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Anticipation and intergenerational repeat instability in spinocerebellar ataxia type 17.

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Anticipation and
Intergenerational Repeat
Instability in Spinocerebellar
Ataxia Type 17
Astrid Rasmussen, MD, PhD,1,2
Irene De Biase, MD, PhD,2
Marcela Fragoso-Benı́tez, MD,3
Marco Antonio Macı́as-Flores, MD,4 Petra Yescas, MSc,1
Adriana Ochoa, MSc,1 Tetsuo Ashizawa, MD,5
Marı́a Elisa Alonso, MD,1 and
Sanjay I. Bidichandani, MBBS, PhD2,6
Spinocerebellar ataxia type 17 (SCA17) is caused by expansion
of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to
offspring without anticipation. We identified three SCA17
families with expansion of uninterrupted alleles, thus greatly
increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small
increments in repeat length resulted in inordinate increases in
anticipation. Anticipation was also associated with childhood
presentation. Sequencing of all SCA17 alleles is required for
effective genetic counseling.
Ann Neurol 2007;61:607– 610
The autosomal dominant spinocerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous
group of disorders associated with mutations in 15
known genes.1 Ten of them are caused by expansion of
unstable microsatellite repeats, most commonly the
polyglutamineencoding CAG triplet repeat. Spinocerebellar ataxia
type 17 (SCA17; MIM 607136) is caused by the ex-
From the 1Department of Neurogenetics and Molecular Biology,
Instituto Nacional de Neurologı́a y Neurocirugı́a Manuel Velasco
Suárez, Mexico City, Mexico; 2Department of Biochemistry and
Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; 3Faculty of Medicine, Universidad La
Salle, Mexico City, Mexico; 4Faculty of Medicine, Universidad
Autónoma de Zacatecas, Zacatecas, Mexico; 5Department of Neurology, University of Texas Medical Branch, Galveston, TX; and
Department of Pediatrics, University of Oklahoma Health Sciences
Center, Oklahoma City, OK.
Received Dec 25, 2006, and in revised form Feb 16, 2007. Accepted for publication Feb 23, 2007.
Published online May 1, 2007, in Wiley InterScience
( DOI: 10.1002/ana.21139
Address correspondence to Dr Bidichandani, Department of Biochemistry and Molecular Biology, University of Oklahoma Health
Sciences Center, 975 NE 10th Street BRC 458, Oklahoma City, OK
73104. E-mail:
pansion of a polyglutamine-encoding CAG/CAA triplet repeat in the gene for TATA-binding protein
(TBP),2,3 and is the cause of approximately 1.5% of
ADCA. Clinically, the phenotype is complex, including ataxia, dementia, chorea, parkinsonism, and psychiatric symptoms. In contrast with the other ADCAs
caused by CAG repeat expansion, anticipation is rare
in SCA17.4 – 6 This has been attributed to the interrupted configuration of the CAG/CAA repeat alleles:
5⬘-(CAG)3(CAA)3(CAG)7-11 CAA CAG CAA
(CAG)9-21 CAA CAG-3⬘, in which CAA also codes for
glutamines but results in stabilization of the repeat
tract during intergenerational transmission. Most expanded pathogenic alleles in SCA17 show this interrupted sequence composition, and expansions usually
involve the second (3⬘) polymorphic CAG tract. In
most parent-to-offspring transmissions, the expanded
allele retains the original size and anticipation is therefore not observed. However, a total of 10 “uninterrupted” alleles have been reported to date that contain
a shorter configuration of the repeat: 5⬘(CAG)3(CAA)3(CAG)⬎32 CAA CAG-3⬘. These alleles
are unstable on parental transmission and may be associated with anticipation.7–10 However, the rarity of
these alleles has precluded a systematic analysis of the
intergenerational instability of such alleles.
We identified 17 additional SCA17 patients belonging to 3 ADCA families, all of whom had expansions
involving the uninterrupted configuration of TBP alleles.
We were able to characterize five intergenerational transmissions in these pedigrees. In addition to the five previously described transmissions, it was possible for the
first time to characterize the properties of intergenerational transmission of these SCA17 alleles. Our study
confirms that these alleles are commonly seen in familial
cases, frequently expand, and result in genetic anticipation. We also found that intergenerational expansions
were significantly dependent on the sex and age of the
transmitting parent. Comparatively small-length gains in
the polyglutamine tract within TBP produced an inordinate effect on the resulting phenotypic severity in subsequent generations. Although SCA17 is not normally
considered in pediatric practice, more than a third of
our patients showed onset of disease in childhood.
