 |
|
Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 6
A Study of 24 Dutch Families
Richard J. Sinke, PhD;
Elly F. Ippel, MD;
Conny M. Diepstraten, BSc;
Frits A. Beemer, MD, PhD;
John H. J. Wokke, MD, PhD;
Bob J. van Hilten, MD, PhD;
Nine V. A. M. Knoers, MD, PhD;
Hans Kristian Ploos van Amstel, PhD;
H. P. H. Kremer, MD, PhD
Arch Neurol. 2001;58:1839-1844.
ABSTRACT
| |
Background Autosomal dominant cerebellar ataxias (ADCAs),
or spinocerebellar ataxias (SCAs), are a heterogeneous group of
neurodegenerative disorders. Mild CAG repeat expansions in the
 1A voltage–dependent calcium channel gene are
associated with SCA type 6 (SCA6).
Objective To obtain further insight into the contribution of
SCA6 mutations to the phenotypic variability in Dutch patients
with ataxia.
Design Survey and case series.
Setting Hospitalized care, referral center.
Patients and Methods The SCA6 locus was analyzed for
CAG repeat expansions in a referred sample of 220 Dutch families with
progressive cerebellar ataxia. Clinical characteristics of patients
with SCA6 were investigated and correlated with molecular findings.
Results The diagnosis SCA6 was confirmed in 24 families
comprising 30 familial and 4 sporadic cases. Mean ± SD
age at onset was 50.1 ± 11.1 years. Expanded CAG repeats
with sizes 22, 23, and 25 were found. These sizes correlated inversely
with age at onset. No intergenerational changes in CAG repeat size were
detected. Despite this, 2 families showed clinical anticipation.
Conclusions This study provides the first detailed description
of Dutch patients with SCA6. Clinical analysis identifies SCA6 as a
late-onset ataxia in which eye movement abnormalities are prominent and
consistent early manifestations. No single clinical sign can be
considered specific for SCA6. Some patients have ataxia combined with
episodic headaches or nausea, suggesting an overlap among SCA6,
eposidic ataxia type 2, and familial hemiplegic migraine.
Spinocerebellar ataxia type 6 accounts for approximately 11% of all
Dutch families with ADCA. Analysis of SCA6 contributes further to the
genetic classification of patients with ADCA, including patients
without a clear family history of the disease.
INTRODUCTION
AUTOSOMAL dominant
cerebellar ataxias (ADCAs) are a group of neurodegenerative hereditary
disorders caused by triplet repeat mutations in various genes.
Clinically, most patients have been classified into ADCA types I to
III, according to the Harding scheme, despite the remarkable similarity
between these phenotypes. To date, patients can be assigned genetically
to 14 different spinocerebellar ataxia (SCA) loci (Table
1). For 9 of these loci
(SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, and
SCA15), the disease gene has been cloned, whereas the
genes for the SCA4, SCA5, SCA11, SCA13, and SCA14
loci have yet to be isolated.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 The association of CAG
repeat expansions in the coding regions of the SCA1, SCA2, SCA3,
SCA6, and SCA7 genes has been firmly established. In
contrast, the precise contribution of SCA8, SCA10, SCA12, and
SCA15 repeat expansions to the ADCA disease spectrum remains
unclear. Still, there are families in which dominant ataxia could not
be assigned to any of these loci (R.J.S., unpublished results,
2001).18, 19
|
|
|
|
Table 1. Characteristics of the 14 Different SCA Loci*
|
|
|
Spinocerebellar ataxia type 6 (SCA6) is associated with CAG repeat
expansions in the gene encoding the 1A
voltage–dependent calcium channel subunit
(CACNA1A)8, 20 and is unique among the other
ADCA genes in 2 respects. First, the
CACNA1A/SCA6 gene product has a known function as part
of a voltage-gated ion channel. Second, other diseases caused by
mutations in the SCA6 gene are known: missense mutations are
associated with familial hemiplegic migraine, and truncating mutations
result in episodic ataxia type 2 (EA-2).20
At the molecular level, the CAG repeat size of SCA6
alleles is smaller than that of other SCA genes (for overviews
see Andrew et al21 and
Sinden22). In addition, SCA6 CAG repeats
are remarkably stable during intergenerational transmission, whereas
all other expanded SCA alleles have been shown to be unstable
to varying degrees. Despite the observed intergenerational stability of
the repeat, clinical anticipation is reported, based on intrafamilial
increased severity of symptoms and earlier age at onset. The molecular
basis of this phenomenon still remains to be elucidated.
