C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Abstract

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (.3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions:Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. Neurology

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

“…Fourth, we have noted no histological distinctions between FTLD‐TDP type A or type B cases carrying expansions in C9ORF72 from those without expansions, other than the presence of p62/DPR in the former [11]. Lastly, the occurrence of several cases of FTLD where an expansion in C9ORF72 is seen in association with either MAPT [27, 28] or GRN [28] mutation suggests this is not likely to be pure chance, and in such cases, either tauopathy or FTLD‐TDP type A histology, typical of the accompanying mutation is present along with the DPR pathology.…”

“…Nonetheless, it remains possible that the expansion in C9ORF72 may act as a ‘gatekeeper’, ‘weakening’ the brain, in a so far mechanistically undiscovered way, thereby allowing or facilitating the development of ‘sporadic’ disease, or promoting other genetic forms of FTLD associated with TDP‐43 [28], or even tau [27, 28], pathology to develop. In such a scenario, there would be no requirement to directly link DPR changes associated with the expansion to those causing TDP‐43 pathology.…”

IsCHCHD10Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?: Figure 1

“…Only the proband underwent a full clinical assessment, but we note that the phenotype of the Pro34Ser-negative individual (significant memory impairment with no frontal features) was different to her sisters. With reference to point (ii), FTD patients with more than one bona fide pathogenic mutation have been described before (van Blitterswijk et al, 2013). However, the convergence of all four strands of evidence indicates that Pro34Ser is not a disease-causing mutation.…”

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

“…Neuropsychiatric profile involves early disinhibition (up to 85%), lack of insight (up to 78%), hallucinations (up to 50%), delusion (up to 50%), anxiety (up to 52%), hyperorality (up to 100%), early apathy (up to 100%), loss of empathy (up to 77%) and obsessive-compulsive symptoms (up to 12%) 5,42,43 . There is an important clinical overlap with probable Alzheimer's disease in the early-onset cases, mainly in Caucasian patients 45,46 , making it difficult to promote a proper genetic evaluation in association with classical genes (APP, PSEN1, PSEN2) 47,48 , although such cases generally present with an older age than with the FTD clinical spectrum 26 . UBQLN2 gene mutations are great mimickers frequently differentiated in clinical means by the absence of psychiatric features (not behavioural symptoms) and lower motor neuron involvement 14 .…”