Autosomal Dominant Cerebellar Ataxia:

Phen.oItYplC Differences in G.eneti.tally

Defined Subtypes?
b

Ludger Schols, MD,* Georgios Amoiridis, MD,* Thomas Buttner, MD,* Horst Przuntek, MD,*
Jorg T. Epplen, MD , t and Olaf Riess, MDt

Seventy-seven families with autosomal dominant cerebellar ataxia were analyzed for the CAG repeat expansions causing
spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The SCAl mutation accounted for 9%, S C A 2 for lo%, S W for 42%,
and SCAG for 22% of German ataxia families. Seven of 27 SCAG patients had no family history of ataxia. Age at onset
correlated inversely with repeat length in a l l subtypes. Yet the average effect of one GAG unit on onset age was different
for each SCA subtype. We compared clinical, electrophysiological, and magnetic resonance imaging (MRI) findings to
identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and
action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral
neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome and patients often had onset after 55 years of age. SCAl was characterized by markedly prolonged
peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar
atrophy in SCAl and S C A 2 . In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6
presented with pure cerebellar atrophy on MRI. However, overlap between the four SCA subtypes was broad.
Schols L, Arnoiridis G, Buttner T, Przuntek H, Epplen JT, Riess 0. Autosornal dominant cerebellar ataxia:
phenotypic differences in genetically defined subtypes? Ann Neurol 1997;42:924-932

Autosomal dominant cerebellar ataxia (ADCA) is a

clinically, pathologically, and genetically heterogeneous
group of neurodegenerative disorders characterized by
progressive ataxia of gait, stance, and limbs, and dysarthria as well as cerebellar oculomotor disturbances
caused by degeneration of the cerebellum and/or its afferent and efferent pathways. The cerebellar syndrome
is frequently associated with signs of cerebral, pyramidal, extrapyramidal, bulbar, spinal, and peripheral nervous system involvement in highly variable combinations. For decades, recurrent efforts have been made to
classify ADCA by using histopathological or clinical
criteria (for review, see Reference [ 11). However, these
classifications rendered unsatisfactory due to substantial
intrafamilial variability of clinical and pathological pictures and broad overlap between families.
Recently, ADCA is increasingly characterized by the
underlying genetic defects and referred to as spinocerebellar ataxia (SCA). Linkage studies revealed gene loci
for SCA on chromosome 6p (SCA1) [2], chromosome
12q (SCA2) [3], chromosome 14q (SCA3 and
Machado-Joseph disease [MJD]) [4, 51, chromosome
16q (SCA4) [6], chromosome 11 (SCA5) [7], chromo-

some 19p (SCAG) [8], and chromosome 3p (SCA7) [9,

101. The mutations responsible for SCAl, SCA2,
SCASIMJD, and SCAG have been identified as unstable expansions of CAG trinucleotide repeats in coding
regions of the responsible genes [8, 11-15]. Although
SCA3 and MJD show clinical differences, both phenotypes are caused by the same mutation, confirming that
the genetic basis of SCA3 and MJD is the same [16].
Despite the recent success in genetic differentiation
of SCA, it remains unclear whether genetically defined
subtypes of SCA present with distinct clinical phenotypes for SCA1, SCA2, SCA3, and SCAG. Initial studies found the clinical picture of SCAl and SCA3 patients to be very similar [17, 181. SCA2 is reported to
present frequently with slow saccades, decreased reflexes, and rarely with pyramidal tract involvement
[ 19-2 11. Direct comparisons of clinical and electrophysiological findings in SCA1, SCA2, SCA3, and
SCA6 patients have not been reported so far.
In this study we compare the clinical presentation of
SCAl, SCA2, SCA3, and SCAG patients from a large
uniformly examined cohort of ADCA families. Furthermore, we performed nerve conduction studies, mo-

From the *Department of Neurology, St Josef Hospital, and tMolecular Human Genetics, Ruhr-University, Bochum, Germany.

Address correspondence to Dr Schols, Neurologische Klinik der

Ruhr-Universitat, St Josef Hospital, GudrunstraBe 56, D-44791 Bochum, Germany.

Received Apr 16, 1997, and in revised form Jul 14. Accepted for
publication Aug 20, 1997.

924

Copyright 0 1997 by the American Neurological Association

tor evoked potentials (MEPs), visual evoked potentials

(VEPs), and magnetic resonance imaging (MRI) scans
to identify phenotypic characteristics between genetically defined subgroups of SCA.

Patients and Methods

Patients
A continuous series of 77 ADCA families were investigated
for the SCAI, SCA2, SCA3, and SCA6 mutations. In total,
118 patients with SCAl (10 patients), SCA2 (21 patients),
SCA3 (60 patients), or SCAG (27 patients) were available for
detailed clinical examination, which was performed according to a standardized protocol by the same neurologist (L.S.).
All patients fulfilled the diagnostic criteria of ADCA type I
according to Harding [22], ie, dominantly inherited progressive ataxia associated with at least one of the following signs:
dementia, ophthalmoplegia, rigidity, spasticity, sphincter disturbance, sensory deficits, weakness, amyotrophy, or abnormal reflex status. Families with pigmentary retinal degeneration characterizing ADCA type I1 or with pure cerebellar
atrophy (ADCA type 111) were not observed in our series.