Clinically, the phenotype caused by SCA6 mutations
presents relatively mild symptoms compared with the other autosomal
dominant ataxias. Spinocerebellar ataxia type 6 is characterized
predominantly by adult-onset ataxia, dysarthria, and early oculomotor
disturbances. However, overlap with the other ADCAs is considerable,
and patients with SCA6 may present with variable clinical symptoms,
ranging from the classic, rather severe ADCA type I (cerebellar ataxia,
dysarthria, pyramidal and extrapyramidal signs, optic atrophy,
ophthalmoplegia, and deep sensory loss or dementia) to ADCA type III
(the late-onset, purely cerebellar
phenotype).23, 24 In general, age at onset seems
to be somewhat later than for other SCAs, and disease progression is
often less severe.8, 25, 26, 27, 28, 29 Also, in contrast to most other
ADCA variants, especially SCA1, SCA2, and SCA3, a clear family history
is not always apparent. Several authors27, 30, 31 describe
sporadic patients who carry a CAG repeat expansion at the SCA6
locus.
To obtain further insight into the contribution of SCA6
mutations to the phenotypic variability of this subset of patients with
ADCA, we report the clinical and molecular analysis of patients with
SCA6 from 24 families that were identified, and consecutively analyzed,
in a large panel of Dutch families with progressive cerebellar
ataxia.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
Patients were identified through their clinical symptoms
or family history of the disease. For genetic classification, DNA
samples from approximately 60% of the population of the Netherlands,
including 5 of the 8 Dutch university hospitals (Amsterdam, Leiden,
Maastricht, Nijmegen, and Utrecht), which often serve as tertiary
referral facilities for general hospitals, were referred to the
Department of Medical Genetics, University Medical Center Utrecht,
Utrecht. Samples were collected over 6 years and represented 220
families with progressive cerebellar ataxia, not all of them
necessarily representing autosomal dominant disease, and a few had been
initially referred as possibly having ADCA or Friedreich ataxia. After
identification of a sample as harboring an SCA6 mutation,
clinical information was collected retrospectively from patient medical
records. The sample comprised 34 affected and 3 presymptomatic cases,
identified through an affected relative. Probands who had positive
findings for Friedreich ataxia were excluded from our
analysis.
MOLECULAR ANALYSIS
High-molecular-weight genomic DNA samples were isolated from
peripheral blood lymphocytes according to standard procedures.
The SCA6 locus was analyzed for CAG repeat expansions
using polymerase chain reactions and S-5-F1 and S-5-R1
primers.8 These reactions were carried out in a PE9600
GenAmp PCR System (Applied Biosystems, Foster City, Calif).
Typically, each reaction contained 100 ng of genomic DNA, 200 ng of
forward (5'-fluorescein isothiocyanate labeled), and reverse
primers in a final volume of 50 µL containing 1.25 U of Taq
polymerase (PerkinElmer, Inc, Wellesley, Mass), 1.5 mM deoxy nucleotide
triphosphate, 10% dimethylsulfoxide, 0.15-mg/mL bovine serum albumin,
67mM Tris-hydrochloride (pH 8.8), 6.7mM magnesium chloride, 10mM
ß-mercaptoethanol, 6.7µM disodium-EDTA, and 16.6mM diammonium
sulphate. The samples were denatured at 94°C for 4 minutes, followed
by 33 cycles of denaturation (94°C for 1 minute),
annealing (55°C for 1 minute), and extension (72°C for 2
minutes). Then, the polymerase chain reaction products
were analyzed on 6% polyacrylamide/7M urea gels on an ABI377
semiautomated DNA Sequencer (Applied Biosystems).
The respective allele sizes were determined using internal size
standards.
GENEALOGICAL STUDIES
To detect possible founder effects, the origin of the SCA6
families was traced back as far as possible to identify common ancestry
by using birth, marriage, and church registries.
RESULTS
MUTATION ANALYSIS
From our DNA bank we identified 34 affected individuals
with SCA6 expansions; 30 presented with a clear family history of the
disease and 3 seemed to be the only affected individual in their
respective families. The remaining proband claimed to be sporadic, but
insufficient family history data did not allow confirmation. In
addition, 3 individuals who submitted DNA for presymptomatic testing
were found to carry an expanded CAG repeat.
