Brain (1992), 115, 1647-1654

AUTOSOMAL DOMINANT PURE CEREBELLAR ATAXIA NEUROLOGICAL AND GENETIC STUDY by M. FRONTALI, 1 M. SPADARO, 2 P. GIUNTI, 2 F. BIANCO, 2 C. JODICE, 3 F. PERSICHETTI, 3 G. B. COLAZZA, 2 P. LULLI, 4 L. TERRENATO 3 and C. MOROCUTTI 2

ABSTRACT A family with late-onset autosomal dominant pure cerebellar ataxia was studied both neurologically and genetically. Neuroimaging and electrophysiological results were in agreement with the clinical evidence showing involvement of the cerebellar system only, even many years after onset. No atrophy of inferior olives was observed by magnetic resonance imaging, while cerebellar atrophy was extremely marked. A very slow disease progression was observed in all patients. The disease can be differentiated from autosomal dominant olivo-ponto-cerebellar atrophies, and in particular from spinocerebellar ataxia type 1 mapping on chromosome 6p, which shows an early multisystemic involvement and a more rapid progression toward inability. A genetic study of the family with the 6p DNA marker D6S89 closely linked to the spinocerebellar ataxia type 1 locus was performed. Results showed significant exclusion of a linkage between the disease and the marker within a distance of 8.5% recombination, indicating that genetic heterogeneity underlies phenotypic differences. INTRODUCTION

Autosomal dominant cerebellar ataxias are a heterogeneous group of late onset disorders for which no agreement about nosology has been so far reached. Classifications based on pathological criteria (e.g. Greenfield, 1954) usually separate a cerebellar cortical atrophy (Holmes' type) with a variable degree of inferior olive degeneration from olivoponto-cerebellar atrophies involving additional alterations of brainstem and spinal cord. However, when pathological and clinical evidence are matched, this distinction becomes far less clear-cut. Often patients with a cerebellar cortical atrophy at necropsy showed clinical involvement of other neurological systems in addition to the cerebellar one (Akelaitis, 1938; Richter, 1940, 1950; Hall etal, 1941; Weber and Greenfield, 1942). Harding (1982) in her classification of dominantly inherited ataxias based on clinical criteria, separates a pure cerebellar ataxia from ataxias associated with non-cerebellar signs, independently from the pathological picture. The pure form, according to the author, is very rare being described only in two families (Hoffman et al., 1971; Harding, 1982). Since then a few additional families have been reported in the context of studies on various forms of inherited ataxias: two with ataxia Holmes' type (Sasaki et al., 1988) Correspondence to: Dr Marina Frontali, Istituto di Medicina Sperimentale CNR, Via Marx 15, Rome 00137, Italy. © Oxford University Press 1992

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(From the lInstituto di Medicina Sperimentale CNR, the 2lstituto di Clinica delle Malattie Nervose e Mentali, Universita La Sapienza, the 3Dipartimento di Biologia, Universita Tor Vergata, and the 4Dipartimento di Medicina Sperimentale, Universita La Sapienza, Rome, Italy)

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SUBJECTS AND METHODS The family was of Italian (Calabrian) origin with a clear autosomal-dominant transmission of the disease over three generations (Fig. 1). All living patients were clinically examined by at least one of the authors. Patient 1-1 who died aged 50 yrs as a result of an accident was affected by tremors and gait imbalance.

0- o 3 - 6 D6S89

[ 2 •13] 2

o 2

-6

6 • 13

6-

Ill 6 - 13

2

-6

FIG. 1. Pedigree of the family with D6S89 genotypes.

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and one with a pure cerebellar ataxia (Polo et al., 1991). Unfortunately, no detailed description of patients has been reported by these authors. One family described by Trouillas et al. (1990) showed a pure cerebellar ataxia but also some degree of pons atrophy at computerized tomography (CT) scan. Overall no study provides a full picture of clinical, neuroimaging and electrophysiological aspects of inequivocally pure cerebellar ataxia. Genetic mapping, recently improved by the recombinant DNA techniques, provides nosography with an additional criterion based on gene location. At present a distinction must be drawn between the dominant ataxias in which the disease locus (spinocerebellar ataxia type 1; Morton et al., 1980) maps on chromosome 6p23, very near the D6S89 marker (Ranum et al., 1991; Zoghbi et al., 1991) and those mapping elsewhere. So far the ataxias found in tight linkage with D6S89 belong to the olivo-ponto-cerebellar atrophy group with a cerebellar plus syndrome (type 1 according to Harding's classification), although some families with a similar phenotype turned out to be unlinked to 6p markers (e.g. Auburger et al., 1990). Still under question is whether other types of late-onset autosomal dominant ataxia might be related to the same 6p gene. A family with a dominantly inherited pure cerebellar ataxia was studied both neurologically and genetically in order to better define the phenotype of the disease and to test its relationship with spinocerebellar ataxia type 1 locus.

