Autosomal Dominant Cerebellar Ataxia: Differences in G efined Subtypes?

Phen .o b ItYplC D

.eneti .tally

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 cere- bellar 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 dys- arthria as well as cerebellar oculomotor disturbances caused by degeneration of the cerebellum and/or its af- ferent and efferent pathways. The cerebellar syndrome is frequently associated with signs of cerebral, pyrami- dal, extrapyramidal, bulbar, spinal, and peripheral ner- vous system involvement in highly variable combina- tions. 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 pic- tures and broad overlap between families.

Recently, ADCA is increasingly characterized by the underlying genetic defects and referred to as spinocer- ebellar 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-

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

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

some 19p (SCAG) [8], and chromosome 3p (SCA7) [9, 101. The mutations responsible for SCAl, SCA2, SCASIMJD, and SCAG have been identified as unsta- ble expansions of CAG trinucleotide repeats in coding regions of the responsible genes [8, 11-15]. Although SCA3 and MJD show clinical differences, both pheno- types 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 pheno- types for SCA1, SCA2, SCA3, and SCAG. Initial stud- ies found the clinical picture of SCAl and SCA3 pa- tients to be very similar [17, 181. SCA2 is reported to present frequently with slow saccades, decreased re- flexes, and rarely with pyramidal tract involvement [ 19 -2 11. Direct comparisons of clinical and electro- physiological 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. Fur- thermore, we performed nerve conduction studies, mo-

Address correspondence to Dr Schols, Neurologische Klinik der Ruhr-Universitat, St Josef Hospital, GudrunstraBe 56, D-44791 Bo- chum, Germany.

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 geneti- cally 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 accord- ing 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 progres- sive ataxia associated with at least one of the following signs: dementia, ophthalmoplegia, rigidity, spasticity, sphincter dis- turbance, sensory deficits, weakness, amyotrophy, or abnor- mal reflex status. Families with pigmentary retinal degenera- tion characterizing ADCA type I1 or with pure cerebellar atrophy (ADCA type 111) were not observed in our series.

Electrophysio logical 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 veloc- ity, 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 sen- sory nerve studies. Electromyography using concentric needle electrodes was performed at least of the tibialis anterior mus- cle with a Counterpoint MK2 (Dantec, Skovlunde, Den- mark).

MEPs to the first dorsal interosseus (FDI) and tibialis an- terior muscle (TA) were performed by a standard technique with a Maglite magnetic stimulator (Dantec). Forty-nine pa- tients were examined for MEPs, including 9 patients with SCAl, 4 with SCA2, 31 with SCA3, and 5 with SCA6. Tib- ial 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, pon- tine 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 ven- tricle 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 re- ported 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 of clinical symptoms were compared by using the x2 test. Sta- tistical analysis of electrophysiological parameters were calcu- lated by analysis of variance followed by the Tukey-Kramer multiple comparison test.

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 misdiag- nosed 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 sev- enth 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 corre- lated 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 pa- tients, 2.5 years in SCA2, 2.2 years in SCA3, and 4.5 years in SCAG patients. Repeat lengths account for 65- 77% 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

70 8

' 40i 30 A 4 4 **

SCAG SCA2 SCAl SCA3 0

0 20 40 60 80

No. of CAG repeats

Fig 1. Inverse correlation of age at onset and number o f 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 S C X , SOB, and SC46

Course of the Disease in SCAl,

SCAl SCA2 SCA3 SCAG

Age at onset (yr) Mean 2 SD Range

Duration of disease (yr)

Mean 2 SD Range

Progression to walking aid (yr)

Mean t SD Range

Progression to wheel- chair

Mean 2 SD Range

n = 10 37 2 7" 3 1 4 2 n = 10

7 2 4 1-14 n = 4

6.0 2 4.2 2-1 1 n = 2

5.5 2 2.1 4-7

n = 2 1 n = 6 3 n = 2 7 3 2 2 1 2 " 3 6 2 9 " 5 3 2 1 1 12-49 15-56 30-71 n = 2 1 n = 6 3 n = 2 7

1 2 2 8 1 0 2 6 1 1 2 9 2-30 0.5-30 1-40 n = 8 n = 3 4 n = 1 4

9.4 Z 3.7 8.8 2 3.8 7.4 t 4.3 6-15 1-18 4-18 n = 3 n = 1 3 n = 9

9.7 2 0.6 13.9 2 5.5 18.6 = 9.5 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) com- pared 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 wheel- chair. 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 progres- sion in SCAl (see Table 1). Due to small numbers

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).