These 34 affected individuals represented 24 separate Dutch families of
the total of 220 tested families (11%). Spinocerebellar
ataxia type 6 accounted for 31% of SCA-positive (ie, SCA1, SCA2, SCA3,
SCA6, or SCA7) families in our cohort (data not shown).
Of these 24 families, 20 index patients had a clear family history of
cerebellar ataxia on initial clinical presentation. Four index patients
were diagnosed initially as being sporadic patients. However, on
identification of the SCA6 mutation, 1 patient had a positive
family history after all. Family investigation did not reveal
additional affected family members of the remaining 3 patients.
Furthermore, the clinical diagnosis was confirmed in 10 additional
affected individuals from 8 families.
CLINICAL CHARACTERISTICS OF PATIENTS WITH SCA6
Symptoms at Onset
Information about symptoms at onset was available for 33 of
the 34 affected patients (16 men and 17 women).
The following were first noticed by the patients
themselves or by their relatives as initial symptoms: unsteadiness of
gait or problems with cycling (n = 20); vertigo or
dizziness that was commonly evoked by head movements
(n = 14); speech difficulties (n = 7);
diplopia or oscilloscopia (n = 2); nausea
(n = 2); and manual clumsiness
(n = 1). Often, multiple symptoms manifested at
more or less the same age, particularly vertigo, unsteadiness, and
speech impairment.
Manual clumsiness, indicative of upper limb ataxia, was always milder
than gait ataxia. In the 6 patients in whom the onset of clumsiness
could be estimated, it followed gait ataxia in 5 patients by 2 to 5
years (mean, 3.4 years). In the sixth patient, manual
clumsiness was associated with gait problems as a presenting symptom.
A 35-year-old woman, with an affected mother and an affected sister,
complained only of episodic nausea and showed subtle eye tracking
difficulties; on neurological examination, no other abnormalities were
found. These episodic manifestations may therefore represent either a
first or a sole disease manifestation.
Age at Onset and Duration
Spinocerebellar ataxia type 6 starts at a relatively
late age (Table 2).
Taking the age of first appearance of any of these symptoms as the age
at onset of the disease, the mean ± SD age at onset is
50.1 ± 11.1 years (n = 31) (range, 16-72
years). The patient who claimed to experience gait
difficulties from age 16 years onward was first examined at age 34
years, when his gait ataxia was still mild, so in this case the
indicated age at onset may have been estimated to be too young.
However, 2 well-documented cases had onset at ages 34 and 35 years,
respectively, whereas 1 patient who mentioned onset at age 72 years had
only slight gait ataxia without dysarthria at age 74 years. Therefore,
these onset ages, 34 vs 72 years, may represent the normal range
of onset (Table 2). Apart from a late onset, SCA6 runs a
protracted course. The mean ± SD duration of disease,
ie, the time from estimated onset until most recent examination, was
12.4 ± 9.1 years (n = 29). Of
these 29 patients, 8 had disease durations of 0 to 5 years; 4, of 6 to
10 years; 12, of 11 to 20 years; 3, of 21 to 30 years; and 2, of 31
years. For 7 patients, information was available on the number of
disease years after which a wheelchair was required (range, 5-23 years;
mean ± SD, 14.4 ± 7.1 years).
Thus, the disease may last more than 3 decades.
|
|
|
|
Table 2. Age at Onset of Spinocerebellar Ataxia Type 6 in Dutch Patients
|
|
|
Clinical Spectrum of SCA6
The full-blown clinical picture generally consisted of the following:
(1) oculomotor abnormalities, (2) gait ataxia, (3) mild upper limb
ataxia, and (4) dysarthria. Findings from at least 1 detailed
neurological examination could be extracted from the medical records
for 27 affected patients.
Oculomotor Abnormalities.
In 26 patients, findings from an oculomotor examination were reported
at least once during the course of the disease. The absence of eye
movement abnormalities was specifically mentioned in only 1 of these
patients, although gait and limb ataxia and dysarthria were present.
