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Background <p>Pathogenic hexanucleotide repeat expansions in <i>C9orf72</i> are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in <i>C9orf72</i> and their relationship to a wide range of neurological presentations, including Alzheimer’s disease, Parkinson’s disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.</p> Aims <p>To assess the prevalence of intermediate <i>C9orf72</i> repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and&#xa0;CBD in neuropathologically confirmed cases.</p> Methods <p>626 cases, including PSP (<i>n</i> = 366), CBS (<i>n</i> = 130), and APS (<i>n</i> = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in <i>C9orf72</i> using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.</p> Results <p>There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large <i>C9orf72</i> repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.</p> Conclusions <p>Intermediate expansions in <i>C9orf72</i> do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.</p>

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Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism

  • 期刊论文

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  • 发表日期：

    2025年3月26日

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  • David P. Vaughan,
  • Raquel Real,
  • Marte Theilmann Jensen,
  • Riona G. Fumi,
  • Megan Hodgson,
  • Edwin Jabbari,
  • Danielle Lux,
  • Lesley Wu,
  • Thomas T. Warner,
  • Zane Jaunmuktane,
  • Tamas Revesz,
  • James B. Rowe,
  • Jonathan Rohrer,
  • Huw R. Morris

摘要

Background

Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer’s disease, Parkinson’s disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.

Aims

To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and CBD in neuropathologically confirmed cases.

Methods

626 cases, including PSP (n = 366), CBS (n = 130), and APS (n = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.

Results

There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.

Conclusions

Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.