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Trinucleotide Repeats in 202 Families With Ataxia
A Small Expanded (CAG)n Allele at the SCA17 Locus
I. Silveira, PhD;
C. Miranda, MSc;
L. Guimarães, BSc;
M.-C. Moreira, MSc;
I. Alonso, BSc;
P. Mendonça, BSc;
A. Ferro, BSc;
J. Pinto-Basto, MD;
J. Coelho, BSc;
F. Ferreirinha, BSc;
J. Poirier, BSc;
E. Parreira, MD;
J. Vale, MD, PhD;
C. Januário, MD;
C. Barbot, MD;
A. Tuna, MD;
J. Barros, MD;
R. Koide, MD;
S. Tsuji, MD, PhD;
S. E. Holmes, PhD;
R. L. Margolis, MD;
L. Jardim, MD, PhD;
M. Pandolfo, MD;
P. Coutinho, MD, PhD;
J. Sequeiros, MD, PhD
Arch Neurol. 2002;59:623-629.
ABSTRACT
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Background Ten neurodegenerative disorders characterized by spinocerebellar ataxia
(SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However,
in some instances the molecular diagnosis is considered indeterminate because
of the overlap between normal and affected allele ranges. In addition, the
mechanism that generates expanded alleles is not completely understood.
Objective To examine the clinical and molecular characteristics of a large group
of Portuguese and Brazilian families with ataxia to improve knowledge of the
molecular diagnosis of SCA.
Patients and Methods We have (1) assessed repeat sizes at all known TNR loci implicated in
SCA; (2) determined frequency distributions of normal alleles and expansions;
and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese
and Brazilian patients with SCA. Molecular analysis of TNR expansions was
performed using polymerase chain reaction amplification.
Results Patients from 110 unrelated families with SCA showed TNR expansions
at 1 of the loci studied. Dominantly transmitted cases had (CAG)n
expansions at the Machado-Joseph disease gene (MJD1)
(63%), at SCA2 (3%), the gene for dentatorubropallidoluysian
atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)n expansions at the SCA8 (2%) gene, whereas (GAA)n expansions in the Freidreich
ataxia gene (FRDA) were found in 64% of families
with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the
TATA-binding protein gene (TBP), with 43 CAGs, was
present in a patient with ataxia and mental deterioration. Associations between
frequencies of SCA2 and SCA6 and a frequency of large normal alleles were
found in Portuguese and Brazilian individuals, respectively. Interestingly,
no association between the frequencies of DRPLA and large normal alleles was
found in the Portuguese group.
Conclusions Our results show that (1) a significant number of isolated cases of
ataxia are due to TNR expansions; (2) expanded DRPLA
alleles in Portuguese families may have evolved from an ancestral haplotype;
and (3) small (CAG)n expansions at the TBP
gene may cause SCA17.
INTRODUCTION
THE SPINOCEREBELLAR ataxias (SCAs) are neurodegenerative disorders that
are clinically and genetically heterogeneous. Ten genetically different SCAs
are known to be caused by trinucleotide repeat (TNR) expansions. In the dominant
SCAs, the mutant proteins show an expanded polyglutamine tract in SCA1, SCA2,
Machado-Joseph disease (MJD), SCA6, SCA7, and dentatorubropallidoluysian atrophy
(DRPLA),1-9
whereas SCA8 and SCA12 are caused by untranslated (CTG)n and (CAG)n expansions, respectively.10-11
In Friedreich ataxia (FRDA), the mutant protein is deficient in homozygotes
for a (GAA)n expansion in intron 1 of the FRDA gene.12 Recently, an expanded CAG repeat
tract has been found at the TATA-binding protein gene (TBP) in an isolated patient with symptoms of ataxia and intellectual
deterioration.13 TBP
repeat expansions have since been described in 4 Japanese families affected
by a new type of ataxia with dementia named SCA17.14
Matsuura et al15 found a large expansion of
pentanucleotide (ATTCT)n in intron 9 of the SCA10 gene in patients with spinocerebellar ataxia type 10, thus being
the first to show the existence of a new class of dynamic mutations.
