A Small Trinucleotide Expansion in the TBP Gene Gives Rise to a Sporadic Case of SCA17 with Abnormal Putaminal Findings on MRI

Watanabe, Mitsunori; Monai, Natsuki; Jackson, Mandy; Yamamoto-Watanabe, Yukiko; Ikeda, Yoshio; Suzuki, Chieko; Tomiyama, Masahiko; Kawarabayashi, Tatsuhiko; Kimura, Takuma; Seino, Yusuke; Wakasaya, Yasuhito; Miki, Yasuo; Matsubara, Etsuro; Shoji, Mikio

doi:10.2169/internalmedicine.47.1499

Cited by 9 publications

(6 citation statements)

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“…In other words, dystonia was also observed in patients with small expansions, 27,33,36,37 and parkinsonism and chorea were also present in patients with large expansions 4,30,38‐41 . ATX‐ TBP patients with parkinsonism showed, in some cases, a phenotype resembling typical PD with response to dopaminergic therapy and, in other cases, a clinical picture indistinguishable from multiple system atrophy (MSA‐C or MSA‐P) with partial or no response to dopaminergic therapy and, in some, characteristic imaging findings of MSA, such as the hyperintense putaminal rim or the hot cross bun sign 13,32,33,39,42‐46 . Dopaminergic single‐photon emission computed tomography/positron emission tomography imaging studies demonstrated presynaptic and postsynaptic dopaminergic deficits involving the nigrostriatal pathway.…”

Section: Discussionmentioning

confidence: 99%

“…4,30,[38][39][40][41] ATX-TBP patients with parkinsonism showed, in some cases, a phenotype resembling typical PD with response to dopaminergic therapy and, in other cases, a clinical picture indistinguishable from multiple system atrophy (MSA-C or MSA-P) with partial or no response to dopaminergic therapy and, in some, characteristic imaging findings of MSA, such as the hyperintense putaminal rim or the hot cross bun sign. 13,32,33,39,[42][43][44][45][46] Dopaminergic single-photon emission computed tomography/positron emission tomography imaging studies demonstrated presynaptic and postsynaptic dopaminergic deficits involving the nigrostriatal pathway. However, presynaptic dopaminergic dysfunction was not consistently found, 29 which might explain the limited or absent response to dopaminergic therapy in some ATX-TBP patients with parkinsonism.…”

Section: Discussionmentioning

confidence: 99%

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Genotype–Phenotype Correlations for ATX‐TBP (SCA17): MDSGene Systematic Review

et al. 2022

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A BS TRACT: Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with subthreshold repeat expansions and of patients with Parkinson's disease (PD) with expanded repeats have cast doubt on the established cutoff values of the expansions and the phenotypic spectrum of this disorder. The objective of this systematic review was to explore the genotype-phenotype relationships for repeat expansions in TBP to delineate the ATX-TBP phenotype and reevaluate the pathological range of repeat expansions. The International Parkinson and Movement Disorder Society Genetic Mutation Database (MDSGene) standardized data extraction protocol was followed. Clinically affected carriers of reported ATX-TBP expansions were included. Publications that contained repeat sizes in screened cohorts of patients with PD and/or healthy individuals were included for a separate evaluation of cutoff values. Phenotypic and genotypic data for 346 ATX-TBP patients were curated. Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray zone of reduced penetrance between 41 and 45 repeats. Pure parkinsonism was more common in ATX-TBP patients with 41 to 45 repeats than in the group with ≥46 repeats, which conversely more often presented with a complex phenotype with mixed movement disorders. An updated genotype-phenotype assessment for ATX-TBP is provided, and new repeat expansion cutoff values of reduced penetrance (41-45 expanded repeats) and full penetrance (46-66 expanded repeats) are proposed. These adjusted cutoff values will have diagnostic and counseling implications and may guide future clinical trial

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Correlations for ATX‐TBP (SCA17): MDSGene Systematic Review

et al. 2022

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“…CHIP protein has multifunctional activities such as binding of heat shock proteins, modulating protein refolding, ubiquitination of substrates, and acceleration of ubiquitin-dependent degradation of chaperone substrates. 45 Haploinsufficiency of CHIP might facilitate the accumulation of TBP in the presence of mildly expanded (40)(41)(42)(43)(44)(45)(46) poly-Q tracts. In contrast, TBP protein with longer poly-Q tracts (≥47 repeats) may accumulate even in the presence of normal CHIP activity.…”

Section: Discussionmentioning

confidence: 99%

“…37 These tests were selected for their sensitivity in detecting multiple dysfunctions in executive, linguistic, and visuospatial domains previously demonstrated in patients with poly-Q SCAs. 10,[37][38][39][40] The SDMT and the calculation test were chosen on the basis of our previous experience in patients and presymptomatic individuals with Huntington's disease. 41 The study protocol was approved by the local ethics committee and written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.…”

Section: Participants and Clinical Evaluationsmentioning

confidence: 99%

Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia

et al. 2023

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Background andObjectives: Spinocerebellar ataxias (SCAs) are autosomal dominant disorders with extensive clinical and genetic heterogeneity. We recently identified a form of SCA transmitted with a digenic pattern of inheritance caused by the concomitant presence of an intermediate-length expansion in TATA-box binding protein gene ) and a heterozygous pathogenic variant in the Stip1-homologous and U-Box containing protein 1 gene (STUB1). This SCA TBP/ STUB1 represents the first example of a cerebellar disorder in which digenic inheritance has been identified. Objectives: We studied a large cohort of patients with SCA TBP/STUB1 with the aim of describing specific clinical and neuroimaging features of this distinctive genotype. Methods: In this observational study, we recruited 65 affected and unaffected family members from 21 SCA TBP/STUB1 families and from eight families with monogenic SCA17. Their characteristics and phenotypes were compared with those of 33 age-matched controls. Results: SCA TBP/STUB1 patients had multi-domain dementia with a more severe impairment in respect to patient carrying only fully expanded SCA17 alleles. Cerebellar volume and thickness of cerebellar cortex were reduced in SCA TBP/STUB1 compared with SCA17 patients (P = 0.03; P = 0.008). Basal ganglia volumes were reduced in both patient groups, as compared with controls, whereas brainstem volumes were significantly reduced in SCA TBP/STUB1 , but not in SCA17 patients. Conclusions: The identification of the complex SCA TBP/STUB1 phenotype may impact on diagnosis and genetic counseling in the families with both hereditary and sporadic ataxia. The independent segregation of TBP and STUB1 alleles needs to be considered for recurrence risk and predictive genetic tests.

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“…Such basal ganglia involvement has not been reported to correlate with symptoms of parkinsonism [17], but it has been suggested to be a function of the severity of the disease with normal uptake of I123 FP-CIT and Fluoro-dopa in pre-clinical stages [14]. Furthermore, basal ganglia involvement has been suggested to be associated with putaminal rim hyperintensity signal on T2 MRI in other cases [6,18,19], and voxel based morphometry has indicated an increased involvement of basal ganglia as the disease progresses [20]. The proband exhibited a rapid and severe decline in cognitive function suggesting an advanced stage of disease, and involvement of the basal ganglia would therefore not have been surprising.…”

Section: Discussionmentioning

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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A Small Trinucleotide Expansion in the TBP Gene Gives Rise to a Sporadic Case of SCA17 with Abnormal Putaminal Findings on MRI

Abstract: Abstract

Cited by 9 publications

References 9 publications

Genotype–Phenotype Correlations for ATX‐TBP (SCA17): MDSGene Systematic Review

Genotype–Phenotype Correlations for ATX‐TBP (SCA17): MDSGene Systematic Review

Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia

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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