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Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCA type II) is genetically different from ADCA type I.

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Autosomal-dominant Cerebellar Ataxia with
Retinal Degeneration (ADCA Type 11) Is
Genetically Different from ADCA Type I
A. Benomar, MD,V E. Le Guern, M D , PhD," A. Diirr, MD,' H. Ouhabi, MD,? G. Stevanin, BS,*
M. Yahyaoui, MD,t T. Chkili, MD,? Y. Agid, MD, PhD,f and A. Brice, MD"
Autosomal-dominant cerebellar ataxia (ADCA) type 11 is a neurodegenerative disorder presenting with cerebellar
ataxia and retinal degeneration. We analyzed the clinical features of 2 1 patients with ADCA t y p e I1 from 3 Moroccan
and 2 French families. Mean age at onset was 17 years earlier in offspring than in their parents, compatible with
anticipation. There was a suggestion of imprinting, with predominantly paternal transmission of early onset and
severe forms of the affection. Candidate genes were tested in the family with the largest pedigree. The two known
loci for ADCA type I (spinal cerebellar ataxia 1 and 2) were excluded, as were candidate loci, retinitis pigmentosa 1
locus (RP1) and the genes for rhodopsine and peripherin-rds, responsible for autosomal dominant retinitis pigmentosa.
ADCA t y p e I1 does not therefore result from an allelic mutation of the tested genes for ADCA type I or autosomal
dominant retinitis pigmentosa.
Benomar A, Le Guern E, Diirr A, Ouhabi H, Stevanin G, Yahyaoui M, Chkili T, Agid Y , Brice A.
Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCR type 11)
is genetically different from ADCA type I. Ann Neurol 1994;35:439-444
Autosomal-dominant cerebellar ataxias (ADCAs) are a
group of genetically and clinically heterogeneous neurodegenerative disorders. Three subgroups are distinguished, at present, on clinical grounds {If. In ADCA
type I and type 11, cerebellar ataxia is variably associated with other neurological disorders such as ophthalmoplegia, dementia, and extrapyramidal signs { 1-51.
In ADCA type 11, retinal degeneration is consistently
observed, suggesting that it may represent a distinct
genetic entity.
The gene responsible for ADCA type 11, even its
localization, remains unknown. Except for exclusion of
the human leukocyte antigen (HLA) locus located at a
distance from the spinal cerebellar ataxia locus 1
(SCA1) on the short arm of chromosome 6, no other
linkage analyses have been performed, probably because of the rarity of the disease {b}.Since the disease
shares clinical features with ADCA type I and autosoma1 dominant retinitis pigmentosa (adRP), linkage of
ADCA type I1 with known loci responsible for these
diseases was undertaken. At least two different loci for
ADCA type I have been identified: SCAl on chromosome Gp23-24.05 {7] and SCA2 on chromosome
1 2 ~ 2 3 - 2 4181. For adRP, two responsible genes, rhodopsin iretinitis pigmentosa 4 locus-RP4) [?] and
peripherin-rds (RP6) [lo]" and a locus, RP1 1111 on
chromosome 8, have been identified.
We report a clinical analysis of 5 families with
ADCA type 11, and the results of linkage with ADCA
type I- and adRP-associated markers, in the largest
family.
From 'INSERM U289, HBpital de la Salpecrih, Paris, Prance, and
tService de Ncurologie, HBpital des Specialit&, Rabat, Morocco.
Addresb correspondence to Dr Benomar, INSERM U 289, H8pital
de la SalpSrriSre, 47 Boulevard de l'H0piral. 7565 I Paris Cedex 13.
France'
Received July 19, 1991, and in revised form Sep 1j.Accepted for
publication Sep 14, 1993.
Patients and Methods
Patients
Five index patients from 3 Moroccan and 2 French families
fulfilled the diagnostic criteria of ADCA type 11: progressive,
unremitting cerebellar ataxia and retinal degeneration.
Twenty-nine at-risk individuals from the Moroccan families
and 6 from the French families, 2 1 of whom were affected,
were interviewed and examined in the hospital or at home
following a standardized protocol. Eleven patients were admitted for complementary investigations, including cerebral
computed tomography (CTj scans, electrophysiological recordings, neuropsychological tests, ophthalmological examination, and standard blood tests. Male-to-male transmission
was observed in 4 out of 5 families demonstrating autosomal
dominant- inheritance (Fig 1j. For comparison of age at onset
among generations and disease duration at death, data were
also included from 11 documented patients who died before
the study was undertaken.