Function of the genes involved is known only for SCA6, SCA12, and SCA17. SCA6 is due to a small CAG expansion (21-33
CAGs) in the coding region of a voltage-gated calcium channel  -subunit
gene (CACNA1A).9 SCA12
is caused by a CAG expansion in the 5'-untranslated region of a brain-specific
regulatory subunit of the protein phosphatase PP2A
gene.11 The recently described SCA17 is caused
by a (CAG)n expansion in the coding region of the transcription
factor TBP gene.13
Associations between prevalence of dominantly inherited SCAs and frequency
of large normal (CAG)n alleles have been found in Japanese and
European populations, indicating that these may contribute to the generation
of expanded alleles in the SCAs.16
In an attempt to improve our understanding of TNR expansions leading
to SCA, we have (1) assessed repeat size at the SCA1, SCA2,
MJD1, SCA6, SCA7, SCA8, SCA12, SCA17/TBP, DRPLA, and FRDA loci in a large group of Portuguese and Brazilian patients with
ataxia; (2) examined TNR distributions of normal alleles at these loci; (3)
determined the frequency of TNR expansions; (4) compared frequencies of large
normal alleles with relative frequencies of SCA at each loci; and (5) looked
for genotype-phenotype correlations.
SUBJECTS, MATERIALS, AND METHODS
SUBJECTS
Individuals with SCAs who were referred to UnIGENe, Instituto de Biologia
Molecular e Celular (Porto, Portugal) between 1997 and 2000 were included
on a consecutive basis. These individuals were referred to this laboratory
for the molecular diagnosis of SCAs. Dominant inheritance was assumed based
on the presence of at least 1 affected family member in 2 or more successive
generations. Recessive transmission was presumed when the patient had a history
of consanguinity or siblings affected without (aged) affected parents. An
isolated occurrence was assumed in the absence of a family history. We studied
202 unrelated families: 145 lived in Portugal, and 57 in Brazil. Dominant
inheritance was apparent in 106 families, whereas recessive transmission was
suspected in 33 Portuguese families; 63 individuals had isolated cases of
SCA.
METHODS
Peripheral blood was collected from patients and their relatives after
written informed consent was obtained. Genomic DNA was isolated from peripheral
blood leukocytes using standard techniques.17
Molecular analysis of the CAG and CTG repeat loci were performed by
polymerase chain reaction (PCR) amplification using the published primer sequences;1, 4, 6, 8-11,18
the PCR was carried out with 1µM of each primer, 200µM of deoxynucleotides,
1.0mM of magnesium chloride, 10mM of Tris (pH 9.0), 50mM of potassium chloride,
1 U of Taq polymerase, and 2% formamide, in a final
volume of 25 µL. Samples were processed as previously described.6, 9, 19-20 Polymerase
chain reaction products were analyzed on 6% polyacrylamide gels. Allele sizes
were determined by comparing migration relative to an M13 sequencing ladder.
DNA sequencing was performed to accurately assess repeat size and the presence
of interruptions. Sequencing reactions were performed using a ThermoSequenase
DNA sequencing kit (USB, Cleveland, Ohio) with 5 µL of amplified DNA.
Both the CTA and CTG repeats on the SCA8 gene are
polymorphic, and PCR assay determines the combined size of the 2 repeats.
The analysis of the intronic (GAA)n on the FRDA gene was performed by PCR using primers 2500F12
and 104FGAA21 for expanded alleles, and primers
GAA-R and GAA-F for normal alleles, following the conditions described.22 Expanded allele sizes were analyzed by comparing
migration relative to molecular weight standards. Normal sizes were assessed
by analysis of fluorescent-labeled PCR products in an automated DNA sequencer
(model 4200; Li-COR, Lincoln, Neb) using 5.5% Long Ranger gels (FMC Bioproducts,
Rockland, Me).
STATISTICAL ANALYSES
Possible differences between Portuguese and Brazilian groups in normal
repeat frequency distributions were assessed using 2 nonparametric tests:
the Kolmogorov-Smirnov 2-sample test and the Mann-Whitney U test. Allele frequencies at each locus were estimated by the gene
count method, and heterozygosity (H) was calculated
as
where Xi is the estimated frequency
of the ith allele at the locus. Statistical analyses
of differences in estimates of heterozygosity between Portuguese and Brazilian
individuals, as well as differences in the frequency of large normal alleles
for each locus, were performed with the Fisher exact test.