Comparison of Clinical Features in SCAI, SCX.2, SCX3, and SCAG Ataxia of gait and stance was present in all SCA pa- tients 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 dysar- thria. Cerebellar oculomotor signs differed significantly between subgroups (Table 2). Saccadic smooth pursuit and gaze evoked nystagmus were significantly less fre- quent 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 pa- tients. 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 ophthalmople- gia 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 affec- tion including spasticity and hyperreflexia were rare in SCA2 in contrast to the other forms of SCA. It is note- worthy that none of our SCAG patients had extensor plantar responses despite other signs of pyramidal in- volvement 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 tem- perature discrimination especially of the limbs but fre- quently 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 _ _

these differences were not significant. However, pro- gression rate was highly variable within every subform,

spinal and sensory origin with only minor cerebellar signs. One family has pronounced parkinsonian signs

926 Annals of Neurology Vol 42 No 6 December 1997

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

SCAl (n = 10) SCA2 (n = 21) SCA3 (n = 60) ~~

SCAG (n = 27)

Cerebellar dysfunction Ataxia of gait and stance Limb ataxia Dysarthria

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

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

Ocular motor disorders

Peripheral neuropathy

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

0 1 20

0 0 0

0 0

70 70f 30d 20

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

0

2Od

lood

100 100 100 100 94' 3 1 k~' 3 8 'J 77"l 86 71 37

5

4 F h 26',d 10 5 0 0

29g

24d

86d 8 1' 29h 25d 80d 75d 14 39k 25',d 11 74 33d

o k , l

33g,h

1 O'ak

5d,k

100 100 98 93

loob 94'4 98"' 1 O",' 59 70 5 bd 5

I S h

7 5 3 5 4F

68d3f 62d,J 44' 4 8' 80h 55h 33h 44l 64 55 18 9 1 d

79h.'.l

3h

5' 3 j h 75 29d

100 100 100 100 100 94'4 961.1 95''' 69 89 24' 0

4 p g 4

9f 4b 4 4 0" 0 Of

43' 35'

30' 5 7 " h 229"

OfG

53b 57b

22k Oh

Oa,b,k

oa,h,k

17

O W

53 6b,c

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.

< 0.05; '.""."p < 0.01 $+k,'p < 0.001

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

Comparison of ELectrophysioLogicaL Findings in SCAI, SCA2, SCA3, and SCAG All subforms of SCA presented with peripheral neurop- athy 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 electro- physiological findings demonstrated significantly slower motor nerve conduction velocities and prolonged F waves in the tibial and peroneal nerves of SCAl pa- tients 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

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 (

.N. tibialis N. peronaeus

- 3 88 Y

.- Y I w ** ** *** * *** I

RN. tibialis IN. peronaeus - -

SCAl SCA2 SCA3 SCA6

SCAl SCA2 SCA3 SCA6

SCAl SCA2 SCA3 SCA6

Fig 2. Nerve conduction studies in SCAI , 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 , , SCAl and with 'SCAd. *, "p .< 0.05; "9 <

0.01; **I < 0.001. Normal values o f our laboratory: pero- neal and tibial nerve, motor nerve conduction velocity = >42 mlsec; minimal F-wave latency = ~c56.0 msec; sural nerve, sensory nerve action potential = =. 10.0 pV SCAl, 2, 3, and 6 = spinocerebellar ataxia types I , 2, 3, and 6, re- spectively.

x ** ***

tor conduction times (PMCT and CMCT) in all pa- tients with SCA2, SCA3, and SCA6 regardless of clin- ical 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, 18 msec (normal, 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.