Blood samples were taken from 65 individuals and high-
Copyright 0 1994 by the American Neurological Association
439
RBT-005
SAL-313
SAL-327
RBT-001
L!
5
Fig 1 . Pedigrees of 5 families with autosomul-dominant cerebellur ataxia lADCAi type I I . Circles represent males: squares, f e maLe.i; black symbols, uf;f.-tedpatients; asterisk indicates exumined and blood sumples taken.
molecular-weight genomic D N A was extracted E12). Lymphoblastoid cell lines were established for the 21 affected
individuals by transformation with the Epstein-Barr virus
[I?}.
Statistical analysis was performed with the Yates-corrected
x 2 test for comparison of percentages, and nonparametric
analyses (Mann-Whitney U test, Wilcoxon test) for comparison of means. Correlation analyses of age at onset were performed to study parent-offspring resemblance.
Genetic Analysis
Genotypes were determined for 38 individuals, including 9
who were affected, from the largest family (RBT-002). Five
candidate loci were studied with 16 microsatellite markers:
SCAl (DbS89, D6S289, D6S259, DGS274); SCA2
(D12S81, D12S78, D12S84, D12S79, D12S76); RP1
(D8S87, D8S255, D8S285, D8S279, D8S84); rhodopsin
gene (intragenic marker RHO);and peripherin-rds gene (intragenic marker RDS) I14-171.
Genotyping was performed by the polymerase chain reaction (PCR)/blotting technique of Hazan and colleagues [ 181,
with slight modifications. After a hot start at 94"C, 1 unit of
Amplitaq D N A polymerase (Cetus) was added, followed by
35 cycles of denaturation at 94°C for 15 seconds, annealing
at 55°C for 15 seconds and elongation at 72°C: for 15 seconds, and a 10-minute final extension at 72°C.
Linkage analysis was performed using the computer program LINKAGE (V5-I) [19]. Because of age-dependent
penetrance, five liability classes were derived from the cumulative age at onset curve E203, with a maximal penetrance of
440 Annals of Neuroiogy Vol 35 No 4 April 1994
99%. over age 65. The disease gene frequency was estimated
at lo-'. We assumed equal recombination fractions for men
and women. Pairwise and multipoint lod scores were calculated using MLlNK and LINKMAP programs 1211.
Multipoint analyses were performed taking into account intermarker recombination rates [ 141.
Results
Clinicaf Characteristics of PatientJ with
ADCA Type I1
The characteristics of the patients are summarized in
Table 1. At examination the mean age was 29 ? 18
years and the duration of the disease at this time was
6.5 5 6 years. The mean age at death was 34 k 18
years (N = 11). Mean age at onset in the 5 families
was 26.2
15 years (N = 31) but decreased from
generation (G) to generation, suggesting anticipation:
GJ (N = 4 ) , 40.3 k 4 years; GI1 (N = 151, 31.7 5
11 years; and GI11 (N = 12), 11.9 % 5 years (N =
12) (Fig 2). This was confirmed by analysis of parentoffspring pairs ( N = 24): The mean difference between the ages at onset in parents and their offspring
was 16.8 5 12 years, and did not increase as a function
of the age at onset in parents (data not shown). The
segregation ratio reached 0.5 in G1 and GII, suggesting
complete penetrance.
Early onset was associated with more rapid disease
progression. The mean disease duration of deceased
patients was significantly longer ( p < 0.05) in GI and
GI1 (15.2 ? 8 years, N = 7) than in GI11 (4.6 i- 2
years, N = 4). Anticipation was significantly greater
( p < 0.05) when the disease was transmitted by males
*
Table I . Clinical Data from 21 Patients in 5 Familiej
First Symptom
Age at
Onset
(yr~
Disease
Duration
(yr)
Decreased
Patient
No.
