Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72

Konno, Tetsuo; Shiga, Atsushi; Tsujino, Akira; Sugai, Akihiro; Kato, Taisuke; Kanai, Kazuaki; Yokoseki, Akio; Eguchi, Hiroto; Kuwabara, Satoshi; Nishizawa, Masatoyo; Takahashi, Hitoshi; Onodera, Osamu

doi:10.1136/jnnp-2012-302272

Cited by 77 publications

(51 citation statements)

References 13 publications

(29 reference statements)

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“…Similar rates are reported for the association between C9ORF72 and fronto-temporal dementia (FTD), linking to the same gene 2 apparent distinct phenotypes. The prevalence of C9ORF72 in ALS cases is much lower in East (less than 4% in Japan) [32] and South Asia (5.9% among familial and 1.6% among sporadic in Iran) [33]. Behavioral clinical features are more common in ALS and FTD with C9ORF72 mutation.…”

Section: C9orf72 and Geographic Spreading Of Genetic Riskmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference

Logroscino

Piccininni

2019

Neuroepidemiology

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Amyotrophic lateral sclerosis (ALS) epidemiology has rapidly developed in the last 30 years alongside the evolving changes in concepts in the field of clinical ALS and also due to the recent proposals of new classification system for motor neuron diseases. Many of these changes in the clinical scenario have been determined through the results of ALS population-based studies conducted in the last 20 years primarily in Europe. All the evidences converge to show that ALS risk is different across continents and ethnicities. In a European registry consortium named EURALS, ALS incident cases were drawn from a source population comprising almost 24 million people across Europe (ALS cases: 1028) and the estimated incidence was 2.2 per 100,000 person-years (py) for the general population. In contrast, other population-based studies have measured the lowest incidence in East Asia to be 0.89 per 100,000 py and in South Asia to be 0.79 per 100,000 py. A large part of Africa, Latin America and Asia does not have any population-based studies. The origin of geographic difference in ALS incidence is a matter of debate. Probably, this is partly due to genes (C9ORF72) and partly due to environmental risk factors. The rapid disappearance of ALS Foci in Guam, Kii, and West Guinea underline the importance of changes in lifestyle and environmental factors. The Global Burden of Disease, a project aiming to describe the burden of all diseases and injuries across all the countries of the world with a standardized protocol, has collected heterogeneous sources of data to estimate the burden of motor neuron diseases. The demographic changes related to increased expectation of life and the growth of the world population indicate that the load of motor neuron disease is rapidly moving toward 400 thousand prevalent cases. The burden is expected to shift toward Asia and Africa in the next decades for the rapid increase of expectation of life of countries with high demographic impact.

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Section: C9orf72 and Geographic Spreading Of Genetic Riskmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference

Logroscino

Piccininni

2019

Neuroepidemiology

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“…However, the reported frequencies in Asian samples have been lower. Four studies have reported a low frequency of HRE in Japanese ALS cases (0 -3.4% in fALS, and 0.4% sALS) [73,78,129,130] and a higher frequency was reported in cases from Taiwan of Han Chinese ancestry (18.2% in fALS, and 2.0% in sALS) [75]. In the present study, the author reports that the frequency of the C9orf72 HRE in Chinese sALS patients is 0.3%.…”

Section: Discussionsupporting

confidence: 45%

“…To date, this is the largest cohort screened in non-Caucasian ALS cases. Previous reports about C9orf72 HRE in different populations support the hypothesis that the pathogenic HRE arose from a single founder haplotype both in Caucasian and Asian populations [11,73,75,78,80,81,129,130], although for cases in Taiwan it was postulated that the HRE was introduced in the 17 th century when Taiwan was under Dutch and Spanish colonial rule. The conjecture that Asian HREs arose on the same European founder seems inconsistent with the mutation occurring in a founder 1,500 years ago [78].…”

Section: Discussionmentioning

confidence: 97%

“…The reported frequencies in Asia have been lower. Two Japanese studies report that the frequencies of the repeat expansion range from 0-3.4% in fALS and 0-0.4% in sALS [73,74]. In contrast, a small study in Taiwanese of Han Chinese ancestry reported higher frequencies of the repeat expansion (18.2% in fALS patients and 2.0% in sALS patients) [75].…”

Section: C9orf72 Gene and Alsmentioning

confidence: 98%

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Genetics of amyotrophic lateral sclerosis in the Han Chinese

He¹

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Amyotrophic lateral sclerosis is the most frequently occurring neuromuscular degenerative disorders, and has an obscure aetiology. Whilst major progress has been made, the majority of the genetic variation involved in ALS is, as yet, undefined. In this thesis, multiple genetic studies have been conducted to advance our understanding of the genetic architecture of the disease. In the light of the paucity of comprehensive genetic studies performed in Chinese, the presented study focused on advancing our current understanding in genetics of ALS in the Han Chinese population. To identify genetic variants altering risk of ALS, a genome-wide association study (GWAS) was performed.The study included 1,324 Chinese ALS cases and 3,115 controls. After quality control, a number of analyses were performed in a cleaned dataset of 1,243 cases and 2,854 controls that included: a genome-wide association analysis to identify SNPs associated with ALS; a genomic restricted maximum likelihood (GREML) analysis to estimate the proportion of the phenotypic variance in ALS liability due to common SNPs; and a genebased analysis to identify genes associated with ALS. There were no genome-wide significant SNPs or genes associated with ALS. However, it was estimated that 17% (SE: 0.05; P=6×10 -5 ) of the phenotypic variance in ALS liability was due to common SNPs. The top associated SNP was within GNAS (rs4812037; p =7×10 -7 ). GNAS was also the most associated gene from the gene-based study (p =2×10 -5 ). Based on GWAS data, a fragment-length and repeat-primed PCR was performed to determine GGGGCC copy number and expansion within the C9orf72 gene in the cohorts (1,092 sporadic ALS and 1,062 controls) from China.A haplotype analysis of 23 SNPs within and surrounding the C9orf72 gene was performed.The C9orf72 hexanucleotide (GGGGCC)n repeat expansion (HRE) was found in three sALS patients (0.3%) but not in control subjects (p = 0.25, Fisher's exact test). Two cases 2 with HRE did not harbor four risk alleles that have previously been determined to be Contributions by others to the thesis

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“…However, FTLD or ALS associated with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansion exhibits pathological aggregation of TDP-43 and, in some cases, low penetration, 20,21 although these mutations are extremely rare in Japan. 22 It was recently reported that the pattern of ubiquilin abnormalities in ALS and FTLD corresponds well with the presence of C9ORF72 hexanucleotide expansion. 23 The UBQLN-2-positive, p62-positive, but TDP-43-negative thick dystrophic neurites are abundantly present in patients with C9ORF72 hexanucleotide expansion, predominantly in the hippocampus and cerebellum.…”

Section: Immunohistochemical Screening Of Hexanucleotide Repeat Expanmentioning

confidence: 97%

Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa–Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

et al. 2014

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IMPORTANCE TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge.OBJECTIVE To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. DESIGN AND SETTING A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). MAIN OUTCOMES AND MEASURES Neuronal TDP-43 pathological changes and neuronal loss.RESULTS Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. CONCLUSIONS AND RELEVANCEThe LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.

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Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72

Abstract: C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

Cited by 77 publications

References 13 publications

Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference

Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference

Genetics of amyotrophic lateral sclerosis in the Han Chinese

Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa–Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

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