RESULTS
TNR DISTRIBUTIONS IN NORMAL ALLELES
The frequency distributions of normal alleles in the dominant SCAs caused
by translated TNR expansions in the Brazilian group were not significantly
different from those in the Portuguese group (P>.05
using the Mann-Whitney U test and Kolmogorov-Smirnov
2-sample test) (Figure 1). In the
case of the SCA2 locus, the normal (CAG)n
alleles ranged in size from 17 to 31 repeats in the Portuguese group and from
19 to 24 repeats in the Brazilian group; the allele with 22 repeats was the
most frequent in both groups. No significant differences were found between
the 2 groups at the most recently identified SCA8,
SCA12, and SCA17/TBP ataxia loci (Figure 1). Interestingly, no SCA8 alleles
smaller than 18 repeats and larger than 35 repeats in the Portuguese patients,
or larger than 30 repeats in the Brazilian patients, were observed. A third
class of extremely large normal alleles at the SCA8
locus, varying in size from 40 to 91 CTG repeats,23
was not found in either group; this might be due to the small sample size.
At the SCA12 locus, small normal alleles were closely distributed around an
allele with 10 CAGs, which represented more than 65% of all normal alleles
in each group; the other class of normal alleles comprised CAG repeat sizes
of 12 to 18 units. A large normal SCA12 allele containing 28 CAG repeats was
also observed in the Portuguese group. The recently described SCA17/TBP ataxia locus presented a distribution of normal allele sizes varying
from 29 to 40 CAGs in both groups, with distributions peaking at the allele
with 38 CAG units. At the FRDA gene, normal alleles
can be subdivided into 2 classes depending on their GAA repeat length: short
normal alleles, with 5 to 10 GAA triplets, and long normal alleles, with 12
to 60 GAA triplets.24 At this locus, long normal
alleles represented 18% and 22% of Portuguese and Brazilian individuals, respectively
(Figure 2A). Although the Brazilian
group had a slightly larger proportion of long normal alleles, this difference
was not significant.
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Figure 1. Distribution of triplet repeats
in normal alleles at SCA1, SCA2, MJD1, SCA6,
SCA7, DRPLA, SCA8, SCA12, and SCA17/TBP
loci in studied individuals of Portuguese (black bars) and Brazilian
(hatched bars) origin. Vertical axes represent allele frequency, and horizontal
axes represent number of repeat units. SCA indicates spinocerebellar ataxia;
MJD, Machado-Joseph disease; DRPLA, dentatorubropallidoluysian atrophy; and
TBP, TATA-binding protein. SCA6 and SCA12 refer to the loci for the respective
diseases, not to the genes themselves.
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Figure 2. A, Distribution of GAA repeats
in normal allele classes at the Friedreich ataxia (FRDA) locus by geographic origin of studied individuals. B, Distribution
of GAA repeats in expanded alleles at the FRDA locus
in 58 chromosomes from Portuguese patients.
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The most polymorphic loci were DRPLA, MJD1, SCA1,
SCA8, SCA17/TBP, and SCA6, whereas SCA2, SCA7, and SCA12 were the least polymorphic ones (Table 1).
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Table 1. Heterozygosity Values for Dominant Ataxia Loci by Geographic
Origin*
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FREQUENCY OF TNR EXPANSIONS
Analysis of loci involved in the SCAs showed that 110 unrelated patients
(55%) had ataxia due to a TNR expansion. Analysis of loci with translated
(CAG)n tracts showed that 78 unrelated patients with ataxia had
1 allele in the expanded range. Expansions at the MJD1
locus were found in 114 individuals, 102 affected and 12 asymptomatic, from
67 families that had ataxia with dominant inheritance (63%), as well as in
4 isolated cases (6%). Six individuals (5 affected) from 3 families with dominant
ataxia (3%) had an expanded allele at the SCA2 gene.
An expanded allele at the DRPLA locus was found in
5 patients and 1 possibly affected individual, from 2 kindreds with dominant
ataxia (2%). One patient from a family that had ataxia with dominant inheritance
(1%) had an expanded allele at the SCA6 locus. Three patients from 1 kindred
with dominant ataxia (1%) had 1 expanded allele at the SCA7 gene. Analysis of the untranslated (CTG)n at the SCA8 gene showed that 4 patients from 2 unrelated families
with dominant ataxia (2%), as well as 4 isolated cases (6%), exhibited 1 expanded
allele. Expansions of the intronic (GAA)n at the FRDA gene (Figure 2B) were
found in both alleles in 31 patients from 21 families with recessively inherited
ataxia (64%) and in 5 isolated cases (8%). Table 2 shows the frequency of TNR expansions for each SCA by geographic
origin.