Patients and Methods
We identified a total of 19 patients with SCA17. All patients
were Mexican mestizos, and whereas 17 belonged to 3
ADCA pedigrees, 2 were sporadic cases. Clinical information
was available for all 19 patients, and DNA samples were
available from both sporadic and 10 of the familial patients
(3 each from Pedigrees I and U, and 4 from Pedigree Z) (Fig
1). Informed consent and genetic testing were performed as
per guidelines of the institutional review board at Instituto
Nacional de Neurologı́a y Neurocirugı́a. Polymerase chain
reaction and direct sequencing was performed to identify the
Rasmussen et al: Anticipation in SCA17
Fig 1. Clinical information of spinocerebellar ataxia type 17 (SCA17) pedigrees segregating uninterrupted expanded alleles. NT ⫽
not tested (DNA not available); NA ⫽ not applicable. Asterisk denotes patient died of unrelated cause.
precise length and repeat configuration of the CAG/CAA alleles in the TBP gene as described previously.3
Information of age at onset of disease, time until dependence on wheelchair, and age at confinement to bed and/or
death was obtained by direct interrogation of the primary caregiver and at least one other family member. Analysis of anticipation and intergenerational repeat instability was conducted
using a combination of our newly identified five parent-tooffspring transmissions and the five previously reported in the
Results and Discussion
By direct sequencing, we analyzed the precise structure
of the expanded CAG/CAA repeats in all 12 patients
from whom DNA samples were available. Surprisingly,
all familial cases (n ⫽ 10) were found to carry the “uninterrupted” configuration of CAG/CAA alleles, and
both sporadic cases showed the more common “interrupted” configuration. The uninterrupted alleles are uncommon, accounting for only 10 of 90 previously reported SCA17 patients.7–10 The length distribution of
the 10 newly identified uninterrupted SCA17 alleles was
similar to the 10 that have been previously reported by
others (mean ⫽ 54.6, median ⫽ 54.5 [range, 51– 61] vs
mean ⫽ 54.2, median ⫽ 53 triplets [range, 49 – 66];
p ⫽ 0.58, Mann–Whitney U test). The age of onset in
our patients with uninterrupted alleles ranged from 11
to 48 years (mean ⫽ 28.3, median ⫽ 28.5 years). A
highly significant correlation was noted between repeat
Annals of Neurology
Vol 61
No 6
June 2007
length and the age of onset for our 10 patients (r ⫽
⫺0.8; p ⫽ 0.003). Including our patients with the 10
previously reported patients with uninterrupted expanded alleles, the age of onset (mean ⫽ 31.25, median ⫽ 34 years [range, 3–76]) showed a highly significant correlation with the length of the expanded allele
(mean ⫽ 54.4, median ⫽ 53 triplets [range, 49 – 66];
r ⫽ ⫺0.94; p ⫽ 10⫺9) (Fig 2A).
The clinical features were consistent with SCA17:
ataxia, dementia, chorea, parkinsonism, and psychiatric
symptoms (see Fig 1). None of our patients had a history of seizures, which may be present in 20 to 25% of
SCA17 patients. Four patients had mild sensorimotor
axonal neuropathy, mainly in lower limbs, and two abnormal somatosensory-evoked potentials. Magnetic resonance imaging showed prominent cerebellar atrophy
with variable degrees of brainstem and cerebral atrophy.
The basal ganglia were normal, a consideration in ruling
out multiple system atrophy.
A systematic analysis was conducted for intergenerational differences in parameters of disease severity. We
compared age of onset, number of years until loss of
independent ambulation (determined as the age at
which wheelchair use became necessary), and number
of years until confinement to bed. All three parameters
of disease severity showed significant increases on intergenerational transmission (Table).
