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Clinical Features and ATTCT Repeat Expansion in Spinocerebellar Ataxia Type 10
Raji P. Grewal, MD;
Madhureeta Achari, MD;
Tohru Matsuura, MD;
Alberto Durazo, MD;
Emilio Tayag, MD;
Lan Zu, PhD;
Stefan M. Pulst, MD;
Tetsuo Ashizawa, MD
Arch Neurol. 2002;59:1285-1290.
ABSTRACT
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Background Spinocerebellar ataxia type 10, an autosomal dominant disease characterized
by ataxia and seizures, is caused by a large expansion of an unstable ATTCT
pentanucleotide repeat.
Objectives To characterize the phenotypic expression of spinocerebellar ataxia
type 10 and to examine the genotype-phenotype correlations in 2 large families.
Design Clinical characterization and genotype-phenotype correlation.
Setting Studies at 2 medical schools with private practice referral.
Patients Twenty-two affected individuals from 2 large Mexican American pedigrees.
Results Of the 22 individuals, ataxia was the initial symptom in 21; seizure
disorders developed in 11, mostly within several years following the onset
of ataxia. The seizure frequency was different in the 2 families: 3 (25%)
of 12 had seizures in family 1, and 8 (80%) of 10 had seizures in family 2
(P = .01). A brain magnetic resonance imaging or
computed tomographic scan showed cerebellar atrophy in all patients examined.
An electroencephalogram demonstrated epileptiform discharges in 4 of 8 patients
studied. Although anticipation was apparent in both families, only family
1 showed a strong inverse correlation between age of onset and repeat number
(r2 = 0.79, P
= .001). In family 1, 8 transmissions, of which 7 were paternal, resulted
in an average gain of 1940 repeats. In contrast, despite anticipation, 2 affected
male subjects transmitted their expanded alleles to 8 progenies, with an average
loss of 755 repeats, in family 2.
Conclusions Seizure is an integral part of the spinocerebellar ataxia type 10 phenotype,
with documented morbidity and mortality. Family-dependent factors may alter
the frequency of the seizure phenotype and the pattern of intergenerational
repeat size changes, making the genotype-phenotype correlation complex.
INTRODUCTION
THE SPINOCEREBELLAR ataxias (SCAs) are a genetically heterogeneous group
of neurodegenerative disorders.1 Traditionally,
the autosomal dominant cerebellar ataxias (ADCAs) have been classified according
to phenotype. In the classification proposed by Harding,2
the ADCAs are divided into 3 different groups (ADCA I, II, and III) depending
on the presence or absence of associated features, such as retinopathy or
other extracerebellar signs. However, there are significant phenotypic overlaps
and variability among these disorders, making a definitive clinical diagnosis
difficult. Recent advances in the molecular genetics of these disorders have
led to a genotypic classification using the SCA prefix.3
They are an expanding group of disorders, and 15 different loci (SCA1-8, SCA10-14, and SCA16-17) have been genetically mapped.1, 3-8
In 6 of the disorders (SCA1-3, SCA6-7, and SCA17),
the disease-producing mutation is an expansion involving the trinucleotide
repeat CAG in the coding portion of the gene. In 2 of the disorders (SCA8
and SCA12), the reported mutations are in the noncoding portions of the disease
genes.1 However, in SCA8, unlike SCA12, the
expanded trinucleotide repeat involves a CTG rather than a CAG expansion.