Generation
SAL-3 13-001
GI
55
13
+
RBT-002-015
RBT-002-016
RBT-002-022
RBT-002-02 1
RBT-001-013
GI1
43
50
13
3
+
39
43
I5
13
24
9
G11
GI1
GI1
GI1
RBT-001-0 18 GI1
RBT-005.0 15 GI I
SAL-313-006 GI1
SAL-3 13-005 GI1
8
9
+
+
+
+
+
+
+
Rrtlndl
optic
Degeneration
Atrophy
+
+
+
+
+
+
+
+
t
+
+
+
+
+
+
+
+
27
4
t
10
22
2*$
+
5
+
+
+
+
+
I
t
t
t
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
12
6
21
i
GI11
+
+
Signs
Decreased
Visual
Acuiry
+
ti111
RBT-002-027 GI11
RBT-002.05 5 GI11
R B T - O O ~ - ~ ~GJII
O
RBT-005.n2 5 GI11
RBT-005-026 GI11
SAL-3 13-016
Sense
Extrapyramidd
5
GI11
GI11
+
+
+
+
+
Ophthdmoplegta
2
RBT-002-029
SAL-327-008
Acuity
Decreased
Vibratioii
27
SAL-327-006
RB'I-002-026
Ataxia
Decreased
Tendon
Reflexes
48
GI1
GI1
SAL-3 11-003
Visual
13
I1
14
1
1')
6
12
6
6
9
15
6
0.5
0.5
I
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
t
+
i
t
I
(25.2 F 9 years, N = 9) than by females (11.7 2 10
years, N = 15). Transmission was predominantly male
( 4 :1) if the disease started before the age of 10, and
predominantly female (14 : 5 ) for onset after age 10
(Fig 3). This difference was not statistically significant
( p = 0.09, x 2 = 2.846) because of the small number
for paternal and maternal transmission.
The initial symptom differed from one generation
to another. In GI, cerebellar ataxia was always the first
+
+
+
t
+
I
t
+
+
symptom, followed or not by loss of vision. In GI11 all
patients had decreased vision, present either prior to
(N = 4 ) or at the same time as (N = 5 ) cerebellar
ataxia. The difference in age at onset of visual loss in
parent-offspring pairs (20.3 2 13 years) was greater
( p < 0.001) than for ataxia (17.8 11 years). Retinal
degeneration was combined with optic atrophy in 4
of 11 patients. In 2 patients from different families,
single-flash and flicker electroretinography supported
*
h
E 50
m
8
Q)
h
v
M
c
k'
t:
30
=
20
0
.CI
c)
$
g
10
c.r
Lo
0-9
10-19 20-29 30-39 40-49 50-59
age at onset (years)
~
Fig 2 Age at onset aciordtng t o generatton Black bars mdziate
Generatzon (G) I ; hatched bars, GII: white bars, GIII.
5
0
40
.
I
0
-
1
0
8
e
-
0
8
0
10
20
30
40
50
age at onset in parents (years)
60
Fig 3. Correkztion betmen age at onset in purents and in their
ofjjpring. White circles represent mother-ofj/;;priizgpairs: black
circles, /athrr-offJpring IiairJ.
Benomar et al: ADCA Type I1
441
the existence of retinal degeneration. Seven ( 3 9 q ) of
the patients with progressive loss of vision had neither
retinal degeneration nor optic atrophy, suggesting that
the retinopathy first involved the macula. The features
of retinitis pigmentosa evolve later. Three patients with
onset after the age of 48 years had no visual symptoms
or funduscopic abnormalities.
Other neurological signs were associated with cerebellar ataxia (see Table 1). They were more frequent
in patients with disease of longer duration but there
was no significant difference in frequency between patients from GI1 and GIII. Extrapyramidal signs were
always of the parkinsonian type. In a patient from GI11
(RBT-002-029), dystonia was associated. Muscle weakness (3/21), amyotrophy (5/2l), dysphagia (7/21),
hearing loss (4/2 1 ), and intellectual impairment (2121)
were also observed. These signs were distributed in
patients from different generations without significant
differences among them. Cerebellar and pontine atrophy was evident on all cerebral CT scans (N = 9) and
magnetic resonance images (N = 3).
Linkage Analysis
1 LOCUS (SCAl). The lod
scores obtained for D6S89 and D6S289, closest to the
SCAl locus, did not permit exclusion of more than 1
centimorgan (cM) around the markers (Table 2). Pairwise lod score for markers D6S274 and D6S259,
flanking D6S89, enlarged the excluded region to 12.4
cM. Multipoint analysis with these markers (Fig 4A)
excluded, however, a 25-cM region from 13 cM centromeric to D6S89 to 12 cM telomeric to this marker,
demonstrating that SCAl is not the locus responsible
for ADCA type 11.
SPINAL CEREBELLAR ATAXIA
SPINAL CEREBELLAR ATAXIA 2 LOCUS (SCA2). The SCA2
gene is located in a 35-cM interval on chromosome 12
between markers D12S58 and PLAZ. Bipoint analysis
was performed with five markers covering this region
(see Table 2). Multipoint analysis with these markers
(Fig 4B) excluded an 85-cM region extending from 10
cM centromeric to D12S81 to 15 cM telomeric to
Dl 2S76, encompassing the entire SCA2 region. This
locus cannot, therefore, be responsible for ADCA type
11.
