Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease

Kim, Ji Sun; Son, Tae Ok; Youn, Jinyoung; Ki, Chang‐Seok; Cho, Jin Whan

doi:10.3988/jcn.2013.9.4.274

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…Similar changes were found in human autopsy tissue, with evidence for demyelination and axonal degeneration in deep cerebellar white matter (Fig B). These sites of white matter pathology are positive for RAN polySer, but not for polyGln (Fig B) and are consistent with white matter abnormalities previously found by imaging and neuropathology in SCA8 patients (Kumar & Miller, ; Kim et al , ; Yokoyama et al , ). In contrast, brain regions that did not show polySer aggregates in SCA8 BAC mouse cerebellum (Fig EV3A) and human cortical white matter (Fig EV3B) did not show evidence of demyelination.…”

Section: Resultssupporting

confidence: 89%

SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F

et al. 2018

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Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

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Section: Resultssupporting

confidence: 89%

SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F

et al. 2018

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“…The genetic causes of AD‐inheritance parkinsonism pedigrees are heterogeneous and include LRRK2 , VPS35 , MAPT , GBA , DNAJC13 , C9orf72 , SCA3, SCA8, and SCA17 , and the phenotypic spectrums were also variable, ranging from levodopa‐responsive parkinsonism to rapid‐progressive parkinsonism mixed with other neurodegenerative symptoms, including FTD, motor neuron disorders, and ataxia. Our findings support previous observations that patients with increased trinucleotide repeats in SCA genes, especially SCA 2, 3, 8, and 17, may present with parkinsonism, especially in Asia . We suggest that screening of abnormal trinucleotide expansions in SCA‐related genes should be considered in patients with parkinsonism in our population.…”

Section: Discussionsupporting

confidence: 87%

“…Our findings support previous observations that patients with increased trinucleotide repeats in SCA genes, especially SCA 2, 3, 8, and 17, may present with parkinsonism, especially in Asia. [52][53][54] We suggest that screening of abnormal trinucleotide expansions in SCA-related genes should be considered in patients with parkinsonism in our population.…”

Section: Discussionmentioning

confidence: 95%

A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

et al. 2019

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Background Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD‐causative genes in a Taiwanese PD cohort. Methods A total of 571 participants including 324 patients with early‐onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next‐generation sequencing panel containing 40 known PD‐causative genes, repeat‐primed polymerase chain reaction, and whole‐exome sequencing analysis. Results Thirty of the 324 patients with early‐onset parkinsonism (9.3%) were found to carry mutations in Parkin , PINK1 , or PLA2G6 or had increased trinucleotide repeats in SCA8 . Twenty‐nine of 109 probands with autosomal‐recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin , PINK1 , GBA , or HTRA2 . The genetic causes for the 138 probands with an autosomal‐dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2 , VPS35 , MAPT , GBA , DNAJC13 , C9orf72 , SCA3, or SCA17 . A novel missense mutation in the UQCRC1 gene was found in a family with autosomal‐dominant inheritance parkinsonism via whole‐exome sequencing analysis. Conclusions Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD‐causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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“…A Japanese group analyzed the SCA8 CTA/CTG repeat for 2806 people including 448 PD patients, and 0.4% had expanded alleles (85–399) while there were no individuals with expansion among the 654 normal controls [ 79 ]. A patient with levodopa-responsive parkinsonism with additional movement disorders such as a dystonic gait and an unusual oscillatory movement of the trunk was reported as having a mutation in SCA8 in Korea [ 80 ].…”

Section: Sca8mentioning

confidence: 99%

Parkinsonism in Spinocerebellar Ataxia

Park

Kim

Jeon

2015

BioMed Research International

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Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs.

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Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease

Cited by 24 publications

References 28 publications

SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F

SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F

A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

Parkinsonism in Spinocerebellar Ataxia

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