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Table 2. Frequency of SCA TNR Expansions by Mode of Inheritance and
Geographic Origin*
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FREQUENCY OF LARGE NORMAL ALLELES
Evidence from several populations has suggested that the disease prevalence
of many of these SCAs may be associated with the presence of large normal
alleles at the respective loci.16 To study
the frequency of TNR expansions in our 2 groups relative to the frequency
of normal alleles of larger size at the various loci, we used the criteria
of Takano et al16 (Table 3). Large normal alleles at the SCA1
(>34 repeats) and SCA6 (>13 repeats) loci were significantly more frequent
in Brazilian individuals than in the Portuguese individuals. Normal alleles
in the upper tail of the SCA2 distribution (>22 repeats)
appeared to be overrepresented in the Portuguese group, but the P value obtained was of borderline statistical significance.
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Table 3. Frequencies of Large Normal Alleles at the Dominantly Inherited
Ataxia Loci in Portuguese and Brazilian Groups*
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GENETIC AND CLINICAL FEATURES OF PATIENTS
The clinical phenotypes were very heterogeneous. All of our affected
individuals showed clinical symptoms of cerebellar ataxia, with or without
other associated features. Epilepsy was present in patients with DRPLA from
1 family, only cognitive impairment was observed in some patients with DRPLA
and SCA8, and visual impairment was seen in affected individuals with SCA7.
Two of the 3 families with SCA2 had been thought to have MJD. The families
with SCA6, SCA7, and SCA8 and 1 of the 2 kindreds with DRPLA did not have
a previous clinical diagnosis of these disorders. Altogether, 13 patients
with no family history tested positive for a TNR expansion: 4 isolated patients
had a mutation for MJD (2 of them having a clinical diagnosis of possible
MJD), 3 of the 5 isolated patients with FRDA expansions
had a clinical diagnosis of the disease, and the (CTG)nexpansion
at the SCA8 gene was present in 4 isolated cases. Table 4 shows the mean age at onset and
expanded allele size ranges for patients with TNR expansions.
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Table 4. Repeat Size and Age at Onset of Patients With Expanded TNRs*
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SCA2 ALLELE WITH 32 CAG REPEATS
The analysis of the SCA2 gene in our patients
disclosed an allele with 32 CAGs in a 48-year-old isolated patient who had
been clinically diagnosed as having atypical FRDA. Her age at onset of gait
ataxia was 2 years; during the following years, she developed a spinocerebellar
syndrome. The disease progressed rapidly as time passed, with evidence of
neuropathy and a mild cognitive impairment; by age 30 years, she was nonambulatory.
We first tested the FRDA gene and identified 2 normal
alleles; thus, we have proceeded with the analysis of other known SCA mutations
and detected an allele with 32 repeats at the SCA2
gene. Sequence analysis of this allele showed an interrupted CAA repeat configuration:
therefore, this is probably not a pathogenic allele. Moreover, a recently
performed muscle biopsy showed ragged-red and cytochrome oxidase–negative
fibers as well as reduced activity of the mitochondrial respiratory chain
on polarography.
SMALL EXPANDED ALLELE AT THE SCA17/TBP LOCUS
Besides the mutations described previously, the analysis of the CAG
repeat at the TBP gene showed an expanded allele
with 43 units in a 64-year-old patient with ataxia. Sequence analysis of this
allele showed an interrupted repeat configuration of (CAG)3(CAA)3(CAG)9 CAACAGCAA(CAG)23CAACAG, encoding 43 glutamines.
This patient began experiencing symptoms of gait ataxia at age 52 years. During
the last 5 years, he exhibited progressive mental deterioration and dementia.