Electrophysiological Findings and MRI

Nerve conduction studies were performed on 70 patients (8
with SCA1,7 with SCA2, 46 with SCA3, and 9 with SCA6)
including determination of distal latency, amplitude of
evoked muscle action potential (EMAP), conduction velocity, and minimal F-wave latency for motor nerve studies, and
sensory nerve action potential (SNAP) as well as conduction
velocity at a standardized skin temperature of 34C in sensory nerve studies. Electromyography using concentric needle
electrodes was performed at least of the tibialis anterior muscle with a Counterpoint MK2 (Dantec, Skovlunde, Denmark).
MEPs to the first dorsal interosseus (FDI) and tibialis anterior muscle (TA) were performed by a standard technique
with a Maglite magnetic stimulator (Dantec). Forty-nine patients were examined for MEPs, including 9 patients with
SCAl, 4 with SCA2, 31 with SCA3, and 5 with SCA6. Tibial and median nerve somatosensory evoked potentials (SEPs)
were recorded by a standard technique using a Counterpoint
MK2 (Dantec). Auditory evoked potentials (AEPs) and
VEPs were performed according to standard protocol with
an Excel (Cadwell, Kennewich, Washington).
MRI scanning of the skull was performed at 1.5 T with a
standard examination program including sagittal T I weighted and axial T2-weighted images. All MRI scans were
evaluated independently by two examiners who did not
know the underlying mutation. Atrophy was assessed in a
semiquantitative manner on a scale ranging from O (normal)
to +++ (severe). Upper and lower cerebellar vermis, pontine base, and cervical spinal cord at the level of the dens
were judged on midsagittal TI-weighted images. Cerebellar
hemispheres, middle cerebellar peduncle, and the fourth ventricle were evaluated on horizontal T2-weighted images.

Molecular Genetic Analyses

EDTA blood samples for genetic tests were taken from all
patients after informed consent was obtained. Technical de-

tails of molecular genetic analyses were performed as reported previously [ 16, 23-25].

Statistical Analyses
The relationship between age at onset and CAG repeat length
was evaluated by linear regression analysis for the SCA1,
S W , SCA3, and SCA6 subgroups, respectively. Frequencies
test. Staof clinical symptoms were compared by using the
tistical analysis of electrophysiological parameters were calculated by analysis of variance followed by the Tukey-Kramer
multiple comparison test.

x2

Results
Frequencies of the SCAl, S W , SCA3, and SCAG
Mutations in ADCA Families
In our series of 77 ADCA families, seven families were
typed as SCAl (!)yo),eight families as SCA2 (lo%), 32
families as SCA3 (42%), and 17 families as SCAG
(22%). Thirteen families (17%) did not carry a CAG
expansion in any of these genes. It is noteworthy that
one SCA2 and seven SCAG families had been misdiagnosed as sporadic cases before molecular genetic tests
were available. In the apparently sporadic patient with
SCA2, a de novo mutation from an intermediate allele
was proven [26]. In 4 of 7 SCAG patients without a
family history of ataxia, one parent died at a younger
age than when ataxia had manifested in their offspring.
In the fifth patient who developed ataxia at age 48, the
father died from appendicitis at age 52, and in the
sixth case with onset at 68 years of age, the parents
died at ages 80 and 84 years, respectively, without gait
difficulties in any member of these families. The seventh patient developed ataxia at age 53, and his mother
experienced gait difficulties ascribed to old age when
she was 88 years old.

Age at Onset and Rate o f Progression

Age at onset varied substantially in all subgroups (Fig
1). Mean age at onset did not differ between SCAl,
SCA2, and SCA3 patients but was significantly later in
SCAG patients compared with SCAl, SCA2, and
SCA3 patients (Table 1). None of our SCAG patients
had juvenile onset (before age 2O), but 12 of 27 SCAG
patients became diseased after 55 years of age.
In all forms of SCA, the CAG repeat lengths correlated inversely with age at onset (see Fig 1). However,
the effect of repeat length variation on onset age (the
slope of the regression curve) was different for each
mutation. The expansion of one CAG unit equals an
average difference in onset of 0.8 years in SCAl patients, 2.5 years in SCA2, 2.2 years in SCA3, and 4.5
years in SCAG patients. Repeat lengths account for 6577% of the variability in age at onset in SCAI, SCA2,
SCA3, and SCA6.
Progression rate was estimated with respect to two
end points, first, as the time between onset of symp-

Schols et al: Phenotypes in Dominant Ataxias

925

with some patients being confined to wheelchairs as

early as 4, 9, 5, and 8 years past onset (SCA1, SCA2,
SCA3, and SCA6, respectively) whereas others were
still ambulant without a walking aid after 11, 31, 18,
and 18 years with the disease (SCA1, SCA2, SCA3,
and SCA6, respectively).

70

**

'40i

4
4

30

Comparison of Clinical Features in SCAI, SCX.2,

SCX3, and SCAG

SCAG

SCA2

SCAl

SCA3

0
0

20

40

60

80

No. of CAG repeats

Fig 1. Inverse correlation of age at onset and number of CAG

repeats (linear regression anahsis): S U l : r = - 0.88;
slope = - 0.85 years per CAG repeat; p < 0.002; n = 3;
range, 42-57 CAG; S W : r = - 0.84; slope = -2.52
years per CAG repeat; p < 0.0001; n = 21; range, 36-52
CAG; SCA3: r = - 0.80; slope = - 2.25 years per CAG
repeat; p < 0.0001; n = 62;range, 67-82 CAG; SCAG:
r = - 0.80; slope = - 4.53 years per CXG repeat; p <
0.0001; n = 27; range, 22-28 CAG. SCAl, 2, 3, and 6 =
spinocerebellar ataxia gpes 1, 2, 3, and 6, reqectiveh.
Table 1. Age at Onset and Course of the Disease in SCAl,
S C X , SOB, and SC46
SCAl

