Degenerative Diseases of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
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).
Anterograde memory in frontotemporal dementia
Lars-Göran Nilsson, Nobuo Ohta in Dementia and Memory, 2013
The inconsistent findings across studies regarding episodic memory in bvFTD are likely to be due to the inclusion of patients who do not have true progressive neurodegenerative disease. In a series of studies from Cambridge and Sydney, we identified a subset of patients who meet current clinical criteria for bvFTD yet show little or no progression over a decade or more (Davies et al., 2006; Kipps et al., 2007; Kipps, Hodges, & Hornberger, 2010; Piguet, Hornberger, Shelley, Kipps, & Hodges, 2009). These non-progressor or bvFTD patients mimic the clinical features of bvFTD but lack the typical brain atrophy found on MRI and demonstrate preserved glucose metabolism on PET (Davies et al., 2006; Kipps et al., 2007; Kipps, Nestor, Acosta-Cabronero, Arnold, & Hodges, 2009). The aetiology of these cases remains unclear. In early papers, we considered that some of these patients might have a very slowly progressive form of neurodegenerative disease. The slow disease progression recently reported in patients with the C9orf72 gene mutation would support this position (Khan et al., 2012). An alternate hypothesis is that such patients have a spectrum of personality disorders or neuropsychiatric disorders that decompensate in late mid life. The prevalence of these nonprogressor cases in existing studies is unknown, but their inclusion is likely to underplay the magnitude of the deficits in progressive, or “real,” bvFTD patients.
Neuromuscular disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Motor neurone disease is generally sporadic. Risks to first-degree relatives in two unselected series were under 1%, although these studies need to be extended in light of molecular advances. About 10% of cases are said to be familial, and more than half of these cases now have their mutational basis identified. By far the most important genetic factor identified is the C9orf72 locus, in which expansion of an unstable hexanucleotide repeat is associated with either amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). This expansion is found in some 40% of cases of familial ALS and rather less than 30% of familial FTD. Factors influencing the penetrance and the mode of disease presentation (as either motor neurone disease or dementia) are uncertain. There is an intermediate range of repeat expansion where the risk of disease is unclear. These uncertainties make the counselling for predictive genetic testing difficult, as the natural history is still only incompletely understood.
Implications of structural and functional brain changes in amyotrophic lateral sclerosis
Published in Expert Review of Neurotherapeutics, 2018
Thanuja Dharmadasa, William Huynh, Jun Tsugawa, Yoshimitsu Shimatani, Yan Ma, Matthew C. Kiernan
Post-mortem studies of the brain have clearly identified primary involvement of motor pathways in ALS, with the major pathological signature being cytoplasmic inclusions of ubiquitinated TDP-43 that appears to occur in distinct stages [11]. However, abnormalities in extra-motor function (encompassing any abnormality not due to dysfunction of the motor pathway) have added an additional layer of complexity to disease heterogeneity [12]. Of particular relevance in this regard is the frequent presence of cognitive impairment, occurring in up to 50% of patients and representing an adverse prognostic sign [13]. The recognition that ALS lies on a spectrum with frontotemporal dementia (FTD) is now well-established [14], with overt frontotemporal dementia (ALS-FTD) found in 15% of patients [15]. A mutation in the C9orf72 gene was identified to link these conditions at a genetic level [16]. Although inheritance in ALS is complex, continual discovery of novel genes such as C9orf72 is lending important insight into distinctions in prognosis and clinical traits [1,13].
A novel D90_K91insN mutation in exon 4 of the SOD1 gene caused familial amyotrophic lateral sclerosis in a Chinese pedigree
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2018
Yanran Li, Bo Sun, Siyu Chen, Yuting Ren, Fang Cui, Fei Yang, Zhaohui Chen, Li Ling, Xusheng Huang
The genomic DNA of 25 blood samples was isolated from white blood cells using a standard procedure. The whole coding areas of SOD1, ALSIN, SETX, SPG11, FUS, VAPB, ANG, TARDBP, FIG4, OPTN, ATXN2, VCP, UBQLN2, SIGMAR1, CHMP2B, PFN1, ERBB4, HNRNPA1, MAYR3 and TUBA4A gene of the proband were tested using targeted high-throughput sequencing. The C9ORF72 gene was amplified through repeat primed PCR (9). Target genes were captured with a target region related gene Enrichment System (MyGenostics Inc, Medford, MA, USA) and amplified by PCR. The PCR product was purified using SPRI beads (Beckman Coulter, Brea, CA, USA). The exome sequencing was performed on Illumina HiSeq 2000 sequencer (Illumina, San Diego, CA, USA) for paired read 150bp. The reads were mapped against UCSC hg19 using SOAPaligner. The SNPs and Indels were detected using GATK and SOAPsnp. Exon 4 in the SOD1 gene in the DNA of other relatives was examined using Sanger sequencing.
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.
Related Knowledge Centers
- Chromosome 9
- Cytoplasm
- Frontotemporal Dementia
- Open Reading Frame
- Protein
- Synapse
- Gene
- Base Pair
- Locus
- Neuron