a good therapeutic response to levodopa and carbidopa (300 mg/day and
30 mg/day, respectively). Bradykinesia increased, and he
demonstrated motor fluctuations, which responded partially
to the introduction of bromocriptine (30 mg/day). Within 2
years of onset, he had developed peak-dose dyskinesia (see
Table). He had recurrent drop attacks and hypotension with
postural drop (blood pressure 90/70 mm Hg supine and
80/60 standing). Within 3 years of onset, he developed an
acute paranoid state, which did not respond to drug withdrawal. During the inpatient withdrawal phase, he became
immobile and rigid but regained good mobility with the reintroduction of levodopa and carbidopa (300 and 30 mg/day
to 500 and 50 mg/day, respectively) and the addition of
benztropine (1.5 mg/day) and selegiline (10 mg/day). Both
the motor and cognitive problems progressed over the ensuing years, and he became increasingly more dependent, requiring institutional care at the age of 52. At this time, the
postural hypotension was severe and unresponsive to treatment, requiring nursing in a semirecumbent chair. Over the
last 2 years of his life he was apathetic, had urinary incontinence, a progressive dementia, and prominent generalized
myoclonic jerks, which were well controlled by sodium valproate (1.2 g/day). He had dysphagia and a number of episodes of aspiration pneumonia. A feeding gastrostomy was
inserted 4 months before his death. Over his last months,
central hypoventilation and periodic apnea were prominent,
and he died of respiratory failure at age 55.
A brain-only autopsy was performed. Severe depigmentation of the substantia nigra and locus ceruleus were the only
macroscopic abnormalities detected. Microscopically, the
substantia nigra and the locus ceruleus exhibited severe cell
loss and gliosis, with Lewy bodies in many of the remaining
neurons. Within these brainstem regions, as well as in the
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dorsal motor nucleus of the vagus nerve, ␣-synuclein–immunoreactive Lewy neurites were extremely prominent (Fig B).
Lewy bodies and Lewy neurites were also seen in the oculomotor nucleus. No senile plaques or neurofibrillary tangles
were found in any of the sampled sections. These findings
fulfill current consensus criteria for the diagnosis of PD.9
In addition to the classic neuropathologic features of PD,
there was mild generalized cortical cell loss. The cortical
mantle was thin, with both the cortex and underlying white
matter gliotic. However, there was no deposition of
␣-synuclein or ubiquitin within the glia. White matter arterioles had thickened vessel walls, hemosiderin, and cellular
infiltrates and enlarged perivascular spaces. Cortical neuritic
pathologic conditions were extensive, although their distribution was restricted to the deeper cortical layers. These neuritic changes were notable in all cortical areas examined but
were most pronounced in the medial temporal regions,
where cell loss was more extreme. In this case, there was
considerable compaction of the tissue, as seen in the sclerotic
hippocampal CA2 and CA3 regions (Fig D). There was no
evidence of cortical intracytoplasmic neuronal inclusions or
neuritic or diffuse plaques. Within the basal ganglia, there
was a marked reactive gliosis, with some associated cell loss
in the putamen and globus pallidus. Basal ganglial glia did
not contain ␣-synuclein or ubiquitin deposits.
Patient II-2 presented at the age of 44 with bilateral resting
hand tremor and mild bradykinesia, more marked in the left
limbs (see Table). There were no eye movement abnormalities or pyramidal signs (see Table). Administration of levodopa and carbidopa (300 and 30 mg/day, respectively) was
instituted with good response. Within 2 years of onset, he
developed moderate dyskinesia (see Table), but therapeutic
control remained excellent, with no tremor or bradykinesia.