SCA2

SCA3

SCAG

Age at onset (yr)

Mean 2 SD

n = 10
37 2 7"

Range
Duration of disease
(yr)
Mean 2 SD
Range
Progression to walking
aid (yr)
Mean t SD
Range
Progression to wheelchair
Mean 2 SD
Range

3142
n = 10

n=21
32212"
12-49
n=21

n=63
3629"
15-56
n=63

n=27
53211
30-71
n=27

724
1-14
n=4

1228
2-30
n=8

1026
0.5-30
n=34

1129
1-40
n=14

6.0 2 4.2 9.4 Z 3.7 8.8 2 3.8

2-1 1
6-15
1-18
n=2
n=3
n=13

7.4 t 4.3
4-18
n=9

5.5 2 2.1 9.7 2 0.6 13.9 2 5.5 18.6 = 9.5

4-7
9-10
5-24
8-37

Progression was estimated as the time benve.cn onset of symptoms and

requirement of a walking aid or confinement to a wheelchair. Age at
onset was significantly later in spinocerebellar ataxia type 6 (SCA6) compared with SCAl, SCA2,and SCA3 ("p < 0,001).

toms and requirement of a walking aid, and second, as

duration of the disease until confinement to a wheelchair. Mean duration until a walking aid was needed
was similar in all subgroups, with an average of 6 to
9.4 years (see Table 1). Data for the progression rate
until patients became chair bound were available for
only 27 patients. There is a tendency to more benign
courses of the disease in SCAG and more rapid progression in SCAl (see Table 1). Due to small numbers
these differences were not significant. However, progression rate was highly variable within every subform,

926 Annals of Neurology Vol 42

No 6

December 1997

Ataxia of gait and stance was present in all SCA patients of this series. All but l patient (SCA3) had limb
ataxia, more pronounced in the legs than in the arms,
and all but 3 (SCA3) presented with cerebellar dysarthria. Cerebellar oculomotor signs differed significantly
between subgroups (Table 2). Saccadic smooth pursuit
and gaze evoked nystagmus were significantly less frequent in SCAl and SCA2 compared with SCA3 and
SCAG patients. In contrast, slow saccades were frequent
in SCAl and SCA2 and rare in SCA3 and SCAG patients. N o differences between subgroups were seen in
optokinetic nystagmus and vestibulo-ocular reflex.
Only 1 of the SCAl and SCA2 patients complained of
double vision, whereas diplopia was frequent in SCA3
and SCAG patients. Double vision was often disabling
when reading and watching television in SCA3 patients
but did not interfere with activities of daily living in
SCAG patients. Frequencies of external ophthalmoplegia did not differ between subgroups.
Action and postural tremor as well as myoclonus was
more frequent in SCA2 than in SCAl, SCA3, and
SCAG patients. Otherwise, extrapyramidal signs did
not differ between subgroups. Signs of pyramidal affection including spasticity and hyperreflexia were rare in
SCA2 in contrast to the other forms of SCA. It is noteworthy that none of our SCAG patients had extensor
plantar responses despite other signs of pyramidal involvement in about 43% of patients (see Table 2).
Peripheral neuropathy was clinically obvious in most
SCA1, SCA2, and SCA3 patients but was significantly
less frequent and always mild in SCAG patients. Ninety
percent of SCA3 patients presented with defective temperature discrimination especially of the limbs but frequently also of the trunk and face. O n clinical grounds
we did not find signs of intellectual impairment in our
cohort of SCAG patients despite old age in many of
them. Mild forms of dementia appeared to be more
frequent in SCA2 and SCAl patients compared with
SCA3 and SCAG patients (see Table 2).
The phenotype in ADCA families without the
SCAl, SCA2, SCA3, and SCAG mutation was highly
variable. Most families presented with a combination
of ataxia, spasticity, and peripheral neuropathy, as it is
observed frequently in SCA1, SCA2, SCA3, and
SCA6. In two families, ataxia appears
_ _ to be mainly of
spinal and sensory origin with only minor cerebellar
signs. One family has pronounced parkinsonian signs

Table 2. Comparison of Pbenoqpes in SCAI, SCA2, SCA3, and SCA6

~~

SCAl (n
Cerebellar dysfunction
Ataxia of gait and stance
Limb ataxia
Dysarthria
Ocular motor disorders
Saccadic smooch pursuit
Gaze evoked nystagmus
Reduced saccadic velocity
Impaired optokinetic nystagmus
Vestibulo-ocular reflex
Ophthalmoplegia
Bulging eyes
Double vision
Extrapyramidal signs
Tremor
Akinesia
Rigidity
Choreiform hyperkinesia
Dystonia
Myoclonus
Pyramidal affection
Spasticity
Babinski sign
H yperreflexia
Peripheral neuropathy
Hyporeflexia
Paresis (dorsal foot flexion)
Amyotrophy (lower leg)
Cramps
Vibration sense ( 5 6 of 8)
Impaired kinesthesia
Impaired thermal sense
Intellectual impairment
Faciolingual fasciculation
Swallowing problems
Incontinence

10)

100

100
100
100
100
50g,h
2OkJ
jo'."
78
70
30
0

1
20

0
0
0

2Od
0
0

70
70f
30d
20

lood
40
10
30d
57
80
25
25k
20
30d
44
0

SCA2 (n
100
100
100
100
94'
31k~'
38

'J

77"l
86
71
37
5

ok,l

4Fh
26',d
10
5
0
0
33g,h
29g
1
24d
5d,k
86d
8 1'
29h
25d
80d
75d
14
39k
25',d
11
74
33d
O'ak

Frequency of symptoms expressed as percentages.

