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Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes

Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes,10.1093/brain/awg155,Brain,Giovanni Stevanin,Hiro

Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes   (Citations: 55)
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Summary We report a group of 252 patients with a Huntington's disease-like (HDL) phenotype, including 60 with typical Huntington's disease, who had tested negative for pathological expansions in the IT15 gene, the major mutation in Huntington's disease. They were screened for repeat expansions in two other genes involved in HDL phenotypes: those encoding the junctophilin-3 (JPH3/HDL2) and prion (PRNP/HDL1) proteins. In addition, because of the clinical overlap between patients with HDL disease and autosomal dominant cer- ebellar ataxia or dentatorubral and pallidoluysian atro- phy (DRPLA), we investigated trinucleotide repeat expansions in genes encoding the TATA-binding protein (TBP/SCA17) and atrophin-1 (DRPLA). Two patients carried 43 and 50 uninterrupted CTG repeats in the JPH3 gene. Two other patients had 44 and 46 CAA/ CAG repeats in the TBP gene. Patients with expansions in the TBP or JPH3 genes had HDL phenotypes indis- tinguishable from Huntington's disease. Taking into account patients with typical Huntington's disease, their frequencies were evaluated as 3% each in our series of typical HDL patients. Interestingly, incomplete pene- trance of the 46 CAA/CAG repeat in the TBP gene was observed in a 59-year-old transmitting, but healthy, parent. Furthermore, we report a new configuration of the expanded TBP allele, with 11 repeats on the first polymorphic stretch of CAGs. Expansions in the DRPLA gene and insertions in the PRNP gene were not found in our group of patients. Further genetic hetero- geneity of the HDL phenotype therefore exists.
Journal: Brain , vol. 126, no. 7, pp. 1599-1603, 2003
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    • ...This gene contributes to the stabilization of the junctional membrane complexes and defects in this gene are the cause of Huntington disease-like type 2, a neurodegenerative disorder [29]...

    António M Ramoset al. The distal end of porcine chromosome 6p is involved in the regulation ...

    • ...Huntington’s disease-like 2 (HDL2) has only been reported to date in families of African ancestry [5, 6]. Symptoms develop in young-mid adulthood, with an age of onset inversely related to size of the trinucleotide repeat expansion [7], and look very similar to those of HD. Dystonia and parkinsonism appear to be more prominent than in HD, regardless of repeat size [8]...
    • ...Parkinsonism, dystonia, and chorea may be seen in SCA17 [6, 14], in addition to the typical phenotype of ataxia, dementia, and hyperreflexia...

    Ruth H. Walker. Differential Diagnosis of Chorea

    • ...In the absence of evidence of co-segregation of the allele with 44 repeats (36,38) and because of the overlap between controls’ and patients’ ranges, caution is needed in diagnosis for such small expansions, which so far have only accounted for sporadic cases...
    • ...Determination of the pathological threshold is also complicated by the existence of an incomplete penetrance, which has been suggested for patients carrying 45 to 49 repeats since healthy carriers with 46, 48 and 49 CAG/CAA repeats aged 59, 69 and 76 years, respectively, have been reported (36,52,54)...
    • ...The remaining families, when the origins have been mentioned, are as follows: nine from Italy (15,46,53,56,58,69), three from Taiwan (37,51), two from England (70), two from France (36), and one each from Belgium (35), the USA (57) and Portugal (47)...
    • ...The frequency of SCA17 ranges from 0.3 to 3% among studies of ADCA families (11,15,35,38,47,48,67) but represents less than 1% of HD-like patients (36,49)...
    • ...More than ten SCA17 cases had no family history of neurological diseases; two of these cases were proven to result from de novo expansions (11,57) while incomplete penetrance was observed in four others (36,38,52,54), which emphasizes the importance of analyzing this gene in isolated cases with a compatible phenotype...
    • ...The clinical signs in SCA17 patients reported in the literature are summarized in Table II. The symptoms at onset, which occur at a mean age of 34.6¡13.2 years (range: 3–75), are predominantly gait instability (15,47,56) or other movement disorders, such as focal dystonia (58,68) or chorea (36,49)...
    • ...Psychiatric disturbances such as behavioural changes, psychosis or depression as well as dementia can also represent the presenting symptoms (11,35,36,49)...
    • ...Stevanin et al. 2003 (36) spo, reduced penetrance 46 CAG...
    • ...CAACAG Stevanin et al. 2003 (36) Spo 44 CAG...
    • ...SCA17 and HDL4 173 (range: 43–52 repeats) (36,46,49,50,72)...

    Giovanni Stevaninet al. Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL...

    • ... A positive diagnosis is made in only 2% of patients where a genetic Huntington’s disease phenocopy is suspected....

    E J Wildet al. The differential diagnosis of chorea

    • ...It was previously mentioned that responsible genes were not checked in the Huntington’s like disease, hence group B may belong to Huntington’s like disease category with several known and unknown responsible genes like PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2, and FTL genes (Stevanin et al. 2003; Costa Mdo et al. 2006)...

    Mohammad Mehdi Banoeiet al. Huntington’s Disease and Mitochondrial DNA Deletions: Event or Regular...

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