Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions
Autor: | Emma L. van der Ende, Adrianna White, Harro Seelaar, Jazmyne L. Jackson, John C. van Swieten, Marka van Blitterswijk |
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Rok vydání: | 2021 |
Předmět: |
Movement disorders
Genetic counseling C9ORF72 Biology Bioinformatics 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being C9orf72 medicine Humans Dementia Clinical significance Neurodegeneration Amyotrophic lateral sclerosis 030304 developmental biology 0303 health sciences DNA Repeat Expansion C9orf72 Protein Amyotrophic Lateral Sclerosis DNA Methylation medicine.disease Psychiatry and Mental health Phenotype Frontotemporal Dementia Surgery Neurology (clinical) ALS medicine.symptom Trinucleotide repeat expansion 030217 neurology & neurosurgery Frontotemporal dementia |
Zdroj: | Journal of Neurology, Neurosurgery, and Psychiatry |
ISSN: | 1468-330X 0022-3050 |
Popis: | Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases. |
Databáze: | OpenAIRE |
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