Acta Neuropathol (1998) 95 : 199–204

© Springer-Verlag 1998

C A S E R E P O RT

Hidenao Sasaki · Hideaki Kojima · Ichiro Yabe ·
Kunio Tashiro · Takeshi Hamada · Hirofumi Sawa ·
Hiroaki Hiraga · Kazuo Nagashima

Neuropathological and molecular studies
of spinocerebellar ataxia type 6 (SCA6)

Received: 7 July 1997 / Revised, accepted: 14 August 1997

Abstract SCA6 is an autosomal dominant spinocerebellar ataxia (SCA) caused by a small CAG repeat expansion
of the gene encoding an α-1A-voltage-dependent Ca channel gene subunit on chromosome 19p13. A Japanese
woman with SCA6, with a 7-year history of progressive
pure cerebellar ataxia, died of malignant lymphoma. Systematic neuropathological examination showed that neuronal degeneration was confined to the cerebellar Purkinje
cells and, to a lesser degree, the granular cells, without
any involvement of other central nervous system structures. Such pathological selectivity correlates with the localized expression of the responsible gene, and coincides
with the neurological manifestation. These findings might
contribute to establishing the phenotype of the SCA6 via
comparison with other dominant ataxias.
Key words Spinocerebellar ataxia type 6 (SCA6) ·
Dominantly inherited ataxia · Late-onset pure cerebellar
ataxia · Purkinje cell degeneration

H. Sasaki · I. Yabe · K. Tashiro
Department of Neurology,
Hokkaido University School of Medicine, Kita-15, Nishi-7,
Kita-ku, Sapporo 060, Japan
H. Kojima
Department of Clinical Pathology,
Tokyo Metropolitan Institute of Neuroscience, Musashidai 2-6,
Fuchu-shi, Tokyo 183, Japan
T. Hamada
Hokuyukai Neurological Hospital, 2-2, 24-ken, Nishi-ku,
Sapporo 063, Japan
H. Sawa · H. Hiraga · K. Nagashima (Y)
Department of Pathology,
Hokkaido University School of Medicine, Kita-15, Nishi-7,
Kita-ku, Sapporo 060, Japan
Tel: 81-11-706-5052; Fax: 81-11-758-4128;
e-mail: knagasi@med.hokudai.ac.jp

Introduction
Spinocerebellar ataxia (SCA) with dominant inheritance
has been classified at least into seven subgroups according to the order of gene mapping and cloning: SCA1 is located on chromosome 6p22-p23 [17], SCA2 on chromosome 12q24.1 [10, 18, 20], Machado-Joseph disease
(MJD/SCA3) on chromosome 14q32.1 [3, 12], SCA4 on
chromosome 16q22.1 [4], SCA5 on chromosome 11 [19],
SCA6 on chromosome 19p13 [26], and SCA7 on chromosome 3p12-p21.1 [1, 5]. Five of these seven dominant
SCA are now known to be caused by dynamic mutation of
CAG repeat expansion in the coding region of each gene.
Clinically, SCA6 manifests pure cerebellar ataxia with
symptoms generally starting in the third to fifth decades
of life [26]. The disorder is a genetically defined subgroup
in “pure” autosomal dominant cerebellar ataxia of late onset,
which has been classified as autosomal dominant cerebellar ataxia (ADCA) type III by Harding [7], and is now
known to be a genetically heterogeneous disease. SCA6 is
an allelic disorder of familial hemiplegic migraine and
episodic ataxia (EA-2) [16] and is caused by a small expansion of CAG repeat in the coding region of the gene
encoding α-1A-voltage-dependent Ca channel subunit
(CACNL1A4) on chromosome 19p13 [26]: CAG repeat
size was 21–27 in mutant SCA6 alleles (n = 8) and 4–16
in control alleles (n = 950). The CACNL1A4 gene is selectively expressed in the central nervous system, predominantly in the cerebellum.
The reported clinicopathological findings on SCA6
have provided a good knowledge base for understanding
the function of the gene and the pathomechanism of the
disease. Few neuropathological details have been reported, however, due both to the rarity of the disease and
the lack of genetic analysis of the patients’ families. Here,
we report an autopsy case of a patient with hereditary
spinocerebellar disease, retrospectively identified as SCA6.
In a study by Yagishita and Inoue [24], many of the SCAs
except for SCA6 were shown to have dysfunction or
pathological changes extending beyond the cerebellum to