The following were noted in these patients: saccadic intrusions during
smooth pursuit in
15, nystagmus (gaze evoked and rotational) in
20, gaze paresis or paralysis in 5 (vertical in 2 and horizontal in 3),
saccade abnormalities in 3, and diplopia in 2. However,
these numbers may represent an underestimate of the true occurrence
of eye movement abnormalities because clinical neuro-ophthalmologic
examination findings were incompletely described in many medical
records.
Gait Ataxia.
In 25 patients, gait ataxia was documented as having occurred during
the course of the disease, whereas gait ataxia was deemed absent in
only 2 patients. However, eye movement abnormalities (saccadic
intrusions in smooth pursuit and gaze evoked nystagmus) were detected
in these 2 patients.
Mild Upper Limb Ataxia.
Mild to severe upper limb ataxia in the course of the
disease was noted in 18 patients, was deemed absent in 2, and was
considered ambiguous in 5. No notes on upper limb ataxia were found for
2 patients.
Dysarthria.
Dysarthria was considered to be present in 21 persons and to be absent
in 5, although other neurological abnormalities were present.
Additional neurological features during the course of the disease
were inconsistently noted in medical records, but the following summary
gives an impression of the evolving clinical picture. In 10 patients,
hyperreflexia was documented in the course of the disease; in 4
patients, this occurred within 5 years of onset. In 2 of these 10
patients, amyotrophy was also documented. Polyneuropathy, not further
specified, was noted in 1 person. In 1 instance, bilateral hand
dystonia was noted, whereas in 1 patient with amyotrophy, a staring
face was prominent, resulting in a clinical picture similar to that of
Machado-Joseph disease. Headache episodes were recorded in 5 patients,
and in 3 these were definitely absent.
GENOTYPE/PHENOTYPE CORRELATION AND ANTICIPATION
The range of the expanded alleles represented is limited, with all but
2 patients having either 22 or 23 repeats and the remaining 2 having 25
repeats (Figure 1). Normal alleles
are represented by sizes 7 to 14. There is no overlap between normal
and disease alleles.
|
|
|
|
Age at onset of spinocerebellar ataxia type 6 (SCA6) as a function of
the number of CAG repeats of the SCA6 allele.
|
|
|
We used an unpaired, 1-tailed t test to compare the
mean ± SD onset age in patients with CAG size 22
(n = 22) vs CAG size 23 (n = 8).
A significant difference between the onset age of the allele size 22
group (53.5 ± 8.9 years) and the allele size 23 group
(47.1 ± 7.3 years) was noted
(P = .03, 1-sided), illustrating the inverse
correlation between CAG repeat size and onset age.
We did not detect any intergenerational change in CAG
repeat size. In 9 families, more than 1 individual with an expanded CAG
repeat is identified, but no intergenerational changes in allele
size have been detected (Table
3). Clinical anticipation,
defined as 5 or more years' difference in disease onset, is present in
2 of 4 families in whom onset data on a parent and at least 1 affected
child were obtained. The onset of cerebellar ataxia in the affected
parent of this last family, however, was assessed retrospectively only,
after many years of illness.
|
|
|
|
Table 3. Ages at Onset and CAG Repeat Numbers of Multiplex Spinocerebellar Ataxia Type 6 in Study Families
|
|
|
Genealogical studies enabled linking of 2 families to 2 other families
in this sample. Two independently referred probands (from families 8
and 11) seemed to be second cousins, whereas 2 other probands (from
families 12 and 13) are related 4 generations back. In this last
extended family, 2 affected individuals are at 8 meioses distance from
one another, yet the CAG size is 22 for both.
COMMENT
Identification of the SCA6 mutation by Zhuchenko et
al8 allows further genetic classification of patients with
ADCA. In their ethnically diverse clinical sample, Zhuchenko et al
identified 6% of the index cases as having SCA6. In our cohort, which
consists of an unselected clinical sample of mainly Dutch ancestry, the
relative prevalence of SCA6 is 11%. Within Europe, this frequency is
comparable to the frequency of SCA6 in the western part of Germany
(10%) but higher than in the United Kingdom (5%), France (2%), and
Spain (1%).31, 32, 33, 34 Similar regional differences
are reported in Japan, where the SCA6 frequency ranges from 6% to 31%
depending on the population studied.35, 36
The mean ± SD age at onset of SCA6 in our patients
(50.1 ± 11.1 years) falls within ranges described by
other researchers,26, 34, 35, 37 which vary
from 43 ± 13 years to 52 ± 13 years.