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Computerized tomography was performed in all three living patients. Magnetic resonance imaging of patient III-1 was performed using a 0.5 T superconducting system with spin echo pulse sequences for T,-weighted images (TR 450 ms; TE 25 ms) on axial and sagittal planes and T2-weighted images (TR 2620 ms; TE 50/100 ms) on axial planes. Motor nerve conduction velocity (MCV) was examined in the median and tibial nerve. Electromyography (EMG), using a concentric needle electrode, was performed in the thenar, first interosseous, anterior tibial and pedidious muscles. Recording of motor evoked potential (MEP) by means of transcranial magnetic stimulation was carried out using electrodes attached over the belly of thenar and anterior tibial muscles, while the magnetic stimulator was placed over the vertex to activate the motor cortex and over the spinal processes to activate the motor roots. Cortical somatosensory evoked potentials (SEP), visual (pattern) evoked potentials (VEP) and brainstem auditory evoked potentials (BAEP) were also performed according to techniques reported by Pozzessere et al. (1988). Blood samples (20 ml) were obtained from the six living family members. DNA was extracted as described in Frontali et al. (1990) and genoryped for the D6S89 GT repeat polymorphism using the polymerase chain reaction method reported by Zoghbi etal. (1991). Lodscores were obtained by using the LINKAGE program (Lathrop et al., 1984).

Neurological examination Patient III-]. Onset was at 16 yrs with writing and gait disturbance, intentional tremor and dysarthria. A neurological examination at 24 yrs showed mild limb and trunk ataxia, light dysmetria and dysdiadochokinesia, hypoactive but symmetrically present deep reflexes. A CT scan at the time showed a marked cerebellar hemisphere and vermian atrophy while the brainstem was spared. The patient was first examined by our group when he was 32 yrs old. He was still fully ambulatory, self-sufficient and working without special provisions. Clinically he showed disturbance of equilibrium particularly while walking, moderate dysmetria and intention tremor, cerebellar dysarthria, nystagmus and upper limb hypotonia. Deep reflexes were hypoactive but symmetrically present. Plantar response was in flexion. No involvement of cranial nerves, muscular strength, exteroceptive and proprioceptive sensation, and of extrapyramidal system was noted. A CT scan showed a cerebellar atrophy of a degree comparable to that of 8 yrs before. Magnetic resonance imaging performed at age 34 yrs showed severe cerebellar atrophy involving both hemispheres and vermis. The brainstem structures, in particular the olivary complex, were normal (Fig. 2). Electrophysiological study showed normal VEP, BAEP, SEP, MEP, EMG and MCV. The clinical follow-up of the patient during 36 mths failed to show a clear-cut disease progression. Patient II-1. The first signs of the disease appeared at age 50 yrs with gait titubation and swaying. At neurological examination, performed by our group when he was aged 64 yrs, moderate ataxic gait, dysarthria, dysmetria and nystagmus were noted. Deep reflexes were hypoactive and no pathological reflex was present. Pyramidal, extrapyramidal, sensory and brainstem signs were absent. The patient was still fully ambulatory and self-sufficient. A CT scan performed at age 57 yrs showed severe atrophy of cerebellar hemispheres and vermis without involvement of the brainstem. Patient II-3. She developed gait ataxia in her early twenties. Examination performed at age 68 yrs showed severe trunk and limb ataxia, walking possible only with assistance, wide nystagmic jerks in all directions, dysarthria of cerebellar type and dysmetria. Tendon reflexes were hypoactive but symmetrically present and plantar response was absent.

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RESULTS

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FIG. 2. Magnetic resonance image of patient III-1 (18 yrs after disease onset). T,-weighted images (TR 450 ms; TE 25 ms) on sagittal (A), and axial (B) planes. Severe atrophy of both cerebellar hemispheres and vermis is evident. Brainstem structures and in particular bulbar olives appear to be spared.

