Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The spinocerebellar ataxia type 17 (SCA17) is characterized by cerebellar ataxia, dementia, and involuntary movements, including chorea and dystonia. In addition, psychiatric symptoms, pyramidal signs, and rigidity are common. MRI shows variable atrophy of the cerebrum, brainstem, and cerebellum. The autosomal dominantly inherited progressive neurodegenerative disorder is caused by an expanded CAA/CAG repeat coding for glutamine. Alleles of the normal range carry 25 to 42 glutamine residues, disease causing alleles 43 to 63. Alleles with 43 to 48 glutamine codons may be associated with incomplete penetrance. The mean age of onset is about 30 years for individuals with full-penetrance alleles, but ranges from three to 55 years.
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PMID:Spinocerebellar ataxia type 17 is caused by mutations in the TATA-box binding protein. 1785 80

We screened a cohort of 181 patients with features of primary progressive ataxia and chorea for spinocerebellar ataxias 17 (SCA17) mutation after excluding other known SCAs, Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and non-genetic causes. This study included patients with known family history of SCA, those with sporadic onset and cases of uncertain family history. Two unrelated patients with Huntington's disease-like phenotype and cerebellar signs are described with homozygous expansions of 47 and 48 CAG/CAA repeats. A family member with early signs of ataxia was found to carry 37 and 48 repeats. There were fewer CAA interruptions in the repeat sequences of patients than in the controls. The normal repeat range in controls was 21-42, with 91% of the alleles located between 33 and 39 repeats. This is the first report of rare homozygous SCA17 mutation in Indian patients presenting with HD-like phenotype.
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PMID:Spinocerebellar ataxia type 17 in Indian patients: two rare cases of homozygous expansions. 2110 34

Spinocerebellar ataxias are a group of rare and heterogeneous autosomal dominant disorders characterized by progressive ataxia and other features. Spinocerebellar ataxia 17 (SCA17) is one of the 32 subtypes described to date and is secondary to CAG/CAA repeat expansion in the gene coding for the TATA-box binding protein (TBP). SCA17 is clinically heterogeneous and typically presents with slowly evolving ataxia, dysarthria, dementia, depression, and other movement disorders such as chorea. More than 41 CAG/CAA repeats are considered diagnostic of SCA17, with more than 49 being associated with full penetrance. We report one patient presenting with isolated rapidly evolving ataxia who was found to have 44 CAG/CAA repeats in the TBP gene. This suggests that, while SCA17 typically slowly progresses over years, its repertoire of presentations should be expanded to include rapidly progressive isolated ataxia resembling paraneoplastic disorders or prion disease.
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PMID:From normal gait to loss of ambulation in 6 months: a novel presentation of SCA17. 2347 85

Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the Huntingtin (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in 'pain' sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery.
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PMID:Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease. 2422 92

Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.
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PMID:From mild ataxia to huntington disease phenocopy: the multiple faces of spinocerebellar ataxia 17. 2534 49

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder.
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PMID:Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17. 3053 92

SCA 17 is a rare, autosomal dominant disorder caused by TBP gene CAG/CAA repeat expansion. Ataxia and dementia are common. The presence of frontal dysfunction at outset of the disease may mimic frontotemporal dementia (FTD). Parkinsonism, chorea, dystonia, and pyramidal signs may occur. We report an Irish family with autosomal dominant partially penetrant frontal dementia with cerebellar atrophy due to SCA17 and present detailed neuropsychological assessment for the first time. A 44-year-old doctor presented with 18-month history of behavioral problems. She slowed down, became apathetic, and unable to multitask. She became more irritable and short tempered, and her work performance deteriorated. Brain MRI showed cerebellar atrophy and cerebellar hypometabolism was noted on FDG-PET. A sister developed personality changes at age 45 with apathy, and had problems with memory and social skills; another sister at age 39 became dysarthric and unsteady. A brother at age 52 demonstrated emotional lability, and became dysarthric, unsteady, and slowed down. Their mother aged 73 had an abnormal antalgic gait due to arthritis; their father was jocular and disinhibited. MAPT testing detected an exon 9 c.726C>T variant in the proband. Subsequent testing in nine siblings and both parents failed to show co-segregation with disease. SCA17 testing revealed a TBP gene 43 repeat expansion that co-segregated in all affected siblings and in the mother whose gait problems were initially attributed to arthritis. In over 80% of cases of FTD with clear autosomal dominant inheritance, causative gene defects involve MAPT, GRN, or C9orf72 mutations. A minority involves VCP, FUS, and CHMP2B. As evident from our case, SCA17 testing should also be considered, especially if cerebellar atrophy if found on imaging. Segregation analysis is crucial. MAPT variant (c.726C>T exon 9) detected in the family was deemed a polymorphism.
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PMID:Autosomal Dominant Gene Negative Frontotemporal Dementia-Think of SCA17. 3061 27