Therefore, SCA6 may be considered to be a relatively late-onset,
autosomal dominant, purely cerebellar ataxia (ADCA type III in the
Harding classification24).
Early eye movement abnormalities are among the earliest and most
consistently detected presenting clinical features. Together with a
history of dizziness, vertigo, or nausea, these manifestations seem to
be more specific for early SCA6 than do gait ataxia or dysarthria,
which are almost always the earliest signs in the other ADCAs. No
single clinical sign can be considered to be specific for SCA6.
The different SCA6 alleles in Dutch patients contained
expanded CAG repeats of 22 to 25 units, whereas the normal alleles
contained 7 to 14 units, which are comparable to the sizes reported
elsewhere.8, 26, 27, 28, 31, 34, 35, 36, 37 Despite the relatively small
sample size, an inverse correlation between onset age and SCA6 repeat
size was noted. We did not observe any change in the SCA6 repeat length
during transmission, as reported in most other studies except
2.36, 38 The stability of the SCA6 CAG repeat is even more
apparent by the detection of SCA6 alleles with identical
repeat numbers in probands of independently referred families linked
through genealogical studies and separated by 6 and 8 meioses. In
addition, preliminary haplotype analysis with polymorphic markers from
the SCA6 region (results not shown) suggests a shared SCA6 haplotype
for several families with identical CAG repeat sizes, indicating SCA6
CAG repeat stability at even more distant relationships.
Despite the stability of the expanded SCA6 repeat alleles, of
the 4 families in whom reliable data were available, 2 show a marked
decrease in age at onset. Taken together with the 3 patients without a
clear family history of the disease, these results suggest clinical
anticipation. Other researchers27, 31, 35, 36, 37 have also
reported clinical anticipation for SCA6, mostly on the basis of age at
onset. However, to our knowledge, the underlying molecular defect, ie,
a further expansion of the SCA6 CAG repeat, has not been identified to
date. Therefore, the observed anticipation in families with SCA6 may
well represent an ascertainment bias caused by the significant
variability of the disease's onset. In a late-onset disorder such as
SCA6, an earlier onset in later generations will accordingly be noted,
whereas an onset at an even later age than the patients' parents will
not be detected in clinical surveys. In the former situation,
the possible effect of additional genetic (modifier genes) or
environmental factors must be considered.
Twenty of the 24 index patients had a positive family history of the
disease. For one of the probands, a positive family history could be
retrospectively elicited after identification of the SCA6
mutation, illustrating once more the importance of taking a detailed
family history. In 3 patients, the disease manifested as sporadic
ataxia, suggesting that SCA6 should be considered in the diagnostic
workup of patients with sporadic late-onset cerebellar ataxia.
A limited number of patients with sporadic SCA6 are reported in most
studies, and herein we identified 4 patients with SCA6 without a known
family history of the disease. To our knowledge, there is no report of
nonpenetrance in SCA6. Thus, the lack of further family analysis of
these patients with sporadic SCA6 still leaves open the possibility
that they indeed represent true sporadic patients carrying de novo
SCA6 mutations. Alternatively, the SCA6 diagnosis for the
parents of these patients may have been missed because the onset may
have been late in life, very mild, or episodic. Episodic features such
as headache and nausea, mentioned by a few of our patients, suggest
that the SCA6-mutated calcium channel subunit may give rise to episodic
clinical complaints, similar to the manifestations of EA-2 and familial
hemiplegic migraine. Similar findings were described by Geschwind et
al.26 Jodice et al38 described a family with
EA-2 in which the ataxia phenotype resulted from a CAG repeat expansion
instead of from point mutations, as reported by Ophoff et
al.20 Patients with a CAG25 allele presented
with severe progressive ataxia, whereas those with a CAG20
allele presented with an EA-2 phenotype. This is the second study, to
our knowledge, of an intergenerational increase in SCA6 allele
size (see also Matsuyama et al36), and it demonstrates the
overlap between EA-2 and SCA6. This may provide new clues for the
apparently true sporadic cases. In addition, Yue et al39
report point mutations in the CACNA1A gene to be the cause
of a severe progressive cerebellar ataxia syndrome with episodic
features. In conclusion, it seems that point mutations and CAG repeat
expansions in the CACNA1A gene result in clinically
overlapping syndromes. Additional family and functional studies will be
required to resolve the overlap between these clinically different
disorders.