The clinical and genetic analysis of a large Mexican American pedigree
with an ADCA has been reported.9 Genetic analysis
showed that in this and one other large family, the disease gene localized
to chromosome 22.10-11 More recently,
the molecular basis of SCA10 as an expansion mutation of a pentanucleotide
(ATTCT) repeat in intron 9 of the SCA10 gene was
established.12 Analysis of 604 chromosomes
from unaffected individuals of various ethnic origins, including Mexicans,
showed a range of 10 to 22 ATTCT repeats with no evidence of expansions, whereas
affected individuals had expansions of greater than 800 ATTCT repeats.12 To our knowledge, this novel class of mutation is
one of the largest microsatellite repeat expansions described in the human
genome. The segregation of the expansion in affected individuals, the absence
of the mutation in healthy control subjects, and the expression of SCA10 in the central nervous system provide compelling evidence that
this is the disease-producing mutation. However, the mechanism of how the
expanded allele causes SCA10 is unknown and will be the subject of future
studies. We present the genotype-phenotype analysis of extended pedigrees
of the original families, including new clinical data on recently identified
members.
PATIENTS AND METHODS
PATIENTS
The index patient (patient III:1 of family 1) (Figure 1A) was identified and examined at University of Southern
California Medical Center. The clinical descriptions and results of investigations
of a part of this pedigree were previously reported.9
The members of family 2 (Figure 1B)
were identified through the index patient (III:6) and examined by one of us
(M.A.) and then also examined at Baylor College of Medicine.11
All living affected members were examined, and the clinical status of deceased
individuals was determined with a corroborating history from at least 2 independent
sources.
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Figure 1. Pedigrees of 2 large families
with spinocerebellar ataxia type 10. The roman numerals on the left indicate
the generations of each family, and the arabic numberals, individual family
members in each family. A, Family 1. B, Family 2. Unfilled symbols indicate
unaffected individuals; fully filled symbols, affected individuals with ataxia
and epilepsy; half-filled symbols, affected individuals with ataxia but without
epilepsy; + sign, the presence of epileptiform discharges on the electroencephalogram
(EEG); - sign, the absence of epileptiform discharges on the EEG; circles,
females; squares, males; a diagonal line over a symbol, a deceased individual;
diamonds, unaffected siblings; and the number within a diamond, the number
of unaffected siblings.
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MUTATION ANALYSIS
After obtaining informed consent, 40 mL of blood was obtained and genomic
DNA was extracted by standard methods. Southern blot analysis was performed
to determine the ATTCT repeat number, as previously described.12
Briefly, 10 µg of genomic DNA was digested with EcoRI, separated by gel electrophoresis (0.8% agarose), and transferred
to a membrane (Hybond N+; Amersham Biosciences, Piscataway, NJ). An SCA10
probe was generated by polymerase chain reaction, amplifying an 800–base
pair fragment located upstream to the pentanucleotide repeat from a genomic
DNA clone of the region using the following primers: DanL (5'-TCCTTCCTCAGTCTTTCTGG-3')
and DanR (5'-TGCCATCTGTTTTCTATTTG-3').
This probe was radiolabeled with phosphorus 32 by random priming, and
hybridization was performed in Church buffer (0.1mM EDTA, pH 8.0; 0.5M sodium
phosphate, pH 7.2; and 7% sodium dodecyl sulfate) at 60°C overnight; the
membrane was washed in 2X SSC (at 60°C for 5 minutes), 1X SSC (at 60°C
for 20 minutes), and 0.5X SSC (at 60°C for 20 minutes) with 0.1% sodium
dodecyl sulfate and then analyzed with autoradiography.
RESULTS
PHENOTYPE ANALYSES
Since the original report,9 changes in
the clinical status of some of the individuals have occurred in family 1 (Table 1 and Figure 1A). One of the subjects in family 1 (patient II:2) died
of complications of status epilepticus at the age of 62 years. His cranial
computed tomographic scan showed marked cerebellar atrophy with no lesions
suggestive of cysticercosis. He had developed seizures at the age of 56 years
and had been treated with carbamazepine and phenytoin; however, no serum levels
were available for review. An electroencephalogram (EEG), which had been performed
several weeks before death, confirmed that he had significant ongoing bilateral
epileptiform discharges. No autopsy was performed. Another affected member
in family 1 (patient III:2) developed a complex partial seizure disorder at
the age of 50 years. The diagnosis was based on a reliable medical history,
abnormal EEG results, and a good response to carbamazepine. Her cranial computed
tomographic scan showed 1 small calcified lesion typical of inactive cysticercosis
in the right occipital lobe. We identified an additional branch of the pedigree,
in which 2 of 13 living members were symptomatic, including 1 (patient II:1
of family 1) who had a history of complex partial seizures with generalization
and subsequently died of the complications of a fall secondary to the seizure
disorder. Thus, of the living patients examined, 3 (25%) of 12 experienced
seizures, either complex partial seizures or complex partial seizures with
secondary generalization. If we include all affected individuals in this pedigree
in whom a reliable medical history could be obtained, there are 4 (25%) of
16 affected individuals who experienced seizures.