The family history indicated that his deceased mother presumably had the same
disease. There are no other patients in this family. The normal allele range
previously described for TBP was 25 to 42 CAG repeats.13, 25-27
COMMENT
DOMINANT ATAXIA AND FRDA
The analysis of TNR sizes at the loci implicated in SCA in a large group
of Portuguese and Brazilian patients allowed the identification of an expansion
in more than half of them, including a significant number without a family
history. This study showed that DRPLA disease, frequent in Asian populations28 but rare in European individuals,16
was present in the Portuguese families. On the other hand, no expanded alleles
were seen at the SCA12 locus, confirming previous impressions that they are
very rare.11 (GAA)n expansions at
the FRDA gene were also frequent among our recessive
Portuguese families with ataxia (64%). The genetic basis of approximately
40% of families with ataxia remains unknown.
In most cases of SCAs, phenotypic features are helpful indicators of
the underlying genotype. Dementia and seizures associated with symptoms of
cerebellar ataxia are characteristic features of DRPLA29;
however, in 1 of our families with the DRPLA mutation,
the only patient available had symptoms of cerebellar ataxia alone.
ISOLATED CASES OF TNR EXPANSIONS
We identified the molecular basis in 13 patients with ataxia who had
no family history. Eight (13%) did not have a clinical diagnosis of a specific
SCA type. A recent study has also shown that 19% of cases of apparently idiopathic
ataxia were due to TNR expansions.30 We propose
that all isolated individuals with ataxia of unknown cause should be investigated
for TNR expansions at known SCA loci.
SMALL CAG EXPANSION AT THE SCA17/TBP GENE
The normal CAG size range described for the TBP
gene (in 2525 chromosomes belonging to individuals of European, Asian, African
American, and Hispanic origin) was 25 to 42 repeat units.13, 25-27
Previous findings have implicated a de novo expansion of 63 CAG repeats at
the TBP gene in a 14-year-old Japanese patient, confined
to a wheelchair at age 13 years with symptoms of ataxia and intellectual deterioration.13 Expansions in the SCA17/TBP
gene have also been found in 4 Japanese families with ataxia and dementia
in which expanded alleles were 47 to 55 CAG units.14
We found a TBP allele with 43 CAG units in a 64-year-old
affected individual with mild ataxia and dementia; the late onset of disease
as well as the mild clinical symptoms seem to correlate with the small size
of the expanded allele (compared with the early onset observed in the patient
with 63 glutamines).
LARGE INDETERMINATE ALLELES AT THE SCA2 GENE
Genetic diagnosis and counseling may sometimes be difficult with these
diseases caused by TNR expansions. In SCA1, for instance, there is no gap
between normal and pathological alleles, whereas SCA2
alleles with 32 and 33 CAGs have been considered of indeterminate significance.
Normal SCA1 and SCA2 CAG
repeats are interrupted by CAT or CAA triplets, respectively, whereas pathogenic
expansions are pure, uninterrupted CAG repeats.6, 29
Uninterrupted alleles with 32 CAGs31 and 33
repeat units32 have been found in young, at-risk
subjects in families with SCA2, both resulting from the contraction of alleles
with 40 repeats. Recently, another SCA2 allele with
33 uninterrupted CAG units was found in a patient with a mild balance problem;
this patient had an onset at age 60 years.33
We found an SCA2 allele with 32 CAGs interrupted
by a CAA triplet in a patient with a childhood onset of severe ataxia. The
severe phenotype, the altered function of the mitochondrial respiratory chain,
and the presence of a CAA interruption suggest that this SCA2 allele is not the cause of the disease in this case. As in SCA1,
in SCA2 there is no gap between normal and pathological alleles.
ASSOCIATIONS BETWEEN PREVALENCE OF SCAs AND LARGE NORMAL ALLELES
Our present findings indicate that for both SCA2
and SCA6 TNRs, large normal alleles may contribute to the generation of expanded
alleles and thus to the relative frequency of these SCAs in the 2 groups.
For the remaining loci, the frequency of normal alleles was similar in the
2 groups. Of interest is the fact that no association between the frequency
of DRPLA and that of large normal alleles was found in the Portuguese group.
This may be owing to the effect of a specific haplotype associated with large
normal alleles, shared with patients who have DRPLA, that is prone to further
expansion into the disease range. In a group of Japanese individuals, all
expanded and intermediate DRPLA alleles shared a
unique haplotype that is frequent in Asian populations and is usually associated
with large normal alleles.28 The same haplotype
has also been found in European patients, although it rarely occurs in normal
chromosomes in this population. This suggests that DRPLA expanded alleles in Japanese28 and
Portuguese patients may have evolved from a common founder chromosome. Haplotype
analyses in our families with DRPLA are now being carried out to test this
hypothesis.