Significant differences compared with " Y C A 1 , ",f.JSCA2,C.g.kSCA3,and d,h.'SCA6:
SCAl, 2, 3, and 6 = spinocerebellar ataxia types 1, 2, 3, and 6, respectively.

after several years with ataxia, whereas in another family various degrees of hypogonadism are observed.

Comparison of ELectrophysioLogicaL Findings in SCAI,

SCA2, SCA3, and SCAG
All subforms of SCA presented with peripheral neuropathy in a substantial number of patients (see Table 2).
In patients with peripheral signs, frequent causes of
polyneuropathy such as diabetes, alcoholism, uremia,
exposure to environmental toxins, vitamin deficiency,
and carcinoma were excluded. Comparison of electrophysiological findings demonstrated significantly slower
motor nerve conduction velocities and prolonged F
waves in the tibial and peroneal nerves of SCAl patients compared with SCA2, SCA3, and SCA6 patients
(Fig 2A and B). No significant differences between
subgroups were found for distal latency and amplitude
of EMAPs of the tibial and peroneal nerve. But distal

21)

SCA3 (n = 60)

SCAG (n

100
100
98
93
loob
94'4
98"'
1O",'
59
70

100
100

5 bd
5
79h.'.l
ISh

3h
7
5
3

5
4F
68d3f
62d,J
44'
4 8'
80h
55h
33h
44l
64
55
18
91 d

27)

100

100
100

94'4

961.1
95'''
69
89
24'
0
4 p g 4

9f
4b
4
4
0"
0
Of
43'
35'

Oa,b,k

30'
57"h
229"
OfG
oa,h,k

53b
57b
17
22k

5'

Oh

3jh
75
29d

53
6b,c

OW

< 0.05; '.""."p < 0.01$+k,'p

< 0.001

latencies were prolonged in the tibial nerve (>4.7

msec) in 25% of SCAl, 43% of SCA2, 30% of SCA3,
and 18% of SCAG patients. EMAPs of the abductor
hallucis muscle were decreased (<1O.O mV) in 50% of
SCAI, 29% of SCA2, 53% of SCA3, and 9% of SCAG
patients. Sensory nerve conduction studies of the sural
nerve revealed decreased SNAPS (<10.0 pV) in many
patients of all subgroups of ataxia (SCA1, 50%; SCA2,
86%; SCA3, 74%; and SCA6, 56%). However, SNAP
was significantly better preserved in SCAI and SCA6
than in SCA2 and SCA3 patients (see Fig 2C). No
differences between subgroups were found for sensory
conduction velocity. Needle electromyography disclosed chronic neurogenic changes mostly in accord
with abnormalities in nerve conduction studies. Pathological spontaneous activity was rare in all subgroups.
MEPs to upper (FDI) and lower limbs (TA) revealed
normal or mildly prolonged peripheral and central mo-

Schols et al: Phenotypes in Dominant Ataxias 927

.N.

.Y

**

tibialis

** ***

N. peronaeus

* *

* *** I

**

* II

SCAl

SCA2

SCA3

SCA6
10

ml

18

Peripheral motor couduction time to FDI [ms]

-3
Y

88

RN. tibialis IN. peronaeus

--

Fig 3. Motor evoked potentiah in SCAI, S W , S C B , and

SCAG. Peripheral motor conduction time to the j r s t dorsal
interosseus muscle (FDI) of >18 msec (normal, < 1 6 5 msec)
and central motor conduction time of > 10 msec (normal,
c8.5 msec) are found exclusively in SCAI. SC41, 2,3, and
6 = spinocerebellar ataxia types I , 2, 3, and 6 respectively.

SCAl

SCAl

SCA2

SCA2

SCA3

SCA6

SCA3

SCA6

Fig 2. Nerve conduction studies in S C A I , SOL?,SCA3, and

SCAd Motor nerve conduction velocity of tibial and peroneal
nerve is significantly slower (A) and minimal F-wave latency
signijcantly prolonged (B) in SCAl compared with other
forms of SCA. Senso y neuropathy with reduced sural nerve
action potentiah is more severe in SCA2 and SCA3 than in
SCAI and SCA6 (C). Signtj%ant dzferences compared with
x ** ***
, , SCAl and with 'SCAd. *, "p .< 0.05; "9 <
0.01; *
<*
0.001.
I
Normal values o f our laboratory: peroneal and tibial nerve, motor nerve conduction velocity =
>42 mlsec; minimal F-wave latency = ~c56.0msec; sural
nerve, sensory nerve action potential = =.10.0 pV SCAl, 2,
3, and 6 = spinocerebellar ataxia types I, 2, 3, and 6, respectively.

tor conduction times (PMCT and CMCT) in all patients with SCA2, SCA3, and SCA6 regardless of clinical affection of the peripheral or central motor
pathways (Fig 3). In SCA1, PMCT or CMCT to FDI
was markedly prolonged in every recording. PMCT to
FDI exceeded 18.0 msec (normal, <16.5 msec) in all
patients with a duration of more than 5 years, and