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Genotype and Phenotype of Patients With SCA10 in 2 Large Families*
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Reexamination of 2 individuals in family 1 (patients III:1 and III:5)
and an initial examination of 1 other affected individual in family 1 (patient
IV:5) showed that there may be some mental status changes. Although a Spanish
translation of a Mini-Mental State Examination showed normal scores with no
major deficits in attention, memory, or language, there seemed to be changes
in personality. All 3 had a flat affect and apathy, showing a general disinterest
in their surroundings. All patients in family 1 denied any vegetative symptoms
of depression. More detailed psychological studies will be performed to further
investigate this clinical impression.
For family 2 (Table 1 and Figure 1B), the original report11
described only outlines of the clinical phenotype. Since then, we identified
1 new affected member (patient III:0). However, 2 individuals (individuals
20 and 23 described in the article by Matsuura et al11)
who had subtle balance problems on the initial examination and scored as being
affected in 1999 were excluded because of their uncertain phenotype and the
absence of the SCA10 mutation in their DNA. Altogether,
10 patients had progressive cerebellar ataxia, including variable degrees
of unstable gait and posture, scanning speech, dysmetria, intention tremor,
dysdiadochokinesia, and fragmented ocular pursuit. Gait imbalance was the
first symptom in all affected members. Most patients showed ocular dysmetria
and gaze-evoked nystagmus of variable magnitude, sometimes causing visual
disturbances; however, no patients showed ophthalmoparesis. Two patients in
family 2 (patients II:1 and II:2) were wheelchair bound, and 2 others in family
2 (patients III:3 and III:6) needed a cane. Seizures occurred in 8 (80%) of
the 10 affected members. All 8 individuals had generalized motor seizures.
Four of them also experienced complex partial seizures, which tended to occur
more frequently than generalized motor seizures and sometimes resulted in
secondary generalization of the seizure, while the remaining 4 denied symptoms
suggestive of complex partial seizures. Although 1 patient in family 2 (patient
III:8) who developed ataxia at the age of 35 years had a history of generalized
motor seizures since the age of 15 years, the remaining 7 patients developed
seizure disorders within 1 to 4 years after the onset of ataxia (Table 1). One patient in family 2 (patient
III:3) who has been free of seizures for more than 1 year since the onset
of ataxia had normal EEG findings, although she has been taking primidone,
prescribed by her local physician, for her tremor. In 6 of the 8 patients,
seizures were well controlled by antiepileptic drugs, such as carbamazepine,
phenytoin, and valproic acid. None of the patients who took therapeutic doses
of antiepileptic drugs reported noticeable changes in their ataxic symptoms.
In 2 patients in family 2 (patients III:0 and III:1), the seizures were not
adequately controlled because of poor compliance and alcoholism, respectively.
Patient III:0 was recently hospitalized for an episode of status epilepticus.