RETINITIS PIGMENTOSA 1 LOCUS (RP1). This locus is assigned to chromosome 8q, in a 40- to 45-cM region
between markers DXS87 and D8S84. With these two
markers, only 3 cM within this interval could be excluded (see Table 2). Multipoint analysis with three
additional markers (Fig 4C), however, permitted definitive exclusion of a 50-cM region, except for 2 lod
score peaks of only - 1.8, extending from 5 cM centromeric to D8S87 to 10 cM telomeric to DXS84. RP1
is not then the morbid locus in ADCA type 11.
KliTlNlTlS PIGMENTOSA 4 LOCUS (RP4). With marker
RHO in the rhodopsin gene, responsible for adRP
type 4 , two point lod scores of less than -2 were
obtained up to a recombination rate of 0.05 (see Table
2). Furthermore, 3 patients were found to be recombinant for this marker (data not shown). This locus is,
therefore, not responsible for ADCA type 11.
RETINITIS PIGMENTOSA 6 LOCUS (RP6). With marker
RDS in the peripherin-rds gene, responsible for adRP
type 6, two point lod scores less than -2 were obtained up to a recombination fraction of 0.015. Two
patients were recombinant for this marker (data not
Table 2. Pairwise Lod Scorn umith 16 hficvosatellite AIurkers t n Farnib RBT-002
Recombination Rates (0)
Locus
SCAl
SCA2
RP 1
RP/1
RP6
Microsatellite
Markers
D6S89
D6S289
D6S259
D6S274
D12S81
D12S78
D12S84
D12S79
D12S76
D8S87
D8S255
D8S285
D8S279
D8S84
RHO
RDS
0.00
0.01
0.05
0.10
0.20
0.30
0.40
-2.45
-2.34
-7.54
-7.81
-7.66
-7.52
-4.52
-8.10
-2.24
-2.38
-3.70
-2.86
-7.42
-8.55
-5.75
-4.86
-0.45
-0.35
-5.49
-1.98
-4.01
-4.15
-2.11
-3.39
-2.04
-0.54
-1.68
-2.30
-3.82
-2.79
-3.68
-2.23
0.19
0.29
-3.50
-0.68
-2.24
-2.93
-0.84
-1.68
-1.12
0.06
-0.94
-1.08
-2.36
-1.40
-1.91
-1.17
0.39
0.49
-2.20
-0.21
-1.41
-1.91
-0.40
-0.83
-0.64
0.24
-0.60
-0.53
- 1.44
-0.81
- 1.09
-0.71
0.44
0.53
-0.95
-0.09
-0.64
-0.86
-0.12
-0.14
-0.24
0.27
-0.27
-0.10
-0.57
-0.20
-0.37
-0.30
0.29
0.35
-0.36
0.10
-0.27
-0.34
-0.05
0.05
-0.08
0.17
-0.09
0.02
-0.18
-0.08
- 0.09
-0.12
0.08
0.11
-0.08
0.03
-0.07
-0.08
-0.02
0.04
-0.02
0.05
-0.02
0.02
-0.03
-0.01
0.00
-0.03
442 Annals of Neurology Vol 35 No 4 April 1994
0 at Z = - 2
0.001
0.001
0.110
0.010
0.065
0.095
0.015
0.035
0.010
0.001
0.005
0.020
0.070
0.030
0.050
0.015
shown). The responsibility of this locus in ADCA type
I1 can therefore be excluded.
A
-4
-
-6 -
-a -
I
-20
,
,
- 10
1
,
0
10
,
20
Map location (cM)
B
Map location (cM)
C
-4
?
__
Map location (cM)
Pig 4. Multipoint linkage analysis in Fami& RBT-002. iAi
SCAl hu.c in 6p23-24.0j. (B)SCA2 locus in 12q23-24.
(CI RPI locus in pericentric region of chromosome 8. Markers
are indicated on the abscissa. Bold type 7epresent.r markers used
in the multipoint dnalysis; light type, approximate position of
markers on genethon map 114, 271. Dotted lines indicate limits of exclusion ilod score = -21. The HaIdane mapping function was used to transform recomhinatim fractions into genetic
distances {20}.