928

Annals of Neurology

Vol 42

No 6

December 1997

CMCT to FDI exceeded 10.0 msec (normal, <8.5

msec) in all SCAl patients at least on one side. MEP
results were specific for SCAl with no overlap to
SCA2, SCA3, and SCAG (see Fig 3).
VEPs revealed normal PlOO latency (5120 msec) in
all SCA patients apart from 1 SCAl (123 and 121
msec), 1 SCA2 (121 and 119 msec), and 2 SCA3 patients (127 and 120; 126 and 121 msec). Mean PI00
amplitude was significantly smaller in SCAl (4.0 2
2.6, n = 10, p < 0.05), SCA2 (4.3 t 1.6, n = 12,
p < 0.01), and SCA3 (4.1 2 2.0, n = 5 6 , p < 0.001)
compared with SCA6 (6.8 i 3.3, n = IS). Amplitudes were significantly reduced (<3.0 pV) in four of
10 SCAl, four of 12 SCA2, 18 of 56 SCA3, and one
of 18 recordings in SCAG patients (frequencies of reduced amplitudes are not significantly different between subgroups). All patients with prolonged PI00 latency had reduced amplitudes.
AEPs were frequently difficult to record due to insufficient relaxation. There were peripheral conduction
deficits (wave I prolonged or missing) in 2 of 3 SCA1,
1 of 6 SCA2, 5 of 22 SCA3, and 3 of 8 SCAG patients.
Signs of brainstem affection (deformed wave 111, IV, or
V, or prolonged interpeak latency 1-111, 111-V, or I-V)
were found in 0 of 3 SCA1, 2 of 6 SCA2, 7 of 22
SCA3, and 0 of 8 SCAG patients.
SEPs were difficult to record appropriately without
sedation and were available only in a small number of
patients, without specific findings between subgroups
of SCA.

MRl in SCAI, SCA2, SCA3, and SCAG

MRI revealed global atrophy of brain structures in the
posterior fossa in most SCAl and SCA2 patients, consistent with the neuropathological concept of olivopontocerebellar atrophy (OPCA) (Table 3). Atrophy was
more pronounced and developed earlier in the course

Table 3. MRI in SCAI, SCA2, SCA3, and SCAG

~

SCAl (n

Upper cerebellar vermis

Lower cerebellar vermis
Cerebellar hemispheres
Middle cerebellar peduncle
Fourth ventricle
Pontine base
Cervical spinal cord
MRI

0 to
0 to

++
++

Oto++
+to++
to
to
0 to

+ ++
+ ++
+

2)

SCA2 (n

3)