A magnetic resonance imaging scan of the brain in 4 patients in family 2 (patients
III:0, III:6, III:8, and III:9) showed a variable degree of pancerebellar
atrophy without atrophy of the brainstem or cerebral hemispheres (Figure 2). The results of an EEG were normal
in 4 patients in family 2 (patients III:3, III:4, III:6, and III:9), but patient
III:0 showed bilateral epileptiform discharges. The results of electromyography
and nerve conduction studies were normal in 4 patients in family 2 (patients
III:1, III:3, III:4, and III:6). Patient III:1 had a long history of alcoholism
and proximal muscle weakness, but in addition to the normal electromyographic/nerve
conduction velocity study results, he had a normal serum creatine kinase level
and normal biceps muscle biopsy findings.
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Figure 2. A brain magnetic resonance imaging
scan of patient III:0 in family 2. Cerebellar atrophy is evident in sagittal
(A) and axial (B) views, while the brainstem is normal. P indicates posterior;
A, anterior; and L, left. A-B, Bar indicates 5 cm.
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GENOTYPE ANALYSES
Table 1 summarizes the clinical
manifestations and genotypes of 22 symptomatic individuals. All affected individuals
carried an expansion mutation, with a range of ATTCT repeats from 800 to 4500.
The mean ± SD of expanded alleles was 2150 ± 1305 (range, 1220-4500)
and 2171 ± 973 (range, 800-2820) ATTCT repeats in affected members
of families 1 and 2, respectively.
In family 1, the intergenerational change in the size of the expanded
ATTCT repeat was a mean ± SD gain of 1940 ± 1332 repeats, while
the age of onset was a mean ± SD of 18.4 ± 4.0 years younger
in the offspring than in the transmitting parent (Table 1, Figure 1A, and Figure 3A and B). Thus, there was a strong
inverse correlation between age of onset and the size of the expanded ATTCT
repeat allele (r2 = 0.79, P = .001). The 4 paternal transmissions in this pedigree resulted in
an average net gain of 2425 repeats (range, 1120-3140 repeats), while 1 maternal
transmission was associated with no change in the repeat size (from patient
III:6 to IV:5 in family 1). An additional 3 maternal transmissions to asymptomatic
offspring showed only small repeat size changes ( 40 repeats) (data not
shown). Furthermore, the patient (patient IV:3 in family 1) with the earliest
onset of disease (at the age of 12 years) in this family acquired the expanded
allele of 4100 through a paternal transmission.
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Figure 3. A, Change of expanded repeat size
from parent to offspring. Family 1 shows intergenerational increases of the
expanded ATTCT repeat alleles, except for 1 maternal transmission, which showed
no repeat size change. In contrast, family 2 shows intergenerational contractions
of the repeat size in all cases. B, Change of age at onset from parent to
offspring. In families 1 and 2, anticipation was observed. Squares indicate
paternal transmission; circles, maternal transmission.
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In family 2, the mean ± SD age of onset of ataxia was 8.7 ±
4.3 years younger in the offspring than in the 2 transmitting fathers (Table 1, Figure 1B, and Figure 3B).
Surprisingly, the intergenerational change in the size of the expanded ATTCT
repeat showed a mean ± SD loss of 755 ± 703 repeats (Table 1, Figure 1B, and Figure 3B).
All transmissions from these 2 male subjects resulted in contractions of the
expanded alleles. Consequently, there was no correlation between age of onset
and the size of the expansion allele in family 2.
COMMENT
Initially, it was reported that the disease in family 1 best fit into
the category of ADCA type III, because symptoms and signs seemed to be restricted
to the cerebellum.9 Although seizures in 2
patients were noted, neurocysticercosis is endemic in this population and
is always a potential cause of seizures. Therefore, whether seizures were
a feature of SCA10 was unclear. However, a high prevalence of seizures in
the patients of family 2 suggested that the combination of relatively pure
cerebellar ataxia and seizures is a unique feature of SCA10.7
There is reliable evidence that 2 more affected members in family 1 have or
had a seizure disorder. In 1 patient in family 1 (patient II:2), a cranial
computed tomographic scan showed 1 cyst typical of calcified inactive neurocysticercosis,
but this is unlikely to be the cause of her seizures.13
Seizures have contributed to the morbidity and mortality of the disease. In
2 patients in family 1, who died and where reliable information existed about
the cause of death, seizures were a significant contributing factor. One patient
in family 2 has been hospitalized for status epilepticus. However, conventional
anticonvulsant therapies adequately control the seizure disorders in most
patients with SCA10 if compliance can be achieved.