Discussion
This study of ADCA type I1 has permitted two important observations. Clinical analysis reveals a phenomenon of anticipation, perhaps with paternal imprinting,
particularly evident for the retinopathy that characterizes the disease. In the family studied, the disease is
not caused by allelic mutations of the SCAl or SCA2
loci of ADCA type I, or the RP1, RP4, or RP6 forms
of adRP, clinically related to ADCA type 11.
As in ADCA of any type, the age, first symptom,
degree of severity, and rate of progression are observed to vary among and within families. Associated
signs, other than retinal degeneration, are also variable.
Their frequency is similar to those previously reported
for ADCA type I1 [ l , 2, 4 ) and type I E22).
The variability in age of onset, a 17-year difference
between parents and offspring in this study, is explained by anticipation. It can be excluded that there
is a bias due to the greater facility in detecting families
where the age of onset is later in parents than in offspring, since the difference in age at onset does not
increase as a function of the age of onset of the disease
in parents. A bias due to incomplete penetrance also
seems unlikely, since the segregation ratio was already
0.5 in GI and GII, indicaring that new cases with late
onset will probably not be observed in these generations. Clinical analyses of previously reported pedigrees 11-5 ] are consistent with this conclusion. Anticipation in this study is associated with a more rapid
clinical course of the disease, as is generally the case
in early-onset disease [ 1, 2, 41.
The molecular mechanism for anticipation in fragile
X syndrome, myotonic dystrophy, Kennedy’s syndrome, Huntington’s disease, and spinal cerebellar
ataxia 1 has been elucidated {23-27). The mutation
consists of trinucleotide repeats, the number of which
increases through successive generations. The length
of the repeat is positively correlated with both clinical
severity and age at onset. The marked anticipation in
the onset of retinal degeneration might be due either
to greater mitotic instability in retinal cells or to an
increased susceptibility to triplet expansion in these
cells. If the disease is indeed caused by unstable D N A
mutations, one would expect to find greater triplet
expansion when the disease is transmitted by the father, since anticipation is much greater in this case.
Since the gene for ADCA type I1 ha5 not yet been
mapped, the hypothesis of allelic heterogeneity was
tested at loci responsible for diseases sharing some features of ADCA type 11, such as other dominant ataxias
or adRP. Exclusion of the rhodopsin gene and peripherin-rds gene, point mutations of which cause adRP,
was demonstrated, because of the existence of several
Henomar et al: ADCA Type 11 443
recombination events with the intragenic markers
used. For the SCA2 and RP1 loci, which have not been
precisely localized, use of recently mapped microsatellite markers 1141 made linkage analysis possible.
Multipoint analysis excluded 25, 85, and 50 cM on
chromosomes 6~23-24.05,1 2 ~ 2 3 - 2 4and
, 8q, thereby
excluding the responsibility of genes at the SCA1,
SCA2, and RP1 loci, respectively. Even if differences
in the relative position of the markers on different
maps of the RP1 and SCA2 loci are taken into account,
both these loci remain excluded. It can, therefore, be
concluded that the molecular mechanism for ADCA
type 11, at least in Family RBT-002, is not an allelic
mutation in the SCAl or SCA2 loci responsible for
ADCA type I or in the rhodopsin and peripherin-rds
genes or the RP1 locus responsible for adRP. However, since further genetic heterogeneity has been
proved for ADCA type I 1281 and adRP, an allelic
mutation at as-yet-unknown loci causing these diseases
may still exist.
The clear demonstration of anticipation in this disease points toward an unstable DNA mechanism. If
this is the case, Family RBT-002 is large enough to
map the responsible locus. The gene can then be identified by the presence of a trinucleotide repeat.
This study was supported by the Association Francaise contre les
Myopathies, the Association pour le Developpemenr de la Recherche sur les Maladies Generiques Neurologiques et Psychiatriques. D r Benomar received a fellowship from the Association
Franqaise de I'Ataxie de Friedreich.
The logistic and technical support of the Genethon is gratefully acknowledged. and particularly Drs Alain Vignal and Jean Weissenhach. The authors are grateful to Prof Josuti. Feingold tor his helpful
advice; to Nicole Ravisti., Christiane Penet, Yolaine Pothin, Mohammed Di&, Mohammed Barahou, and lsabelle Lagroua for technical
and medical assistance; and to D r Merle Ruberg for critical reading
o f the manuscript.
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autosomal, retina, ataxia, cerebellar, dominantly, degeneration, different, genetically, typed, adcas
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