To study germline instability of uninterrupted SCA17
Fig 2. (A) Correlation of age of onset with the length (in triplets) of the uninterrupted expanded spinocerebellar ataxia type 17
(SCA17) allele. (B) Correlation of genetic anticipation with age of the parent transmitting the uninterrupted expanded SCA17 allele.
alleles and whether this correlates with anticipation, we
analyzed five of our intergenerational transmissions (see
Fig 1) and five that have been reported previously in the
literature. Six transmissions occurred via the paternal
germline and four were maternal transmissions. The uninterrupted expanded alleles were prone to further expansion; further expansion was noted in 9 of 10 transmissions (range, 1–13 repeats/generation; mean ⫽ 3.8;
95% confidence interval [CI], 2.11–5.49), and only one
allele remained unchanged. Notwithstanding the small
number of transmissions, it was noted that larger expansions occurred during paternal transmission (paternal:
median ⫽ 4.5; maternal: median ⫽ 1.5; p ⫽ 0.04). Anticipation was seen in all intergenerational transmissions,
with the age of onset being 1 to 35 years earlier in the
subsequent generation (mean ⫽ 18.7 years; 95% CI,
13.4 –23.9). Anticipation correlated with parental age
(r ⫽ 0.75; p ⫽ 0.007), suggestive of progressive agedependent instability of the uninterrupted repeat tract in
the germline (see Fig 2B). A definite parental bias was
noted with greater anticipation occurring via paternal
transmission (range, 16 –35 years; mean ⫽ 26.83; 95%
CI, 24 –29.7) compared with maternal transmission
(range, 1–14 years; mean ⫽ 5.5; 95% CI, 3.9 –9),
which was highly significant ( p ⫽ 0.009).
The observed anticipation, measured as number of
years per generation, is relatively high when compared
with other diseases caused by expansion of CAG repeats.
It is similar to SCA7,11 which is known to have high
levels of anticipation (mean SCA17 vs SCA7: 18.7 vs
23.8 yr/generation). However, the high level of anticipation seen in SCA7 families is usually associated with correspondingly large intergenerational increases in repeat
length (mean ⫽ 10 triplets). Comparatively, much
smaller intergenerational changes in repeat length were
required in SCA17 (mean ⫽ 3.8 triplets; 95% CI, 2.1–
5.5). Each triplet gained on intergenerational transmission has a greater impact for anticipation in SCA17
(mean ⫽ 5.69 yr/triplet gained) than in SCA7 (mean ⫽
1.9 yr/triplet gained),12 indicating that the context of
the polyglutamine tract within TBP may be more critical than in other polyglutamine-bearing proteins. This is
perhaps not too surprising, given the widespread effects
one might expect from changes in the numerous genes
with which TATA-binding protein normally interacts.
SCA17 is not normally considered in pediatric practice. However, 7 of our 17 ADCA patients (41%) had
an age of onset of younger than 21 years. Each of the
three pedigrees had at least one child with onset of
younger than 21 years (see Fig 1). In addition, in one
child (Patient U1), the onset preceded that of the parent and others in the parental generation. These data
stress the importance of considering SCA17 in the differential diagnosis of pediatric ataxia patients.
The detection of expanded alleles for the diagnosis of
ADCAs is commonly performed by estimating sizes of the
alleles by electrophoresis of amplified alleles. However,
given the dramatic difference in the intergenerational in-
Table. Anticipation in Spinocerebellar Ataxia Type 17 (SCA17) Pedigrees with Uninterrupted Alleles
Age of onset (range), yr
Loss of independent ambulation (range), yr
Confinement to bed (range), yr
Generation I
Generation II
Rasmussen et al: Anticipation in SCA17
stability of uninterrupted and interrupted SCA17 alleles,
we recommend that all SCA17 alleles should be sequenced to provide effective genetic counseling.
In conclusion, we have shown that intergenerational
transmission of the uninterrupted mutant alleles in
SCA17 almost always results in further expansion and
genetic anticipation. Previously inconclusive observations regarding genetic anticipation in SCA17 were
most likely due to the lack of distinction between interrupted and uninterrupted alleles. TBP is unusual in
its susceptibility to small gains in polyglutamine tract
length, resulting in high levels of genetic anticipation
for relatively small increments in repeat length.
This work was supported by Consejo Nacional de Ciencia y Tecnologı́a (SALUD-2003-C01-028, A.R.), the NIH (NINDSNS047596, S.I.B.; NS041547, T.A.), Muscular Dystrophy Association (MDA 3973, S.I.B.), Oklahoma Center for the Advancement
of Sciences and Technology (HR05-009, S.I.B.), Friedreich Ataxia
Research Alliance (S.I.B.), and postdoctoral fellowship from the National Ataxia Foundation (I.D.B.).
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