Dyskinesia became accentuated over the ensuing years to the
point where the patient withdrew levodopa because he considered the involuntary movements to be more troublesome
than the modest features of parkinsonism. Over the next 6
years, there was an obvious progression, with the emergence
of more significant bradykinesia. Therapy with levodopa and
carbidopa was reinstituted (300 and 30 mg/day, respectively), again with good response, although peak-dose dyskinesia
and end-of-dose failure were prominent. Within 10 years of
onset, there was evidence of cognitive decline, with periods
of confusion, hallucinations, and marked paranoid ideation
structured around repeated sexual accusations. Despite withdrawal of all of his medications, the cognitive problems persisted. During a 1-week period of drug withdrawal, he became progressively more rigid and was eventually bed bound
and totally immobile. There was little response to the reintroduction of his former dose of 30 mg/day levodopa and
carbidopa, but with the return to benztropine (1.5 mg/day),
he demonstrated a dramatic recovery and returned to his
former independent mobility without accentuation of the
cognitive components. Although he remained levodopa responsive, there was progression in his disability, with the
emergence of marked postural hypotension, which resisted
fludrocortisone, ergotamine, and pressure stockings. Urinary
incontinence and myoclonus became problems during the
last 7 years of his life. Initially the myoclonus was nocturnal,
but in the last years of his life myoclonus was a prominent
feature throughout the day. He developed both central hypoventilation and obstructive apnea. During the last year of
his life, he was nursed semirecumbent because his sitting
blood pressure could not be maintained above 80 mm Hg
systolic. Even when recumbent, he was apathetic, confused,
and noncommunicative, and there were a number of admissions for aspiration pneumonia, necessitating the insertion of
a feeding gastrostomy. In the last month of his life, there
were recurrent bouts of apnea lasting for up to a minute in
the absence of any evidence of respiratory obstruction. The
attacks progressed to the point of central cyanosis, and arterial blood gas determinations revealed changes of central hypoventilation (see Table). He died of central hypoventilation
16 years into the course of his illness. The family declined
postmortem examination.
We describe a family affected by a parkinsonian syndrome with an ␣-synuclein gene mutation (Ala53Thr).
Affected members demonstrated several clinical and
pathological changes that have not been reported previously with this mutation.
This is the thirteenth family to be described with an
Ala53Thr ␣-synuclein gene mutation. The others are 1
large Italian-American family and 11 other Greek families.1,10 –12 DNA polymorphism haplotype data indicate that the reported Greek and Italian-American cases
may have a common founder.11 A German family with
a different synuclein mutation (Ala30Pro) has also
been reported.13
Detailed clinical and neuropathological observations
have been reported in only 1 Ala53Thr ␣-synuclein
gene mutation family (the Italian-American Contursi
family). Although these two ␣-synuclein mutations are
extremely rare,3,5,6,14,15 the relevance of ␣-synuclein
mutations to the clinical features of PD cannot be
overstated, because ␣-synuclein is now thought to be
an important protein in the pathogenesis of the disease.16 –22 Recent evidence from a transgenic mouse
model with an extra copy of the gene suggests that
overdose of ␣-synuclein can result in Lewy body formation and motor defects.23
Previous descriptions of families with the Ala53Thr
mutation have suggested that their features differ only
slightly from those of idiopathic PD.7,8,15 In the Contursi pedigree, the average age of onset was 45.6 years,
and the initial symptoms were variable, including resting tremor, bradykinesia, or gait disturbance. Affected
family members initially responded well to levodopa. A
high proportion of affected members had dementia,
with an average disease duration of 9 ⫾ 5 years.7 Histopathologic study revealed neuronal degeneration, gliosis, and Lewy body formation in the substantia nigra
and locus ceruleus. Some cortical Lewy bodies were
also seen.
Our cases had all the features reported in the Contursi family, with similar onset and disease duration
but significant additional clinical features that have not
been described previously with the Ala53Thr mutation.
These features included central hypoventilation, postural hypotension, myoclonus, and incontinence of
urine. In particular, the marked central hypoventilation
led to the deaths of 2 and possibly all 3 of the patients
we describe. The hypoventilation was clearly of central
origin, with the high arterial pCO2 and low pO2 recordings (see Table) obtained at a time when there was no
evidence of respiratory obstruction. Additional pathological features were also observed, including substantial cortical neuritic features associated with vacuolation and significant basal ganglial gliosis. These features
have not been described in previous reports, although
they were prominent in the family described here. Although most of these additional clinical features occurred later in the disease in these patients, some variance in symptom onset, severity, and duration was
observed. For example, tremor was a feature found
only in patient II-2, whereas myoclonus was seen early
in patient II-6. Such variance may reflect environmental interactions with gene polymorphisms.24
Although central hypoventilation has not been reported previously in families with an ␣-synuclein gene
mutation, four families have been described in the literature with parkinsonism associated with apathy and
central hypoventilation.25–29 Disease onset in these
families occurs in the fifth decade, duration is 4 to 6
years, and there is a poor response to levodopa.26 –28
This disorder is therefore unlikely to be caused by the
␣-synuclein gene mutation. The neuropathological
findings associated with this condition are striatal and
pallidal gliosis,25 a feature also found in our cases with
the Ala53Thr ␣-synuclein gene mutation. In our cases,
no ␣-synuclein deposits were associated with this basal
ganglia pathologic condition, suggesting that the
pathological changes are indirectly related to the protein defect.