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involve basal ganglia function, olivary-pontine degeneration, spinal cord changes, oculomotor disturbance, and
neuropathy. Interestingly, the same study found that SCA6
was unique in its distribution of the degeneration, with
only Purkinje cells of the cerebellar cortex selectively affected by a slight decrease in number of granule cells,
while cerebellar white matter, dentate, olivary and pontine
nuclei, and extracerebellar systems were left intact.

tion to spontaneous down beat nystagmus. Her ataxia advanced to
the point that she needed assistance to walk. Her mentation was
normal and sphincter function was not impaired throughout the
course. Magnetic resonance imaging of the brain showed cerebellar atrophy with no pathological changes in other central nervous
system structures.

Materials and methods
DNA analyses

Case report
The female patient developed a slowly progressing ataxia at the
age of 55 years. In 1987, when she was 59 years old, nonHodgkin’s lymphoma (follicular large cell type) was detected and
she twice received radiation therapy to the neck, combined with a
course of chemotherapy (vincristine, cyclophosphamide, and predonine). Following the chemotherapy the patient developed radiating back pain and was examined neurologically. The examination
disclosed slight dysarthria, horizontal nystagmus on lateral gaze,
ocular hypermetria, slight hypotonia of limb muscles, mild ataxia
of the limbs and trunk, and superficial sensory disturbance of fingers and toes; limb reflexes were preserved, without any signs of
pyramidal or extrapyramidal system involvement. Her cognition,
memory, and sphincter control were not impaired. A brain X-ray
computed tomography scan showed mild cerebellar atrophy with
bilateral calcification of the globus pallidus and dentate nuclei.
Because her sensory disturbance correlated with the course of
chemotherapy, it was regarded a sequelae of this treatment.
The lymphoma recurred repeatedly despite the chemoradiotherapy, and bone marrow suppression with thrombocytopenia developed in February 1988. Early in January 1989, she developed
herpes zoster with intractable pain, requiring epidural anesthesia.
Marked thrombocytopenia and bloody stool followed, and the patient died on February 5, 1989 at the age of 61 years.
Her family history disclosed that the disease was dominantly
inherited SCA as shown in the family tree (Fig. 1). Her father, who
died at the age of 60, was reported to have been affected with
ataxic disorders. Of her two siblings, her brother was not affected,
whereas her younger sister had developed an unsteady gait and
speech difficulties at the age of 54. Neurological examination of
this sister at age 58 showed mild limb and gait ataxia, obvious
dysarthria, and limb hypotonia. Neither gaze nystagmus nor ocular
overshoot was observed at that time. Her ataxia progressed
steadily. At age 66, she showed marked gaze nystagmus in addi-

With informed consent, peripheral blood was obtained from each
of the siblings and high molecular weight DNA was extracted from
white blood cells or lymphoblastoid cell lines. Genotyping of the
SCA6 mutation was performed according to the original report
[26]. After amplification by the polymerase chain reaction method,
products flanking the CAG repeat polymorphism of the α-1A-voltage-dependent Ca channel subunit gene were analyzed with an
ABI PRISM 377 (PE Applied Biosystems, Foster City, Calif.), and
allele size was determined by GeneScan (PE Applied Biosystems).
The size of the CAG repeat was calculated by comparing the sequenced index allele.
Neuropathological examination
An autopsy was performed 3.5 h after death. Slight subarachnoid
hemorrhage was found around the posterior part of the cerebellum
and the spinal cord from the first lumbar to the cauda equina, but
no berry aneurysm or rupture thereof was evident. The hemorrhages were considered to be caused by thrombocytopenia-related
hemorrhagic diathesis. Malignant lymphoma was not detected
anywhere in the organs, probably due to effective chemotherapy.
To avoid postmortem autolysis the brain was fixed by perfusion
fixation with 10% buffered formalin via the bilateral carotid arteries. The brain was then examined by routine histological staining
using the hematoxylin-eosin, Klüver-Barrera, Bodian, and Holzer
methods. The Gallyas-Braak method was also performed [2]. For
the immunohistochemical analysis, antibodies against glial fibrillary acidic protein (GFAP; Dako), synaptophysin (Dako), and neurofilament triplet (Dako) were used. In addition, parvalbumin
(Sigma) [23], calbindin-D (Sigma) [11], and the EAAT4 subtype
of glutamate transporter [25] were used. The antibodies of the latter three proteins are known to label Purkinje cells and their dendrites. As a positive control, four age-matched cases of the cerebellum and a sporadic case of multiple system atrophy with typical
olivopontocerebellar degeneration were also analyzed.