AUTHOR INFORMATION
Accepted for publication March 20, 2001.
We thank Eric Hennekam, MSc, for his excellent genealogical studies.
From the Departments of Medical Genetics (Drs
Sinke, Ippel, Diepstraten, Beemer,
and Ploos van Amstel) and
Neurology (Dr Wokke), University Medical Center Utrecht, Utrecht; the
Department of Neurology, Leiden University Medical Center, Leiden (Dr
van Hilten); and the Departments of Human Genetics (Dr Knoers) and
Neurology (Dr Kremer), University Medical Center Nijmegen, Nijmegen,
the Netherlands.
Corresponding author: R. J. Sinke, Department of Medical Genetics,
University Medical Center Utrecht, KC04.084.2, PO Box 85090, 3508 AB
Utrecht, the Netherlands (e-mail: R.J.Sinke{at}dmg.azu.nl).
REFERENCES
| |
1. Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable
trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat
Genet. 1993;4:221-226.
FULL TEXT
|
ISI
| PUBMED
2. 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 Genet. 1996;14:285-291.
FULL TEXT
|
ISI
| PUBMED
3. 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.
FULL TEXT
|
ISI
| PUBMED
4. 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.
FULL TEXT
|
ISI
| PUBMED
5. Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a
novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat
Genet. 1994;8:221-228.
FULL TEXT
|
ISI
| PUBMED
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
Hum Genet. 1996;59:392-399.
ISI
| PUBMED
7. Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM. Spinocerebellar
ataxia type 5 in a family descended from the grandparents of President
Lincoln maps to chromosome 11. Nat Genet. 1994;8:280-284.
FULL TEXT
|
ISI
| PUBMED
8. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar
ataxia (SCA6) associated with small polyglutamine expansions in the
1A-voltage–dependent calcium channel. Nat
Genet. 1997;15:62-69.
FULL TEXT
|
ISI
| PUBMED
9. David G, Abbas N, Stevanin G, et al. Cloning of the SCA7 gene
reveals a highly unstable CAG repeat expansion. Nat Genet. 1997;17:65-70.
FULL TEXT
|
ISI
| PUBMED
10. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion
causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21:379-384.
FULL TEXT
|
ISI
| PUBMED
11. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the
ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet. 2000;26:191-194.
FULL TEXT
|
ISI
| PUBMED
12. Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. Autosomal dominant cerebellar ataxia type III: linkage in a large
British family to a 7.6-cM region on chromosome 15q14-21.3. Am J
Hum Genet. 1999;65:420-426.
FULL TEXT
|
ISI
| PUBMED
13. Holmes SE, O'Hearn EE, McInnis MG, et al. Expansion of a novel CAG
trinucleotide repeat in the 5' region of PPP2R2B is associated with
SCA12. Nat Genet. 1999;23:391-392.
FULL TEXT
|
ISI
| PUBMED
14. Herman-Bert A, Stevanin G, Netter JC, et al. Mapping of spinocerebellar
ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal
dominant cerebellar ataxia and mental retardation. Am J Hum
Genet. 2000;67:229-235.
FULL TEXT
|
ISI
| PUBMED
15. Yamashita I, Sasaki H, Yabe I, et al. A novel locus for dominant
cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206
and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 2000;48:156-163.
FULL TEXT
|
ISI
| PUBMED
16. Koide R, Kobayashi S, Shimohata T, et al. A neurological disease caused
by an expanded CAG trinucleotide repeat in the TATA-binding protein
gene: a new polyglutamine disease? Hum Mol Genet. 1999;8:2047-2053.
FREE FULL TEXT
17. Nakamura K, Jeong S-Y, Uchihara T, et al. SCA17, a novel autosomal
dominant cerebellar ataxia caused by an expanded polyglutamine in
TATA-binding protein. Hum Mol Genet. 2001;10:1441-1448.
FREE FULL TEXT
18. Grewal RP, Tayag E, Figueroa KP, et al. Clinical and genetic analysis
of a distinct autosomal dominant spinocerebellar ataxia. Neurology. 1998;51:1423-1426.
FREE FULL TEXT
19. Ishikawa K, Mizusawa H, Saito M, et al. Autosomal dominant pure
cerebellar ataxia: a clinical and genetic analysis of eight Japanese
families. Brain. 1996;119:1173-1182.
