Compound heterozygous intermediate MJD alleles cause cerebellar ataxia with sensory neuropathy

Takahashi, Yūji; Kanai, Masahiro; Tomoya, Taminato; Watanabe, Shoko; Matsumoto, Chihiro; Araki, Toshiyuki; Okamoto, Tomoko; Ogawa, Masanori; Matsushima, Miho

doi:10.1212/nxg.0000000000000123

Cited by 3 publications

(2 citation statements)

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“…The highest homozygous number of repeats was 12 repeats (Additional file 1 : Supplementary Table 5) indicating that most of the risk genotypes were compound heterozygotes. Compound heterozygote effect of the intermediate-length CAG-repeat alleles has been previously shown in spinocerebellar ataxia 3 [ 22 ]. The “two copy effect” was further supported by the association of the risk haplotype marker homozygosity with ALS (Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Kaivola

Salmi

Jansson

et al. 2020

acta neuropathol commun

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The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

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Section: Discussionmentioning

confidence: 99%

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Kaivola

Salmi

Jansson

et al. 2020

acta neuropathol commun

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“…2, Patient :1) in our research harboring intermediate ( 55) CAG repeat lengths showed only progressive tremor of his arms without other neurological signs, such as ataxia. Previous reports also described SCA3 patients with intermediate repeats involved with peripheral nervous system dysfunction [32][33][34][35] , like restless legs syndrome, and sensory axonal neuropathy. One assumption in explaining the mild performance of our patient is that only one intermediate allele is not enough to trigger polyglutamine-derived cytotoxicity compared with two intermediate alleles together.…”

Section: Discussionmentioning

confidence: 99%

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China

Zheng,

Zhu,

et al. 2024

Mol Biol Rep

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BackgroundEssential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. MethodWe investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. ResultWe found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. ConclusionTremor can be the initial phenotype of certain SCA and it is necessary to screen SCAs in ET patients, especially in early-onset and familial patients.

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Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China

Zheng

Zhu

et al. 2023

Preprint

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Background Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown.Method We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022.Result We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions.Conclusion Tremor can be the initial phenotype of certain SCA and it is necessary to screen SCAs in ET patients, especially in early-onset and familial patients.

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Compound heterozygous intermediate MJD alleles cause cerebellar ataxia with sensory neuropathy

Cited by 3 publications

References 7 publications

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China

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