Results
SCA genotyping
The sizes of CAG repeats of the α-1A-voltage-dependent
Ca channel subunit gene are shown in Table 1 for each
subject. The present case had 16/22 repeats, and her affected sister had 13/22 repeats. The healthy brother had
11/16 repeats. Each of the two sisters carried one expanded allele the repeat size of which fell into the range of
the SCA6 mutation.
Fig. 1 Family tree with number of CAG repeats. CAG repeat size
of SCA6 alleles was presented in numbers of short/long repeat in
each allele. The genotype of the deceased parents (presented in
parenthesis) were deduced from the data of their three children
(see also Table 1) (/ deceased, m man, p woman, solid symbols affected, empty symbols not affected)

Neuropathology
Macroscopically, the brain of the autopsied subject, which
weighed 1300 g, showed no significant changes except
for the slight subarachnoid hemorrhage described above.

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Table 1 Family data with
number of CAG repeats. Blood
from the family was obtained
in 1987 with informed consent
(see also legend to Fig. 1) (NE
not examined)

Family

ID

Disease

Father
Mother
Proband (this case)
Younger brother
Younger sister

A
B
C
D
E

+
–
+
–
+

Fig. 2 Macroscopic view of the cerebellum. Atrophy of folia is
evident in the vermis (center), but cerebellar white matter as well
as dentate nuclei are seen well preserved

On coronal section there were no remarkable changes in
the cerebral cortex, white matter, or basal ganglia, or in
the midbrain, pons, medulla oblongata, or spinal cord.
The cerebellum was externally symmetric. The cerebellum was sectioned tangentially through the vermis and the
hemisphere through the dentate nucleus on the right side.
The left side of the cerebellar hemisphere was sectioned
horizontally through the dentate nucleus. Atrophy of folia
was noted in the vermis (Fig. 2). The cerebellar white
matter and dentate nuclei were well preserved.
Microscopically, degenerative changes were found
confined to the cerebellar cortex. The number of Purkinje
cells was found to have decreased to approximately onethird to one-fourth that in the age-matched controls. The
loss was evident in the cerebellar vermis, and especially
marked in the declive (Fig. 3a), and in the cerebellar
hemisphere, less markedly in the lobuli quadragularis and
simplex. Granular cells were slightly decreased in number, and torpedoes were frequently observed among their
sparse nuclei (Fig. 3a, arrow). Immunostaining for neurofilament disclosed many empty basket fibers, mainly
around Purkinje cells and torpedoes (Fig. 3b). CalbindinD immunostaining demonstrated a decreased number of
dendrites in the molecular layers of Purkinje cells. However, those of the remaining Purkinje cells were well preserved and among them many spiny dendrites were
clearly demonstrated (Fig. 3c). Antibodies to glutamic
acid transporter (GAT) and parvalbumin also disclosed a

Age at onset
(years)

Age of deatha, and
at blood samplingb
(years)