The profound and resistant hypotension encountered in patients II-2 and II-5 was most unusual in its
severity, eventually precluding even a sitting posture.
Hypotension was documented in only one of the Contursi kindred7 but has been described in members of
families with other types of familial parkinsonism.30 –33
Some postural hypotension can occur late in the course
of idiopathic PD, reflecting the increasing pathologic
involvement of autonomic neurons in the disease process.34,35 Brainstem involvement and Lewy body formation are common to all. The severity of the brainstem Lewy neuritic pathologic features in our cases has
not been described previously in familial PD and may
explain the severity of this clinical feature.
In the present study, myoclonus was a prominent
feature. Myoclonus is rarely observed in idiopathic
Spira et al: Clinical and Pathological Description of ␣-Synuclein Gene Mutation
PD,36,37 although it has been reported as a side effect
of levodopa therapy.38 However, in our cases myoclonus remained despite reduction of levodopa doses. Myoclonus has previously been noted as a feature of familial Lewy body disease,31,33 including a family linked
to a 4p locus near the gene for ␣-synuclein.39 In the
latter family, a sporadic myoclonus developed and increased in amplitude progressively, much as was seen in
our cases. The brainstem neuropathologic condition
described in this family is similar to that seen in our
family, although the only cortical change in common is
vacuolation in the temporal cortex. This feature was
prominent in patient II-6, who had a short disease duration, whereas in patient II-5 the cortical tissue was
somewhat collapsed, reflecting more advanced disease.
In patient II-6, the vacuolation was associated with striking ␣-synuclein Lewy neurites. Vacuolation in cases with
cortical Lewy bodies is thought to reflect rapid neuronal
loss.40 In our cases, few neurons remained in the regions
with high densities of ␣-synuclein neurites (substantia
nigra, CA2 and CA3 regions of the hippocampus, and
deep layers of the temporal lobe), consistent with this
concept. As with Creutzfeldt-Jakob disease, the rapid
loss of cortical tissue, causing vacuolation, could be responsible for the development of cortical myoclonus.
Progressive cognitive decline was seen in all 3 of our
cases, and this finding has been reported previously in
families with the ␣-synuclein gene mutation.7 In addition, 2 of our patients (II-2 and II-5) displayed prominent paranoid ideation, with minimal improvement
following withdrawal of antiparkinsonian drugs. The
dementia and behavioral changes seen in our patients
occurred late in the disease course and are likely related
to the abnormal cortical accumulation of ␣-synuclein
in dystrophic neurites, because cortical Lewy bodies
were not a feature. Similar prominent cortical neuritic
pathologic features have recently been described in hereditary parkinsonism and dementia linked to chromosome 4p.41
In summary, examination of our cases over many
years revealed a disease characterized by the constellation of levodopa-responsive parkinsonism, marked postural hypotension, central hypoventilation, myoclonus,
urinary incontinence, and dementia. These clinical features overlap with idiopathic PD, multiple-system atrophy (autonomic abnormalities), and dementia with
Lewy bodies. The abnormal deposition of ␣-synuclein
is a feature common to all of these disorders.16 –22
There is increasing evidence that mutations in the
␣-synuclein gene significantly alter the physicochemical
properties of the protein, making it more likely to aggregate.42 This may explain the earlier clinical presentation, more severe clinical and pathological expression,
and more widespread clinical and pathological manifestations of the disease in our cases.
Annals of Neurology
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This study was supported by grant assistance from the National
Health and Medical Research Council of Australia to Drs Nicholson
and Halliday.
We thank family members for their assistance and cooperation. The
University of Sydney and Concord Hospital provided infrastructure
support. At the Prince of Wales Medical Research Institute, we
thank Heather McCann for the preparation of the histological slides
and Heidi Cartwright for assistance with the figure. Professor Aglaia
Athanassiadou, University of Patras, Greece, kindly gave advice on
the present number of Greek families with the Ala53Thr mutation.
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Spira et al: Clinical and Pathological Description of ␣-Synuclein Gene Mutation
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features, mutation, pathologic, clinical, syndrome, synucleins, family, ala53thr, parkinsonism
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