++ to +++
+ t o +++
+ to +++
i s to +++
++ to +++
++to+++
+ + t o +++

~~

SCA3 (n
+to
0 to
0 to
0 to
0 to
0 to

+++
++
++
++
+++
++

Oto++

16)

~~~

SCAG (n = 10)

+ to +++
0 to +++
+ to +++
0 to +
0 to
0 to
0 to

++

+
+

magnetic resonance imaging; SCA1, 2, 3, and 6 = spinocerebellar ataxia types 1, 2, 3, and 6, respectively; 0 = normal;
mild atrophy; + = moderate atrophy; + + + = severe atrophy.

of the disease in SCA2 patients compared with SCAl.

In SCA3, MRI changes were most variable and ranged
from near normal to moderate atrophy of the cerebellum and/or the brainstem including the cervical spinal
cord. Enlargement of the fourth ventricle was present
in most SCA3 patients. MRI abnormalities in SCA6
patients were rather homogeneous and consisted of
pure cerebellar atrophy of both vermis and hemispheres, consistent with the pathological concept of
cerebellar cortical atrophy. Brainstem structures were
near normal in SCAG patients, even in patients with
swallowing problems and gaze limitation (see Table 3 ) .
In all subgroups of SCA, MRI changes were more pronounced in patients with long-standing disease than at
the beginning of symptoms.
Discussion
In this study we searched for characteristic phenotypic
features of SCA1, SCA2, SCA3, and SCA6. In a series
of 77 ADCA families, the SCA3 mutation appeared to
be by far the most frequent cause of ADCA in our
cohort, responsible for more than 40% of dominantly inherited ataxias. SCAl and SCA2 both represented
about 10% of ADCA families and SCAG was more frequent (22%). For 13 ADCA families (17%),CAG expansions in the SCAl, SCA2, SCA3, and SCAG genes
have not been found. However, frequency distribution
of SCA mutations may vary considerably in different
geographic regions due to founder effects [16]. Our
data represent the distribution in the western parr of
Germany.
Our series includes 7 patients with apparently sporadic ataxia in whom the SCAG mutation was found.
Apart from a de novo mutation in SCA2 [26], SCAG is
the first mutation that gives a molecular basis to some
cases from the group of patients with idiopathic sporadic cerebellar ataxia. Therefore, we recommend study
of the SCAG mutation in ataxia patients with apparently sporadic disease, especially with late onset.
Age at onset was influenced negatively by CAG repeat length in all subforms of SCA. CAG repeat length
is responsible for approximately 70% of the variability
in age at onset in SCA1, SCA2, SCA3, and SCA6.

However, the effect of one CAC unit on age at onset

was different for each SCA type (see Fig 1). It is noteworthy that the expanded alleles in SCAG contain
CAG numbers that are in the normal range of the
SCA1, SCA2, and SCA3 repeats, suggesting that the
expanded polyglutamine tract itself is not the diseasecausing factor. However, repeat length is an important
factor influencing progression rate and phenotype, as
has been shown for SCA3 [27, 281. Other genetic or
nongenetic factors must exist in addition to repeat
length to explain the full range of variability in onset
age and phenotype in SCAs.
The phenotypes of SCA1, SCA2, SCA3, and SCA6
showed large variability within the diseases and a substantial overlap between them (see Table 2). Despite
the great variety of symptoms accompanying ataxia, no
clinical sign was restricted to one genetically defined
subgroup of SCA. However, there are some constellations of clinical, electrophysiological, and MRI findings
that appear to be characteristic for either SCA1, SCA2,
SCA3, or SCA6 (Table 4). The combination of slow
saccadic eye movements, areflexia, myoclonus, and action or postural tremor suggests the SCA2 mutation.
Our SCA2 data confirm similar findings of other
groups [lS, 19, 211.
SCA3 frequently presents with severe cerebellar oculomotor signs such as saccadic smooth pursuit, gaze
evoked nystagmus, and diplopia. These are similar in
SCA6, but SCA3 patients typically show additional
symptoms, such as pronounced spasticity in younger
patients (onset before 40 years) or severe peripheral
neuropathy in older patients (onset after 40 years).
Furthermore, temperature discrimination at the limbs
and also ofien at the trunk is frequently impaired in
SCA3 patients. Faciolingual fasciculation, bulging
eyes due to lid retraction, and dystonia are reported to
be characteristics of MJD [29]. Although MJD is
shown to be genetically identical with SCA3 [16],
these characteristic symptoms of MJD were rare in
SCA3 patients of our series and were not restricted to
SCA3, apart from dystonia (see Table 2).
SCAG is characterized by a predominantly cerebellar
syndrome and frequently late onset, after 55 or even 60

Schols et al: Phenotypes in Dominant Ataxias

929

Table 4. Characteristic Findings in SCAl, SCA2, SCAS, and SCAG Patients

~

SCAl
Onset beyond 55 yr
Diplopia
Impaired smooth pursuit
Gaze evoked nystagmus
Slow saccades
Tremor
Myoclonus
Dystonia
Spasticity
Babinski sign
Hyperreflexia
Hyporeflexia
Amyotrophy (lower leg)
Weakness
Impaired thermal sense
CMCT to FDI > I 0 msec
PMCT to FDI >18 msec
MRI

scA2

scA3
t

++
++
+++
+
++

++
+
++
-

-+

+
+
++
+
2
+
+++
+++

+
2
+++
+
+
++

OPCA

OPCA

++++
++++

++
++
++++
++++

t
?

If:

+++

Frequency of symptoms are symbolized as follows:

>90%.

+++

SCAG

+++
++
++
++
++
++
++++
-

++
++
+

= 0%; ? = 510%;

+=

11-30%;

IV

CA

++ = 31-60%; +++ = 61-90%; ++++ =

SCA1, 2, 3, and 6

= spinocerebellar ataxia type 1, 2, 3, and 6, respectively; CMCT = central motor conduction time: FDI = first dorsal
interosseus muscle; PMCT = peripheral motor conduction time in motor-evoked potentials: MRI = magnetic resonance imaging; OPCA =
olivopontocerebellar atrophy; IV = enlargement of the fourth ventricle; CA = cerebellar atrophy.

years of age (see Table 4 and Fig 1). In contrast to

SCA3, pronounced spasticity or severe peripheral neuropathy do not occur in SCA6. Extensor plantar responses, weakness, or amyotrophy are essentially absent
in SCA6. Diplopia is frequent, but seldom disabling,
in SCA6. Consequently, SCAG patients were not interested in testing prism glasses to compensate for diplopia, which is helpful to many SCA3 patients. Oculomotor findings in SCAG differ significantly from SCAl
and SCA2 but not from SCA3 (see Table 2).
In our series we did not find clinical signs to be typical for SCAl. However, MEP findings with markedly
prolonged C M C T and PMCT appear to be specific for
SCAl, independent of clinical affections of the central
or peripheral motor pathways. Therefore, MEP is a
powerful, noninvasive tool for predicting an underlying