Overall, there is a seizure frequency of 50% (11 of 22 patients) in
our patients with SCA10. In comparing the 2 large families with SCA10, the
frequencies of seizures were significantly different (3 [25%] of 12 patients
in family 1 vs 8 [80%] of 10 patients in family 2; P
= .01). There was no correlation between the seizure phenotype and the ATTCT
repeat expansion size. Thus, family-specific factors, in addition to the repeat
expansion itself, may contribute to the expression of seizure phenotype in
individuals with SCA10. Because of the variability of seizure prevalence,
the absence of seizures may not exclude the diagnosis of SCA10, especially
in relatively small families. Nevertheless, from a practical clinical standpoint,
when relatively pure cerebellar signs and symptoms are variably associated
with seizures in a patient, DNA testing for SCA10 should be justified for
diagnosis.
The mechanism by which the SCA10 mutation leads
to the seizure disorder remains unknown. Although imaging studies of the brain
of patients with seizures from both families consistently exhibited cerebellar
atrophy, they failed to show any evidence of extracerebellar abnormalities
that can account for the seizure disorder. Gait ataxia is the first symptom
in most patients. It is interesting that seizures have developed in a condition
in which all patients universally experience neurodegeneration, apparently
confined to the cerebellum. This structure is not typically thought of as
involved in the cause of epilepsy, although there have been reports14 of seizures of cerebellar origin. Alternatively,
the seizures may indicate that the neurodegeneration is not restricted to
the cerebellum and may be more widespread. Focal EEG abnormalities and the
mental changes seen in our patients have also been found in patients with
SCA10 in Mexico,15 and may support the latter
possibility.
Four smaller families with SCA10 from Mexico have recently been described;
they have a wider spectrum of the clinical phenotype, including a low IQ,
sensory polyneuropathy, subtle pyramidal signs, and possible hepatic and hematologic
abnormalities, with high interfamilial variability. Families 1 and 2 described
herein did not show these findings despite our careful clinical evaluation,
except that 2 patients in family 2 (patients III:0 and III:1) had a mild elevation
of serum hepatic enzyme levels. Thus, the variability of the SCA10 phenotype
is present not only in families 1 and 2 but also among other families with
SCA10; this further supports the hypothesis that family-specific factors modify
the phenotypic expression of the SCA10 mutation.
Anticipation is a biological phenomenon in which there is an increase
in severity or a decrease in the age of onset of a genetic disease with successive
generations, and is commonly observed for the trinucleotide repeat disorders.1 Intergenerational mutant allele instability is a feature
common to many trinucleotide repeat disorders and provides the molecular basis
for this phenomenon. In family 1, the possible presence of anticipation was
reported.9 Although less striking, family 2
also exhibited anticipation.11 In family 1,
anticipation was accompanied by intergenerational gains of the ATTCT repeat
units (Table 1, Figure 1A, and Figure 3A and B), giving rise to the strong inverse correlation between ATTCT repeat
size and the age of onset (r2 = 0.79, P = .001). In this family, there may be a difference depending
on the sex of the parent transmitting the mutant allele, with further expansions
of expanded ATTCT repeat alleles through paternal transmissions, in contrast
to no gain or loss of repeat units through maternal transmissions. Studies
of additional maternal transmissions in this and other families are needed
to confirm this observation. Surprisingly, 2 affected fathers in family 2
transmitted smaller alleles to their offspring. The mechanism of the discrepancy
in the directionality of the ATTCT repeat instability remains unclear. The
paternal expansion alleles were much larger in family 2 (2780 repeats in patient
II:1 and 2820 repeats in patient II:2) than in family 1 (1380 repeats in patient
III:1 and 1360 repeats in patient III:3). Although the small sample size does
not allow for any conclusions, it raises the possibility that there is an
expansion limit in the male germline. Alternatively, family-specific cis- or trans-acting factors may
determine the directionality of the ATTCT repeat instability in male germlines.
