Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion

Obayashi, Masato; Stevanin, Giovanni; Synofzik, Matthis; Monin, Marie‐Lorraine; Duyckaerts, Charles; Sato, Nozomu; Streichenberger, Nathalie; Vighetto, Alain; Desestret, Virginie; Tesson, Christelle; Wichmann, H‐Erich; Illig, Thomas; Huttenlocher, Johanna; Kita, Yasushi; Izumi, Yuishin; Mizusawa, Hidehiro; Schöls, Lüdger; Klopstock, Thomas; Brice, Alexis; Ishikawa, Kinya; Dürr, Alexandra

doi:10.1136/jnnp-2014-309153

Cited by 55 publications

(62 citation statements)

References 31 publications

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“…When compared with other reports, the prevalence of SCA36 in the United States (n = 577, 0.7%) appears to be less frequent than in most other countries evaluated to date, including Spain (n = 160, 6.3%), 9 France (n = 270, 4.4%), 8 Western Japan (n = 251, 3.6%), 7 and Eastern Japan (n = 231, 2.2%) 8 and is more similar to that of China (n = 512, 0.6%) 10 and Germany (n = 175, 0.0%) 8 (table 3). It should be noted that our cohort was of general undiagnosed patients with ataxia, unselected by mode of inheritance or other features, in whom the most frequent genetic etiologies had been previously excluded.…”

Section: Discussionmentioning

confidence: 53%

“…Because RP-PCR lacks the ability to quantitate expansion size, Southern blot analysis was used as a second confirmatory technique, detecting NOP56 repeat expansions in the probands from families A and B (figure 1B). Given that SCA36 is considered a rare repeat expansion disorder, but has been observed to have varying prevalence in different ethnic populations, 7–10 the finding of 2 consecutive SCA36 families prompted us to evaluate our entire clinical cohort for the disease to determine the prevalence in a US ataxic population. We analyzed 577 index cases using fluorescent RP-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…7 Individuals with this disorder show progressive, late-onset, ataxic symptoms affecting limb, trunk, and/or gait stability. 7 To date, SCA36 prevalence has been reported in regions of Japan, 7,8 Spain, 9 France, 8 Germany, 8 and most recently, in China, 10 but its prevalence in the United States is undetermined. Through combined methods of exome sequencing, linkage analysis, and fluorescent repeat primed PCR (RP-PCR), we molecularly identified SCA36 in 4 index cases, representing less than 1% of the undiagnosed population at a tertiary referral ataxia center.…”

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confidence: 99%

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Prevalence of spinocerebellar ataxia 36 in a US population

et al. 2017

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Objective:To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States.Methods:A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the NOP56 gene.Results:Fragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56 in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment.Conclusions:In a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort.

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Section: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Prevalence of spinocerebellar ataxia 36 in a US population

et al. 2017

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“…SCA36 was initially identified in Japan, and SCA36 causative mutation proved to be the same in a familial ataxia in Spain 2 . SCA36 patients have also been found in France and China 3, 4, 5. The mean onset age of SCA36 is in the fifth decade, and the mean duration of the illness is over 10 years 6 .…”

Section: Introductionmentioning

confidence: 99%

Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs

Matsuzono

Imamura

Murakami

et al. 2017

Molecular Therapy - Nucleic Acids

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Spinocerebellar ataxia type 36 is a late-onset, slowly progressive cerebellar syndrome with motor neuron degeneration that is caused by expansions of a hexanucleotide repeat (GGCCTG) in the noncoding region of NOP56 gene, with a histopathological feature of RNA foci formation in postmortem tissues. Here, we report a cellular model using the spinocerebellar ataxia type 36 patient induced pluripotent stem cells (iPSCs). We generated iPSCs from spinocerebellar ataxia type 36 patients and differentiated them into neurons. The number of RNA-foci-positive cells was increased in patient iPSCs and iPSC-derived neurons. Treatment of the 2′-O, 4′-C-ethylene-bridged nucleic acid antisense oligonucleotides (ASOs) targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to ∼50% in patient iPSCs and iPSC-derived neurons. NOP56 mRNA expression levels were lower in patient iPSCs and iPSC-derived neurons than in healthy control neurons. One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons. These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36.

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“…In the cerebellum, the dysfunction and death of Purkinje cells, granule cells or interneurons can cause SCA [3]. Molecular mechanisms for this pathology commonly include polyglutamine tract expansion [4], flawed basal transcription and defective DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Successful Diagnosis of Spinocerebellar Ataxia in a Patient Presenting with Progressive Incoordination of Movements

Memon¹,

Memon²,

Memon³

2017

J Neurol Disord

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A number of disorders cause ataxia which are the determinants of the choice of treatment for the patients affected by it. Correct diagnosis of the underlying disorder depends, not only on the qualification of the attending doctor but also on the accurate communication of the patient with the doctor. History thus plays a vital role in the diagnosis. Proper management might follow counselling sessions at times just to highlight the importance of history to a patient who is unaware about it. Here we present the case of a 32-year-old male who was experiencing progressive motor impairment. This report highlights the value of proper history in the diagnosis of the disease our patient is affected with.

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Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion

Cited by 55 publications

References 31 publications

Prevalence of spinocerebellar ataxia 36 in a US population

Prevalence of spinocerebellar ataxia 36 in a US population

Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs

Successful Diagnosis of Spinocerebellar Ataxia in a Patient Presenting with Progressive Incoordination of Movements

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