SCAl mutation in dominant ataxia patients. Furthermore, MEP can demonstrate subclinical affections of
the pyramidal tract in SCA1. Nerve conduction studies
and VEPs reveal further differences in electrophysiological findings between SCAl and other forms of SCA.
These are mainly statistical values, which are less helpful in the management of individual patients.
Our data are in agreement with those of Dubourg
and colleagues [17] and Durr and associates [18], in
which no clinical differences were found between
SCAl and SCA3. Only Burk and co-workers [all described more pyramidal and fewer peripheral signs in
SCAl compared with SCA3. Their SCA3 cohort had
the latest age at onset of all studies and may therefore
include more patients with peripheral neuropathy,

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December 1397

which is associated with the late-onset form of SCA3

[28]. We found differences between SCAl and SCA3
in oculomotor abnormalities and temperature discrimination, parameters not analyzed in the other studies.
MRI scanning enabled us to compare brain morphology in SCAl, SCA2, SCA3, and SCAG patients in
vivo (see Tables 3 and 4). MRI scanning revealed
OPCA in SCAl and SCA2. OPCA was more pronounced and developed earlier in the disease in SCA2
compared with SCAl. In SCA3, atrophy was mild, in
contrast to severe clinical signs in many patients; however, the fourth ventricle was enlarged in most SCA3
patients. SCAG is characterized in MRI by pancerebellar atrophy, widely sparing brainstem structures. The
diagnostic value of MRI in SCA1, SCA2, SCA3, and
SCAG is diminished, however, by a substantial overlap
of MRI changes between SCA1, SCA2, SCA3, and
SCAG patients, due to high variability of MRI morphology in all subforms of SCA.
The retrospective character of our study and variations in image acquisition determine the relevance of
our findings. Our MRI data for SCA1, SCA2, and
SCA3 patients are in good agreement with a prospective study by Burk and co-workers [21] who used a
standard examination program and an image analyzer
for quantitative volume evaluation of defined brain areas. Furthermore, our MRI results correspond to postmortem examinations in SCA1, SCA2, SCA3, and
SCAG patients [18, 20, 30-341, In SCAl, neuropathological abnormalities consist of Purkinje cell loss, degeneration of the dentate nucleus, inferior olives, and

pontine nuclei IX, X, and XI, as well as atrophy of

spinocerebellar tracts and posterior columns [ 18, 30,
311. In a similar manner, in SCA2, severe Purkinje cell
loss and atrophy of inferior olives, pontine nuclei, and
substantia nigra have been described consistently with
OPCA [20, 321. SCA3 pathology is different from
SCAl and SCM by sparing the cerebellar cortex and
inferior olives. Degeneration in SCA3 involves the dentate nucleus, spinocerebellar tracts, intermediolateral
column, anterior horn cells, and motor cranial nerve
nuclei as well as the substantia nigra [18, 331. In 2
deceased SCAG patients, the cerebellum revealed nearly
total loss of Purkinje cells, moderate loss of granule
cells, dentate nucleus neurons, and inferior olivary neurons, but no significant atrophy of the brainstem [8,
341. These findings are consistent with the pathoanatomical concept of cerebello-olivary degeneration or
cerebellar cortical atrophy. However, neuropathological
changes are also variable [30, 331.
Synopsis of clinical, electrophysiological, and MRI
results enables the physician experienced in ataxias to
guess the underlying mutation in most ADCA patients.
But predictions are not reliable for individual patients.
We found it most difficult to foresee the ADCA families with unknown mutations (SCA4, SCA5, and unmapped types). The complex overlap between the SCA
phenotypes and the high variability within SCA subforms explains why neurologists during the past one
hundred years experienced immense problems when attempting to classify hereditary ataxias satisfactorily by
means of underlying defects, clinical course, or prognosis. It is the merit of Anita Harding that she defined
ADCA type I as a distinct group of ataxias that are
difficult to split into disease entities, with clinical tools
even today, without the help of molecular genetics.
ADCA type I1 is characterized by pigmentary retinal
degeneration associated with ataxia and is genetically
defined as SCA7 [9, 10, 221. It will be interesting to
learn whether the ADCA type 111, compromising pure
cerebellar atrophy, really exists in terms of its genetic
classification. SCA5 is supposed to present with pure
cerebellar symptoms, but there is only one family reported [7].
Even in this family, early-onset cases show
bulbar involvement. The SCA5 phenotype appears
similar to SCAG, which primarily affects the cerebellum but is not pure cerebellar disease.
We recommend differentiating ADCA, according to
the disease-causing mutations, into SCAl through
SCA7 subtypes. This classification appears mandatory,
because the different mutations most likely represent
different pathophysiology leading to distinct neuronal
damage. Understanding of the underlying pathophysiology is essential for the development of specific therapies. A first example may arise for SCA6, in which the
disease-causing mutation is located in the gene for the
a,,-subunit of the voltage-dependent calcium channel.

This type of calcium channel is essential for Purkinje

and granule cell survival [35], explaining why degeneration is restricted mainly to the cerebellar cortex in
SCA6. Until now, the physiological functions of the
other SCA genes were not known. However, in the
a,,-calcium channel gene in which the (CAG)n repeat
expansion is responsible for SCA6, point mutations
have been identified recently that cause two further
neurological disorders, episodic ataxia type 2 (EA2)
and familial hemiplegic migraine [36]. Because EA2 responds to acetazolamide and because calcium channel
blockers reduce the frequency of migraine, candidates
for therapeutic trials exist on a pathophysiological rationale in a first form of SCA. In addition, the development of transgenic animals [37-331 provides potent
models to improve the understanding of the underlying
pathophysiology in SCAs and related disorders and
supports the likelihood of effective treatment in the
future .

This study was supported in part by the Deutsche Heredo-Ataxie

Gesellschaft, Stuttgart, Germany. Work in the laboratory of O.R. is
supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany.
We thank all the patients who participated in this study. We are
