期刊
ACTA NEUROPATHOLOGICA
卷 127, 期 3, 页码 333-345出版社
SPRINGER
DOI: 10.1007/s00401-014-1251-9
关键词
Amyotrophic lateral sclerosis; Frontotemporal lobar dementia; C9ORF72; G4C2 expansion; Phenotypic variation; Genetic modifiers
资金
- Motor Neurone Disease Association/Medical Research Council Lady Edith Wolfson Fellowship
- NIHR Senior Investigator
- MNDA, a European Community under the Euro-MOTOR project [259867]
- European Union Joint Programme-Neurodegenerative Disease Research (JPND)
- Nationale de la Recherche (ANR)
- Germany, Bundesministerium fur Bildung und Forschung (BMBF)
- Ireland, Health Research Board (HRB)
- Italy, Ministero della Salute
- The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw)
- Poland, Narodowe Centrum Badan i Rozwoju
- Portugal, Fundacao a Ciencia e a Tecnologia
- Spain, Ministerio de Ciencia e Innovacion
- Switzerland, Schweizerischer Nationalfonds zur Forderung der wissenschaftlichen Forschung (SNF)
- Turkey, Tubitak
- United Kingdom, Medical Research Council (MRC)
- MRC [MR/K003771/1, MR/K000039/1] Funding Source: UKRI
- Medical Research Council [MR/K000039/1, MR/K003771/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
The GGGGCC (G(4)C(2)) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G(4)C(2) repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G(4)C(2) repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.
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