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Other neurological systems appeared completely normal. A CT scan performed at the same age showed (Fig. 3) extreme and diffuse cerebellar atrophy, while other structures and the brainstem in particular appeared normal.

Genetic examination Figure 1 shows the D6S89 genotypes of the family members. Out of eight examined meioses four were informative for the disease gene and three showed recombination between the disease and the marker. Lodscore function reported in Fig. 4 showed significant exclusion (lodscore less than - 2 ) of a disease location within 8.5% recombination from the marker. It should be noted that the spinocerebellar ataxia type 1 locus maps 1% recombination from D6S89 and that the 95% confidence interval is up to 5.9% recombination (Persichetti et al., 1991). DISCUSSION

The disease segregating in the present family is characterized by (i) a pure cerebellar ataxia without involvement of other neurological systems, as shown by the clinical and the electrophysiological investigation; (ii) a severe and diffuse cerebellar atrophy with

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FIG. 3. Computerized tomography scan of II-3, performed after more than 40 yrs of disease duration, showing very severe atrophy of cerebellar hemispheres (A) and vermis (B) with sparing of brainstem in both sections.

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0.1

% Recombination 0.2 0.3 0.4

FIG. 4. Lodscores between the disease and the D6S89 marker as a function of genetic distance (percent recombination).

sparing of the brainstem even after more than 40 yrs of disease duration; (iii) a very variable age at onset (16-50 yrs); (iv) a slow progression of the disease toward inability. The phenotype appears to be very similar to that decribed by Hoffman et al. (1971) and by Harding (1982) except for age at onset. In the present family mean age at onset is 3 0 ± 14.6 yrs, while in the two previous reports it was 54 yrs and over 60 yrs, respectively. Unfortunately, in these reports no standard error of the mean is reported, preventing the assessment of the difference statistical significance. However, a wide range of age at onset (26—70 yrs) is described also in the family studied by Hoffman et al. (1971). In four patients, onset was 'below 40 yrs', and was attributed by the authors to the triggering effects of intervening infectious diseases. With such variability, due either to intrinsic or extrinsic factors, it appears unlikely that any statistically significant difference will be found. The clinical, neuroimaging and electrophysiological results in the present family contribute to improved delineation of the phenotype of pure cerebellar ataxia which is dominantly transmitted and support Harding's (1982) view that it differs from other autosomal dominant ataxias. In particular, diversity appears to be clear-cut when compared with spinocerebellar ataxia type 1 phenotype shown to be in linkage with 6p markers. The present form, in fact, is characterized by anomalies confined to the cerebellum even after more than 40 yrs of disease duration, a very slow progression towards total inability and/or with normal life expectancy. Recent data on spinocerebellar ataxia type 1 families show that the disease is multisystemic from the beginning with early involvement of cranial nerves and of the sensory and peripheral motor system. It produces a nearly complete inability after 10 yrs from onset and a reduced life expectancy (Spadaro et al., 1992). The genetic results clearly indicate that in the present family the disease locus does

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-6J

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not map in the same region as the spinocerebellar ataxia type 1 locus. A previous attempt to test whether Holmes' ataxia gene had a location similar to the spinocerebellar ataxia 1 gene was performed by Sasaki et al. (1988) through linkage analysis with histocompatibility leukocyte antigen (HLA) markers in two families. However, results were inconclusive because lodscores between the disease and HLA markers did not significantly exclude linkage at the expected genetic distance (20% recombination). The present result provides definite evidence that pure cerebellar ataxia and the spinocerebellar ataxia type 1 gene are distinct nosological entities both on a phenotypic and on a genetic ground.

ACKNOWLEDGEMENT This research was funded by CNR PF Ingegneria Genetica (M.F.), CNR contract nos PF 89.00227.70, 90.000107.PF70 and 91.04181.ST75.

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The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. American Journal of Human Genetics, 49, 2 3 - 3 0 . (Received May 27, 1992. Accepted July 5, 1992)

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Autosomal dominant pure cerebellar ataxia. Neurological and genetic study.

A family with late-onset autosomal dominant pure cerebellar ataxia was studied both neurologically and genetically. Neuroimaging and electrophysiologi...
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