CAG
repeat

55

60a, from unknown cause
80a, from heart failure
60b (61a)
58b
55b

NE
NE
16/22
11/16
13/22

54

decreased number of Purkinje cells and their dendrites in
the molecular layer similar to immunostaining with calbindin-D (data not shown). A few remaining Purkinje
cells and their dendritic spines were intensely labeled with
GAT and parvalbumin. Torpedoes and Purkinje cell axons
running in the white matter as well as around neurons of
the dentate nucleus were strongly labeled by calbindin-D
and parvalbumin. Synaptophysin staining disclosed numerous positive synaptic glomeruli in the granular cell
layer. In addition, intensely immunolabeled synaptophysin fibers were noted around neurons of the dentate
nuclei (Fig. 3d). This intense staining of synaptic protein
around the neurons of dentate nuclei was also observed in
a sporadic case of multiple system atrophy. There was a
small concentration of GFAP-positive astrocytic fibers in
the molecular layer and white matter, and around the dentate nuclei. Myelin sheaths of the cerebellar white matter
were well preserved. Oligodendroglial inclusion bodies
were not found in the preparation stained with GallyasBraak method, although the inclusions were demonstrated
in the preparations of multiple system atrophy used for
positive control.
There were no abnormalities found in the cerebral cortex, white matter, or basal ganglia. The putamen, pallidum, caudate nucleus, thalamus, subthalamic nucleus
(Luysian body), Ammon’s horn, basal nucleus of Meynert, substantia nigra, and red nucleus were well preserved.
Nothing remarkable was observed in the pontine tegmentum (including the superior cerebellar peduncle), the pontine base (including ponto-cerebellar fibers), or the
medulla oblongata (including the inferior olivary nuclei).
The spinal cord was intact in both the pyramidal and spinocerebellar tracts. Spinal autonomic nuclei, such as nucleus intermediolateralis, and Onuf’s nucleus were also
intact. The only localized change of note was in the right
second lumbar spinal ganglion, which was focally
necrotic with lymphocytic infiltration. This was considered a sequela to herpes zoster.

Discussion
The DNA genotyping for SCA6 mutation in the present
family indicates that abnormal expansion was selectively
associated with two affected individuals, but not in the
asymptomatic brother. The size of these two expanded alleles was consistent with the original report [26]. Our pre-

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a

b

c

d

Fig. 3a–d Histological and immunohistochemical findings of the
cerebellum. a Moderately decreased number of Purkinje cells of
the vermis. The number of granule cells is also decreased. Note a
few axon torpedoes among the sparsely arranged granule cells (arrows); H & E stain. b Empty baskets in the Purkinje cell layer and
torpedoes in the granular layer are clearly seen; immunostaining
with neurofilament.c Well-preserved cell body and its dendrites in
the surviving Purkinje cell; immunostaining with calbindin-D.
d Intensely visible synaptic terminals around the neurons of dentate nucleus; immunostaining with synaptophysin. a–d × 200

vious study on a large cohort of Japanese patients indicated that such a small expansion was selectively detected
in SCA6 (21–33 repeats, n = 56 alleles) and not in control
alleles (4–18, n = 1148 alleles) (Yabe et al., submitted).
This earlier study suggested that SCA6 is a prevalent SCA
irrespective of ethnicity. The genetic data on these earlier
subjects provides firm evidence for the diagnosis of the
present family. Clinically, the symptoms of both the present patient and her sister began in the sixth decade of life,
with cerebellar ataxia being the predominant feature
throughout their clinical courses, without any neurologi-

cal signs indicating other neural system involvement. This
clinical presentation would be a typical one for ADCA
type III [7]. The sensory disturbances observed were
thought to be related to chemotherapy, since they were relieved after withdrawal of chemotherapy and did not occur in the subject’s sister. It is also unlikely that paraneoplastic cerebellar degeneration developed in association
with malignant lymphoma, because cerebellar signs was
slowly progressive, and the signs had not been improved
after disappearance of lymphoma.
Pathologically, SCA6 is unique among SCAs in which
pathological findings have been reported. SCA1 is largely
characterized by degeneration of spinocerebellar (SC) and
olivopontocerebellar (OPC) systems with frequent involvement of dentate, rubral and pallidal systems, and
SCA2 by those of SC and OPC systems with frequent involvement of substantia nigra [24]. In SCA3 the OPC system is spared, but the involvement of the SC system and
the extracerebellar systems including dentate nuclei are
constant findings [24]. No pathological findings comparable to the present ones have been reported for SCA4,