CMCT to FDI exceeded 10.0 msec (normal,

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

SCAl (n = 2) SCA2 (n = 3 ) SCA3 (n = 16) SCAG (n = 10)

Upper cerebellar vermis 0 to ++ ++ to +++ + t o +++ + to +++ Cerebellar hemispheres O t o + + + to +++ 0 to ++ + to +++ Middle cerebellar peduncle + t o + + i s to +++ 0 to ++ 0 to +

Cervical spinal cord 0 to + + + t o +++ O t o + + 0 to +

Lower cerebellar vermis 0 to ++ + t o +++ 0 to ++ 0 to +++

Fourth ventricle + to ++ ++ to +++ 0 to +++ 0 to ++ Pontine base + to ++ + + t o + + + 0 to ++ 0 to +

MRI = 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 cerebel- lum 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 hemi- spheres, 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 pro- nounced 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 dominant- ly inherited ataxias. SCAl and SCA2 both represented about 10% of ADCA families and SCAG was more fre- quent (22%). For 13 ADCA families (17%), CAG ex- pansions 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 spo- radic 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 spo- radic cerebellar ataxia. Therefore, we recommend study of the SCAG mutation in ataxia patients with appar- ently sporadic disease, especially with late onset.

Age at onset was influenced negatively by CAG re- peat 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 note- worthy 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 disease- causing 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 sub- stantial 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 constella- tions 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 ac- tion 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 ocu- lomotor 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 scA2 scA3 SCAG

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 > I0 msec PMCT to FDI >18 msec MRI

5 ++ + ++ -

+++ + + ++ + 2 + +++ +++ OPCA

++ ++ +++ + ++ -+ + 2 +++ + + ++

OPCA

t +++ ++++ ++++ ? t ? If: +++ ++ ++ ++ ++ ++ ++++ -

-

IV

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

++ ++ + -

-

+

CA

Frequency of symptoms are symbolized as follows: - = 0%; ? = 510%; + = 11-30%; ++ = 31-60%; +++ = 61-90%; ++++ = >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 neu- ropathy do not occur in SCA6. Extensor plantar re- sponses, weakness, or amyotrophy are essentially absent in SCA6. Diplopia is frequent, but seldom disabling, in SCA6. Consequently, SCAG patients were not inter- ested in testing prism glasses to compensate for diplo- pia, which is helpful to many SCA3 patients. Oculo- motor 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 typ- ical for SCAl. However, MEP findings with markedly prolonged CMCT 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. Further- more, MEP can demonstrate subclinical affections of the pyramidal tract in SCA1. Nerve conduction studies and VEPs reveal further differences in electrophysiolog- ical findings between SCAl and other forms of SCA. These are mainly statistical values, which are less help- ful 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 [a l l de- scribed 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,

which is associated with the late-onset form of SCA3 [28]. We found differences between SCAl and SCA3 in oculomotor abnormalities and temperature discrim- ination, parameters not analyzed in the other studies.

MRI scanning enabled us to compare brain mor- phology 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 pro- nounced 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; how- ever, the fourth ventricle was enlarged in most SCA3 patients. SCAG is characterized in MRI by pancerebel- lar 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 mor- phology in all subforms of SCA.

The retrospective character of our study and varia- tions in image acquisition determine the relevance of our findings. Our MRI data for SCA1, SCA2, and SCA3 patients are in good agreement with a prospec- tive study by Burk and co-workers [21] who used a standard examination program and an image analyzer for quantitative volume evaluation of defined brain ar- eas. Furthermore, our MRI results correspond to post- mortem examinations in SCA1, SCA2, SCA3, and SCAG patients [18, 20, 30-341, In SCAl, neuropatho- logical abnormalities consist of Purkinje cell loss, de- generation of the dentate nucleus, inferior olives, and

930 Annals of Neurology Vol 42 No 6 December 1397

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 den- tate 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 neu- rons, but no significant atrophy of the brainstem [8, 341. These findings are consistent with the pathoana- tomical 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 fam- ilies with unknown mutations (SCA4, SCA5, and un- mapped types). The complex overlap between the SCA phenotypes and the high variability within SCA sub- forms explains why neurologists during the past one hundred years experienced immense problems when at- tempting to classify hereditary ataxias satisfactorily by means of underlying defects, clinical course, or prog- nosis. 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 re- ported [7]. Even in this family, early-onset cases show bulbar involvement. The SCA5 phenotype appears similar to SCAG, which primarily affects the cerebel- lum 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 pathophysi- ology is essential for the development of specific ther- apies. 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 degener- ation 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 re- sponds to acetazolamide and because calcium channel blockers reduce the frequency of migraine, candidates for therapeutic trials exist on a pathophysiological ra- tionale in a first form of SCA. In addition, the devel- opment 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, Ger- many.

We thank all the patients who participated in this study. We are grateful to Ana Maria Menezes Vieira-Saecker for her excellent tech- nical assistance.

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