AUTHOR INFORMATION
Accepted for publication December 19, 2001.
Author contributions: Study concept and design (Drs Silveira, Januário, Margolis, Koide, Tsuji, and Holmes
and Ms Guimarães); acquisition of data (Drs
Pinto-Basto, Vale, Parreira, Januário, Barbot, Tuna, Barros, Holmes,
Margolis, Jardim, Pandolfo, Coutinho, and Sequeiros, Messrs Miranda, Moreira,
Mendonça, and Coelho, and Mss Alonso, Ferro, Ferreirinha, and Poirier); analysis and interpretation of data (Drs Barbot,
Koide, Pandolfo, Tsuji, and Sequeiros, Mr Miranda, and Ms Poirier);
drafting of the manuscript (Drs Silveira, Januário,
Margolis, Koide, Tsuji, and Holmes and Ms Guimarães); critical
revision of the manuscript for important intellectual content (Drs Pinto-Basto, Parreira, Vale, Januário, Barbot, Tuna, Barros, Jardim,
Coutinho, and Sequeiros, Messrs Mendonça and Coelho, and Mss Moreira,
Alonso, Ferro, Ferreirinha, and Poirier); statistical expertise (Ms Guimarães); obtained funding (Drs Barbot, Pandolfo, and Sequeiros); administrative, technical, and
material support (Drs Pinto-Basto, Vale, Januário,
Tuna, Barros, Koide, Tsuji, Holmes, Margolis, Pandolfo, and Sequieros, Messrs
Miranda, Moreira, Mendonça, and Coelho, and Mss Alonso, Ferro, Ferreirinha,
and Poirier); study supervision (Drs Silveira, Pandolfo,
Coutinho, and Sequeiros).
This work was supported by research grant PRAXIS/SAU/13226/1998 and
the Financiamento Plurianual de Unidades de Investigação from
Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal.
Messrs Miranda and Mendonça and Mss Moreira, Alonso, Ferro, and Ferreirinha
are the recipients of scholarships from the PRAXIS Programme, FCT.
We thank C. A. Ross, PhD, for collaboration, C. Costa, MD, for referring
patients, and the family members for cooperation.
Corresponding author and reprints: Isabel Silveira, UnIGENe, IBMC,
Rua do Campo Alegre 823, 4150-180, Porto, Portugal (e-mail: isilveir{at}ibmc.up.pt).
From UnIGENe, Instituto de Biologia Molecular e Celular (Drs Silveira,
Pinto-Basto, and Sequeiros, Messrs Miranda, Mendonça, and Coelho, and
Mss Guimarães, Moreira, Alonso, Ferro, and Ferreirinha) and Laboratório
de Genética Médica, Instituto de Ciências Biomédicas
Abel Salazar, Universidade do Porto (Dr Sequeiros, Mr Miranda, and Mss Guimarães,
Moreira, Alonso, Ferro, and Ferreirinha), Serviço de Neuropediatria,
Hospital Maria Pia (Dr Barbot), and Serviço de Neurologia, Hospital
Geral de Santo António (Drs Tuna and Barros), Porto, Serviço
de Neurologia, Hospital Fernando Fonseca, Amadora (Dr Parreira), Serviço
de Neurologia, Hospital Egas Moniz, Lisbon (Dr Vale), Serviço de Neurologia,
Hospital Universidade Coimbra, Coimbra (Dr Januário), and Serviço
de Neurologia, Hospital São Sebastião, Feira (Dr Coutinho),
Portugal; Centre Hospitalier de l'Université de Montréal, Hôpital
Notre-Dame, Montréal, Quebec (Dr Pandolfo, Mr Miranda, and Ms Poirier);
Serviço de Genética Médica, Hospital Clínicas,
Porto Alegre, Brazil (Dr Jardim); Department of Neurology, Brain Research
Institute, Niigata University, Niigata, Japan (Drs Tsuji and Koide); and Johns
Hopkins University School of Medicine, Baltimore, Md (Drs Holmes and Margolis).
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