Spinocerebellar ataxia type 17 associated with an expansion of 42 glutamine residues in TATA-box binding protein gene

Nolte, Dagmar; Sobanski, Esther; A, Wissen; Ju, Regula; Lichy, Christoph; Müller, Ulrich

doi:10.1136/jnnp.2009.180711

Cited by 39 publications

(26 citation statements)

References 25 publications

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“…However, it should be appreciated that a substantial proportion of the variance in age of onset in Huntington disease is due either to variation in genes other than HTT or in the environment (Wexler et al 2004). Other repeat expansion disorders characterized by reduced penetrance of alleles of intermediate size include fragile X-associated tremor/ataxia syndrome (Jacquemont et al 2004; Sévin et al 2009), spinocerebellar ataxia types 10 (Alonso et al 2006; Rankin et al 2008) and 17 (Oda et al 2004; Nolte et al 2010), inherited prion disease (Kaski et al 2011) and amyotrophic lateral sclerosis (Boeve et al 2012; Ogaki et al 2012). …”

Section: Influence Of Mutation Type On Penetrancementioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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Section: Influence Of Mutation Type On Penetrancementioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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“…somal dominantly inherited ataxia caused by the expansion of a CAG trinucleotide repeat from normally 25-41 CAG motifs to 42 or more CAG motifs in the TBP gene coding for the general transcription initiation factor tumor-associated transplantation antigen-binding protein (1,2).…”

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confidence: 99%

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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“…Considering that alleles with repeat lengths of 42–48 have previously been reported to cause disease with reduced penetrance [5] and that repeat lengths in the shorter end of this range usually cause mild disease progression [5,9,12,13], our case is interesting because of the rapid deterioration observed.…”

Section: Discussionmentioning

confidence: 99%

“…The normal range of glutamine stretches in TBP is 25–41. Stretches of 49 or more glutamines are disease causing with full penetrance, whereas stretches of 42–48 glutamines are associated with reduced penetrance [5]. The clinical diagnosing of SCA17 patients is complex.…”

Section: Introductionmentioning

confidence: 99%

Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: A case report

et al. 2012

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BackgroundThe autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington’s disease.Case presentationWe report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype.ConclusionsThe current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

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Spinocerebellar ataxia type 17 associated with an expansion of 42 glutamine residues in TATA-box binding protein gene

Abstract: The reference definition of at least 43 CAG/CAA codons for pathological SCA17 alleles should be lowered to 42.

Cited by 39 publications

References 25 publications

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

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

Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: A case report

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