These factors may also affect the postzygotic instability of expanded ATTCT
repeats in somatic tissues in parent and offspring. The paradoxical association
of intergenerational contractions of the expanded ATTCT repeat alleles with
clinically observed anticipation in family 2 is even more puzzling. However,
a similar paradox has been observed in myotonic dystrophy type 1, in which
the postzygotic somatic expansion of the blood allele in the transmitting
father was substantially greater than that of his offspring. This extraordinary
somatic expansion of the father's allele gave rise to the apparent intergenerational
contraction of the repeat size when the blood alleles of the father and the
offspring were compared. In such cases, the estimated progenitor allele size
in the father was actually smaller than that of his offspring, accounting
for the clinically observed anticipation.16
More families and transmissions, with investigations of the germline and somatic
instability of their ATTCT repeats, would provide further insight into the
genotype-phenotype correlations.
AUTHOR INFORMATION
Accepted for publication March 13, 2002.
Author contributions: Study concept and design (Drs Grewal, Achari, Matsuura, and Ashizawa); acquisition
of data (Drs Grewal, Achari, Matsuura, Durazo, Tayag, Zu,
Pulst, and Ashizawa); analysis and interpretation of data (Drs Grewal, Achari, Matsuura, Zu, Pulst, and Ashizawa); drafting of
the manuscript (Drs Grewal, Matsuura, and Ashizawa);
critical revision of the manuscript for important intellectual content (Drs Grewal, Achari, Matsuura, Durazo, Tayag, Zu, Pulst, and Ashizawa); statistical expertise (Drs Matsuura and Ashizawa); obtained funding (Drs Matsuura and Ashizawa);
administrative, technical, and material support (Drs Matsuura,
Durazo, Tayag, Zu, Pulst, and Ashizawa); study supervision (Drs Grewal, Matsuura, Zu, and Ashizawa); defined clinical syndrome
and obtained access to patients (Dr Achari); contributed
equally and should be regarded to share the first authorship (Drs Grewal, Achari, and Matsuura).
This study was supported by grants K12-AG0052-01 (Dr Grewal), NS33123
and NS37883 (Dr Pulst), and NS41547 (Dr Ashizawa) from the National Institutes
of Health, Bethesda, Md; grants from the National Ataxia Foundation (Drs Matsuura
and Pulst) and a grant from the Oxnard Foundation/the National Ataxia Foundation
(Dr Ashizawa), Minneapolis, Minn; and a fellowship that was supported in part
by the Uehara Memorial Foundation, Tokyo, Japan (Dr Matsuura).
We thank the family members who participated in this study, and Dr Grewal
particularly thanks Paula Alvarado of family 1.
Corresponding author and reprints: Tetsuo Ashizawa, MD, Department
of Neurology, Baylor College of Medicine, 6550 Fannin, Houston, TX 77030 (e-mail: tetsuoa{at}bcm.tmc.edu).
From the New Jersey Neuroscience Institute, Seton Hall University,
Edison (Dr Grewal); the Department of Neurology, Baylor College of Medicine,
and the Veterans Affairs Medical Center, Houston, Tex (Drs Matsuura and Ashizawa);
the Department of Neurology, University of Southern California, Los Angeles
(Dr Tayag); and Rose Moss Laboratory for Parkinson and Neurodegenerative Diseases,
Burns and Allen Research Institute, Division of Neurology, Cedars-Sinai Medical
Center, University of California, Los Angeles, UCLA School of Medicine, Los
Angeles (Drs Zu and Pulst). Drs Achari and Durazo are in private practice
in Houston and Tijuana, Calif, respectively.
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