grateful to Ana Maria Menezes Vieira-Saecker for her excellent technical assistance.

References
1. Harding AE. The hereditary ataxias and related disorders.
Edinburgh: Churchill Livingstone, 1984
2. Yakura H, Wakisaka A, Fujimoto S, Itakura K. Hereditary
ataxia and HLA genotypes. N Engl J Med 1374;291:154-155
3. Gispert S, Twells R, Orozco G, et al. Chromosomal assignment
of the second locus for autosomal dominant cerebellar ataxia
(SCA2) to chromosome 12q23-24. I . Nat Genet 1993;4:295299
4. Stevanin G, Le Guern E, Ravise N, et al. A third locus for
autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus.
Am J Hum Genet 1994;54:11-20
5. Takiyama Y, Nishizawa M, Tanaka H , et al. The gene for
Machado-Joseph disease maps to human chromosome 14q. Nat
Genet 1993;4:300-303
6. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant
spinocerebellar ataxia with sensory axonal neuropathy (SCA4):
clinical description and genetic localization to chromosome
16q22.1. Am J H u m Genet 1996;59:392-399
7. Ranum LPW, Schur LJ, Lundgren JK, et al. Spinocerebellar
ataxia type 5 in a family descended from rhe grandparenrs of
President Lincoln maps to chromosome 1 1. Nat Genet 1974;
8:280-284
8. Zhuchenko 0,
Bailey J, Bonnen P, et al. Autosomal dominant
cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a,A-voltage-dependent calcium channel. Nat
Genet 1997;15:62-69
9. Benomar A, Krols L, Stevanin G, et al. The gene for autosomal
dominant ataxia with pigmentary macular dystrophy maps to
chromosome 3p12-p21.1. Nat Genet 1995;10:84-88
10. Gouw LG, Kaplan CD, Haines J H , et al. Retinal degeneration

Schols et al: Phenotypes in Dominant Ataxias

931

characterizes a spinocerebellar ataxia mapping to chromosome

3p. Nat Gener 1995;10:89-93
11. Orr HT, Chung M, Banfi S, er al. Expansion of an unstable
rrinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat
Genet 1993;4:221-226
12. Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;14:269-276
13. Sanpei K, Takano H, Igarashi S, et al. Identification of the
spinocerebellar ataxia type 2 gene using a direct identification of
repeat expansion and cloning technique, DIRECT. Nat Genet
1996;14:277-284
14. Imbert G, Saudou F, Yvert G, et al. Cloning of the gene for
spinocerebellar ataxia 2 reveals a locus with high sensitivity to
expanded CAG/glutamine repeats. Nat Gener 1996; 14:28529 1
15. Kawaguchi Y, Okamoro T, Taniwaki M, et al. CAG expansions
in a novel gene for Machado-Joseph disease a t chromosome
14q32.1. Nat Genet 1994;8:221-228
16. Schols L, Vieira-Saecker AMM, Schols S, et al. Trinucleotide
expansion within the MJDI gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA
patients. Hum Mol Genet 1995;4:1001-1005
17. Dubourg 0, Diirr A, Cancel G, et al. Analysis of the SCAl
CAG repeat in a large number of families with dominant ataxia:
clinical and molecular correlations. Ann Neurol 1995;37: 176180
18. Diirr A, Stevanin G, Cancel G, et al. Spinocerebellar ataxia 3
and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 1996;39:490-499
19. Orozco G, Nodarse Fleites A, CordovCs Sagaz R, Auburger G.
Autosomal dominant cerebellar ataxia: clinical analysis of 263
patients from a homogeneous population in Holguin, Cuba.
Neurology 1990;40:1369-1375
20. Durr A, Smadja D, Cancel G, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three
unrelated SCA2 families. Brain 1995;118:1573-1581
21. Burk K, Abele M, Fetter M, et al. Aucosomal dominant cerebellar ataxia type I. Clinical features and MRI in families with
SCAl, SCA2 and SCA3. Brain 1996;l 19:1497-1505
22. Harding AE. The clinical features and classification of the late
onser autosomal dominant cerebellar ataxias. Brain 1982;105:
1-28
23. Schols L, Riess 0, Schols S, et al. Spinocerebellar ataxia type 1:
clinical and neurophysiological characteristics in German kindreds. Acta Neurol Scand 1995;92:478-485
24. Riess 0,
Laccone FA, Gispert S, et al. Trinucleotide expansion
in German SCA2 patients. Neurogenetics 1997;1:59-64
25. Riess 0, Schols L, Bottger H, et al. SCA6 is caused by mod-

932 Annals of Neurology

Vol 42

No 6

December 1997

erate CAG expansion in the aIA-voltage dependent calcium

channel gene. Hum Mol Genet 1997;6:1289-1293
26. Schols L, Gispert S, Vorgerd M, et al. Spinocerebellar ataxia
type 2: genotype and phenotype in German kindreds. Arch
Neurol 1997;54:1073-1 080
27. Klockgether
Kramer 6, Liidtke R, et al. Repeat length and
disease progression in spinocerebellar ataxia type 3. Lancet
1996;348:830 (Letter)
28. Schols L, Amoiridis G, Epplen JT, et al. Relations between genotype and phenotype in German patients with the MachadoJoseph disease mutation. J Neurol Neurosurg Psychiatry 1996;
6 1:466-470
23. Lima L, Coutinho P. Clinical criteria for diagnosis of MachadoJoseph disease: report of a non-Azorean Portuguese Family.
19-322
Neurology 1>)80;30:3
30. Schut JW. Hereditary ataxia: clinical study through six generations. Arch Neurol Psychiatry 1950;63:535-568
31. Sparado M, Giunti P,Lulli P, et al. HLA-linked spinocerebellar
ataxia: a clinical and genetic study of large Italian kindreds.
Acta Neurol Scand 1992;85:257-265
32. Orozco G, Estrada R, Perry TL, et al. Dominantly inherired
olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 1989;93:
37-50
33. Sequeiros j, Coutinho P. Epidemiology and clinical aspecrs of
Machado-Joseph disease. In: Harding AE, Deufel T, eds. Advances in neurology, vol 61. New York: Raven Press, 1993:
139-153
34. Subramony SH, Fratkin JD, Manyam BV, Currier RD. Dominantly inherited cerebello-olivary atrophy is not due to mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or
denrato-rubro-pallido-luysian atrophy locus. Mov Disord 1996;
111174-180
35. Fletcher CF, Lutz CM, OSullivan T N , et al. Absence epilepsy
in tottering mutant mice is associated with calcium channel defecrs. Cell 1996;87:607-617
36. Ophoff RA, Tenvindt GM, Vergouwe MN, et al. Familial
hemiplegic migraine and episodic ataxia type-2 are caused by
mutations in rhe Ca2 channel gene CACNLlA4. Cell 1996;
87~543-552
37. Burright EN, Clark HB, Servadio A, et al. SCAl transgenic
mice: a model for neurodegeneration caused by an expanded
CAG trinucleotide repeat. Cell 1995;82:937-948
38. Ikeda H, Yamaguchi M, Sugai S, et al. Expanded polyglutamine in the Machado-Joseph disease protein induces cell
death in vitro and in vivo. Nat Genet 1996;13:196-202
39. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the H D
gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in rransgenic mice. Cell 1996;
87:493-506

r,