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SCA5, or SCA7. In contrast in SCA6, degeneration was
confined to cerebellar cortex, particularly to Purkinje
cells. Since the CAG repeat expansion occurred in the
coding region of a gene which is important for normal
Purkinje cell function and survival [13, 15], it would be
reasonable to speculate that Purkinje cells were a victim
of this gene abnormality.
Immunohistochemical studies using Purkinje cell
markers clearly demonstrated the decreased number of
Purkinje cells and subsequent reduction of their dendrites
in the molecular layer. These findings were consistent with
reported cerebellar disorders [11, 23]. However, these proteins were intensely expressed in the remaining Purkinje
cells and their dendritic spines. This was different from the
reported cases in which these protein expressions were decreased in the surviving Purkinje cells in other types of
cerebellar degeneration [23]. This difference may stem not
from the disorders involved, but from the different stages
at which the patients died; our subject died of malignant
lymphoma during the mid-stage of the ataxic disorder.
However, an examination of numerous cases of different
types of SCA would be needed to evaluate these protein
expressions. An intense expression of synaptophysin protein around the neurons of dentate nuclei could be interpreted as reactive overexpression from the surviving Purkinje cells to compensate the lost axonal input.
Before the identification of the genetic locus of SCA6,
there were reports of cerebellar ataxia which could be
considered to be SCA6 based on the clinical as well as
pathological findings. Key words may be (1) autosomal
dominant inheritance, (2) late adult onset with relatively
pure cerebellar signs, and (3) pure Purkinje cell degeneration with relatively preserved olivary nuclei. Such cases
have been usually classified as Holmes type, although the
case reported by Holmes (1907) had olivary degeneration,
and seemed to be an autosomal recessive disorder since he
described that “Neither parent of the family was afflicted
with any form of nervous disease; the father died at 70
years of age, the mother at 89, with chronic rheumatism
and bronchitis” [9]. Moreover, hypogonadism was also reported in Holmes’ cases. Among the reports described as
“Holmes type”, however, we have found a few cases of
autosomal dominant inheritance and no mental or gonadal
abnormalities. Hall et al. [6] reported a three to four generation family of late-onset cerebellar ataxia. The reported
family tree showed an autosomal dominant heredity of the
disease. An autopsy of an 80-year-old man disclosed that
the degeneration was confined to the cerebellar cortex
with olivary involvement. Hoffman et al. [8] reported a
four generation family with autosomal dominant late-onset cerebellar degeneration in northern Georgia, USA.
Pathological findings of one of their cases were quite similar to our case, except for olivary involvement. Takahashi
et al. [22] reported in their second case that a 54-year-old
woman with dominant family history suffered from progressive ataxia and died of rectal cancer at the age of 65
years. An autopsy disclosed degenerative changes limited
to the cerebellar cortex with slight loss of neurons and
slight gliosis of the olivary nucleus. Muzusawa et al. [14]

reported a dominantly inherited cerebellar cortical atrophy of an 84-year-old who had suffered from progressive
cerebellar ataxia since he was 57. Neuropathology confirmed pure cerebellar cortical degeneration without involvement of the olivary nucleus. However, for each of
these four reports, specific gene mutations are unknown.
More recently, Subramony et al. [21] have described two
autopsy cases of dominantly inherited cerebello-olivary
atrophy. Neuropathologically, their cases were characterized by major loss of Purkinje cells, modest inferior olivary neuronal loss, and some thinning granule cell layer
in the cerebellum. The family members of these two cases
were later subjected in the study for SCA mutation and
were subsequently demonstrated to carry SCA6 mutation
[26]. Therefore, these two cases [21] represent the first
description of SCA6 pathology, as far as we know, and
our case is the third. Inconsistent findings in these three
autopsy cases indicate that whether inferior olivary nucleus is degenerated or not is not a main characteristic of
SCA6 pathology. However, it is not known whether there
is further variation in SCA6 pathology, or whether there
are any difference between SCA6 and non-SCA6 in
ADCA type III. As SCA6 was identified in the present
case by molecular analysis, there is a pressing need for
neuropathologists to establish a system of DNA analysis
using paraffin-embedded tissues.
Acknowledgments We thank the members of the families for
participation in this study, and Dr. Watanabe for a generous gift of
monoclonal antibody of glutamate transporter [25]. This study was
supported by a Grant-in-Aid for Scientific Research on Priority
Areas and a Grant-in-Aid for Scientific Research (A & B) from the
Ministry of Education, Science, Sports and Culture, Japan, and by
a grant from Research on Ataxic Diseases from the Ministry of
Health and Welfare, Japan.

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