Journal
LANCET NEUROLOGY
Volume 14, Issue 3, Pages 291-301Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S1474-4422(14)70233-9
Keywords
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Funding
- Medical Research Council, UK
- Alzheimer's Research UK
- Motor Neurone Disease Association, UK
- National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit
- Leonard Wolfson Experimental Neurology Centre
- University College London Hospitals NHS Trust Biomedical Research Centre
- Brain Research Trust
- Wellcome Trust Senior Clinical Fellowship [091673/Z/10/Z]
- Alzheimers Research UK [ARUK-PPG2012B-13, ARUK-RF2012-1, ARUK-PPG2012A-14, ARUK-PhD2012-29] Funding Source: researchfish
- Medical Research Council [MR/M023664/1, MR/J009482/1, MR/M008525/1, MR/M008606/1] Funding Source: researchfish
- Motor Neurone Disease Association [Fratta/Jan15/946-795, Isaacs/Apr13/818-791] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10033, CL-2012-18-010] Funding Source: researchfish
- MRC [MR/M023664/1, MR/M008606/1, MR/M008525/1, MR/J009482/1] Funding Source: UKRI
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C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.
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