FREE FULL TEXT
20. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic
migraine and episodic ataxia type-2 are caused by mutations in the
Ca2+ channel gene CACNL1A4. Cell. 1996;87:543-552.
FULL TEXT
|
ISI
| PUBMED
21. Andrew SE, Goldberg YP, Hayden MR. Rethinking genotype and phenotype
correlations in polyglutamine expansion disorders. Hum Mol Genet. 1997;6:2005-2010.
FREE FULL TEXT
22. Sinden RR. Biological implications of the DNA structures associated
with disease-causing triplet repeats. Am J Hum Genet. 1999;64:346-353.
FULL TEXT
|
ISI
| PUBMED
23. Harding AE. The clinical features and classification of the late onset
autosomal dominant cerebellar ataxias: a study of 11 families,
including descendants of the "the Drew family of Walworth." Brain. 1982;105:1-28.
FREE FULL TEXT
24. Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1-14.
PUBMED
25. Gomez CM, Thompson RM, Gammack JT, et al. Spinocerebellar ataxia type
6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and
variable age of onset. Ann Neurol. 1997;42:933-950.
FULL TEXT
|
ISI
| PUBMED
26. Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6: frequency of the mutation and
genotype-phenotype correlations. Neurology. 1997;49:1247-1251.
FREE FULL TEXT
27. Ikeuchi T, Takano H, Koide R, et al. Spinocerebellar ataxia type 6: CAG
repeat expansion in 1A voltage–dependent calcium
channel gene and clinical variations in Japanese population. Ann
Neurol. 1997;42:879-884.
FULL TEXT
|
ISI
| PUBMED
28. Matsumura R, Futamura N, Fujimoto Y, et al. Spinocerebellar ataxia type
6: molecular and clinical features of 35 Japanese patients including
one homozygous for the CAG repeat expansion. Neurology. 1997;49:1238-1243.
FREE FULL TEXT
29. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in
genetically defined subtypes? Ann Neurol. 1997;42:924-932.
FULL TEXT
|
ISI
| PUBMED
30. Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant
spinocerebellar and Friedreich triplet repeats among 361 ataxia
families. Neurology. 1998;51:1666-1671.
FREE FULL TEXT
31. Riess O, Schols L, Bottger H, et al. SCA6 is caused by moderate CAG
expansion in the 1A-voltage–dependent calcium channel
gene. Hum Mol Genet. 1997;6:1289-1293.
FREE FULL TEXT
32. Leggo J, Dalton A, Morrison PJ, et al. Analysis of spinocerebellar
ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and
Friedreich's ataxia genes in spinocerebellar ataxia patients in the
UK. J Med Genet. 1997;34:982-985.
FREE FULL TEXT
33. Pujana MA, Corral J, Gratacos M, et al for the Ataxia Study Group. Spinocerebellar ataxias in Spanish patients: genetic analysis of
familial and sporadic cases. Hum Genet. 1999;104:516-522.
FULL TEXT
|
ISI
| PUBMED
34. Stevanin G, Durr A, David G, et al. Clinical and molecular features of
spinocerebellar ataxia type 6. Neurology. 1997;49:1243-1246.
FREE FULL TEXT
35. Watanabe H, Tanaka F, Matsumoto M, et al. Frequency analysis of
autosomal dominant cerebellar ataxias in Japanese patients and clinical
characterization of spinocerebellar ataxia type 6. Clin Genet. 1998;53:13-19.
FULL TEXT
|
ISI
| PUBMED
36. Matsuyama Z, Kawakami H, Maruyama H, et al. Molecular features of the
CAG repeats of spinocerebellar ataxia 6 (SCA6). Hum Mol
Genet. 1997;6:1283-1287.
FREE FULL TEXT
37. Schols L, Kruger R, Amoiridis G, Przuntek H, Epplen JT, Riess O. Spinocerebellar ataxia type 6: genotype and phenotype in German
kindreds. J Neurol Neurosurg Psychiatry. 1998;64:67-73.
FREE FULL TEXT
38. Jodice C, Mantuano E, Veneziano L, et al. Episodic ataxia type 2 (EA2)
and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in
the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997;6:1973-1978.
FREE FULL TEXT
39. Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a
missense mutation in a calcium-channel gene. Am J Hum Genet. 1997;61:1078-1087.
< |
