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Clinical presentation and differential diagnosis of dementia in younger people
Published in Marjolein de Vugt, Janet Carter, Understanding Young Onset Dementia, 2021
Yolande A.L. Pijnenburg, Cynthia Klaassen
Genetic testing for the known mutations is recommended in the case of bvFTD with at least one first-degree family member affected with FTD or dementia, Parkinson's disease or related disorders, ALS or late onset psychiatric disorder. Since the clinical picture of C9ORF72 is more variable and includes psychiatric presentations, genetic testing for this mutation is recommended in all cases of late onset and unexplained behavioural change (Ducharme et al., 2020).
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Up to 25% of FTD cases appear to have an autosomal dominant inheritance pattern; however, 20–40% show instead a polygenic familial inheritance pattern. Mutations in the following genes are associated with familial FTDs:15–19MAPτ on chromosome 17q21–22, encoding tau protein.GRN on chromosome 17q21.32, encoding progranulin.C9orf72 on the short arm of chromosome 9, noncoding.VCP, CHMP2B, TBK1, FUS, and TARDBP (less commonly).
Pharmacological Management of Amyotrophic Lateral Sclerosis
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Tanya Sharma, Manisha Singh
In case of ALS, both the upper and lower motor neurons undergo for progressive degeneration. It leads to a range of disorders that lead to front temporal dementia at the other end (Philips and Robberecht, 2013). Although many of the sporadic cases lack the knowledge of a known genetic cause, a large number of the familial forms of ALS have now been known to bear a genetic background which are associated by means of some mutation in genes such as SOD1, FUS, C9ORF72, and TARDBP (Renton et al., 2013). The mutations reported in these proteins are known to trigger their aggregate formation which can further exhibit the toxic effect that leads to cell-specific deterioration (Ferraiuolo et al., 2011). Till date, the suitable drugs which can considerably diminish this gain-of-toxic function of these proteins are yet to be discovered. However, targeting the synthesis of such toxic protein by various specific approaches such by targeting the RNA can probably attain this goal. RNA-targeted Therapeutic approaches based upon targeting the RNA, which involve small interfering RNA (siRNA) as well as antisense oligonucleotides (ASOs) are in the developmental process for genetic forms of ALS (Evers et al., 2015).
Electrical impedance myography (EIM) in a natural history study of C9ORF72 mutation carriers
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Michelle B. Offit, Tianxia Wu, Mary Kay Floeter, Tanya J. Lehky
One of the most common genetic defects associated with ALS in the United States is the C9ORF72 expansion mutation, accounting for up to 40% familial ALS and 5–10% of sporadic ALS (1–3). The mutation consists of a hexanucleotide repeat expansion located in the C9ORF72’s first intron (4). The spectrum of clinical manifestations of C9ORF72 gene mutations includes ALS, frontotemporal dementia or other dementia (FTD/dementia), combined ALS-FTD, and asymptomatic carriers (ASYMP) (5,6). The development of symptoms is age-dependent, with a wide range of ALS symptom onset from mid-20s to nearly 90 years old and median onset at age 58. Males who develop ALS tend to be younger, while FTD patients and females with ALS develop symptoms at slightly older ages (7,8). In designing clinical trials targeted at ALS patients with the C9ORF72 gene mutation, there is a critical need for biomarkers that are sensitive to change in small population groups (9).
Spectroscopic markers of neurodegeneration in the mesial prefrontal cortex predict survival in ALS
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Chris Hanstock, Kerry Sun, Changho Choi, Dean Eurich, Richard Camicioli, Wendy Johnston, Sanjay Kalra
A limitation of the study is that the scanning technique we utilized precluded the quantification of other metabolites, including choline, whose prognostic value has been explored previously (20). The status of a C9ORF72 mutation is unknown for these patients, as the study was conducted before the discovery of this cause of ALS. As the C9ORF72 hexanucleotide expansion is accompanied by differing CNS changes as determined by MRI (22), future studies could examine the neuroanatomical basis of reduced survival in this group compared to those without the expansion (38,40). A further limitation is the small sample size. This study is being replicated in the Canadian ALS Neuroimaging Consortium (CALSNIC), wherein the baseline MRS characteristics have recently been reported in 65 patients with ALS (41). The patients will be followed prospectively to determine the prognostic utility of MRS (among other imaging measures) on survival. The CALSNIC study will also be able to determine the contribution of other potentially important clinical factors that were not available in our cohort of patients, such as diagnostic delay and the rate of ALSFRS-R decline.
How can an understanding of the C9orf72 gene translate into amyotrophic lateral sclerosis therapies?
Published in Expert Review of Neurotherapeutics, 2019
Sarah H. Berth, Thomas E. Lloyd
The recent discovery that a major cellular process affected by mutated C9orf72 is nucleocytoplasmic transport (NCT) [4–6] has opened promising avenues of research. Using a genetic screen in a Drosophila model expressing GGGGCC repeats, RanGAP, a major regulator of NCT, was identified as a suppressor of NRE toxicity [4]. RanGAP is a GTPase-activating protein (GAP) localized to the cytoplasmic face of the nuclear pore complex (NPC) that stimulates the hydrolysis of RanGTPase in the cytoplasm, favoring importin-mediated nuclear import of proteins containing a nuclear localization sequence (NLS). Importantly, RanGAP is inhibited by the GGGGCC repeat, leading to mislocalization of Ran to the cytoplasm in fly models and also in induced pluripotent stem cells differentiated into neurons (iPSN) from patients with C9orf72 mutation causing ALS [4]. This alteration of the Ran gradient has been shown to disrupt the nuclear import of NLS-containing proteins in fly and iPSN models of C9-ALS. Additionally, accumulation of nuclear transport proteins within stress granules (SGs) in response to cellular stress may be a common pathogenic mechanism in multiple neurodegenerative diseases including C9-ALS [7,8], and thus SGs are a promising therapeutic target upstream of NCT disruption.