CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia

Fujigasaki, Hiroto; Martin, Jean‐Jacques; Deyn, Peter Paul De; Camuzat, Agnès; Deffond, D; Stevanin, Giovanni; Dermaut, Bart; Broeckhoven, Christine Van; Dürr, Alexandra; Brice, Alexis

doi:10.1093/brain/124.10.1939

Cited by 155 publications

(135 citation statements)

References 24 publications

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“…Further, striatal degeneration assessed with 18 F-FDG PET and MRI was more pronounced in the caudate nucleus than in the putamen. Consistently, substantia nigra showed only moderate degeneration in SCA17 (1,3,10,11). However, the moderate extent of nigrostriatal dopaminergic degeneration in our SCA17 sample may not be the only explanation for the lack of parkinsonian features.…”

Section: Discussionsupporting

confidence: 51%

“…Age-and sex-matched healthy individuals served as controls for 11 C-D-threo-methylphenidate ( 11 C-dMP), 11 C-raclopride, and 18 F-FDG PET. Healthy controls for MRI analysis were matched for sex but were older than the SCA17 cohort ( Table 2).…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, autopsy studies have revealed not only cerebellar degeneration but also cell loss and gliosis of the basal ganglia and cortex (1,3,10,11). Degeneration of the substantia nigra is much milder in SCA17 than in other SCA subtypes, especially SCA2 and SCA3 (3,12).…”

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confidence: 99%

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PET and MRI Reveal Early Evidence of Neurodegeneration in Spinocerebellar Ataxia Type 17

Brockmann¹,

Reimold²,

Globas³

et al. 2012

J Nucl Med

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Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly inherited neurodegenerative disorder presenting with a variable phenotype including ataxia, dystonia, chorea, and parkinsonism, as well as cognitive impairment. We evaluated morphologic and functional imaging characteristics to elucidate evidence of neurodegeneration in SCA17, even in the presymptomatic stage of the disease. Methods: Nine individuals of 3 large SCA17 pedigrees, including 4 presymptomatic mutation carriers, underwent cranial 3-dimensional MRI volumetry, as well as multitracer PET with 18 F-FDG, 11 C-Dthreo-methylphenidate, and 11 C-raclopride. Healthy subjects showing no signs of a neurologic or psychiatric disease served as controls. Results: MRI volumetry revealed atrophy of the cerebellum and caudate nucleus in manifesting patients (P 5 0.04 and 0.05, respectively) and in presymptomatic mutation carriers (P 5 0.04 and 0.01, respectively). PET demonstrated decreased glucose metabolism in the striatum, as well as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients and presymptomatic mutation carriers. In addition, PET was closely correlated with motor performance as assessed by the Scale for the Assessment and Rating of Ataxia (P 5 0.037) and Unified Parkinson Disease Rating Scale (P 5 0.05) and with cognitive function as assessed by the Mini-Mental Status Examination (P 5 0.037). Furthermore, 11 C-raclopride PET showed impairment of the postsynaptic dopaminergic compartment of the putamen and caudate nucleus not only in manifest SCA17 patients (P 5 0.04 and 0.008, respectively) but also in yet-unaffected mutation carriers (P 5 0.05 and 0.05, respectively). The degree of postsynaptic dopaminergic dysfunction was associated with impairment of motor performance. In contrast, significant presynaptic dopaminergic deficits assessed with 11 C-D-threo-methylphenidate PET were not detected. Conclusion: MRI volumetry, as well as 11 C-raclopride and 18 F-FDG PET, reveal neuronal dysfunction and neurodegeneration even in the presymptomatic stage and may serve as markers for disease activity in upcoming interventional trials on SCA17.

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Section: Discussionsupporting

confidence: 51%

Section: Methodsmentioning

confidence: 99%

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PET and MRI Reveal Early Evidence of Neurodegeneration in Spinocerebellar Ataxia Type 17

Brockmann¹,

Reimold²,

Globas³

et al. 2012

J Nucl Med

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“…SCA17 repeat sizes were determined using previously described methods. 5 The sizes of the repeats were determined by comparison with the GeneScan 500 Rox Size Standard (Applied Biosystems). Each run included positive control samples of known CAG repeat length.…”

Section: Methodsmentioning

confidence: 99%

Inherited polyglutamine spinocerebellar ataxias in South Africa

et al. 2012

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“…11 The main clinical features were cerebellar ataxia, dementia, and behavioural disturbances with onset in the fourth to sixth decade. Alleles ranging from 47 to 55 repeats in Japanese patients with cerebellar ataxia and additional extracerebellar symptoms including dementia, pyramidal and basal ganglia symptoms were also found to be stable during transmission.…”

Section: Introductionmentioning

confidence: 99%

SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6

Zühlke

Spranger

et al. 2003

Eur J Hum Genet

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An expanded polyglutamine domain in the TATA-binding protein (TBP) has been described in patients with spinocerebellar ataxia type 17 (SCA17) characterized by cerebellar ataxia associated with dementia. TBP is a general transcription initiation factor that regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. SCA17, as an autosomal dominantly inherited progressive neurodegenerative disorder, is caused by heterozygous expansion of a CAG repeat coding for glutamine. Alleles with 27 to a maximum of 44 glutamine residues were found as the normal range, whereas expansions above 45 repeat units were considered pathological. Here, we present a patient with a very severe phenotype with a late onset but rapidly progressing ataxia associated with dementia and homozygous 47 glutamine residues caused by an apparent partial isodisomy 6. This extraordinary case has important implications for the insights of TBP and SCA17. The expanded polyglutamine domain in both TBP copies is not correlated with embryonic death indicating that the normal function of the protein is not disrupted by this kind of mutation but may account for the dementia seen in this patient.

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CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia

Cited by 155 publications

References 24 publications

PET and MRI Reveal Early Evidence of Neurodegeneration in Spinocerebellar Ataxia Type 17

PET and MRI Reveal Early Evidence of Neurodegeneration in Spinocerebellar Ataxia Type 17

Inherited polyglutamine spinocerebellar ataxias in South Africa

SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6

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