Unravelling the clinical spectrum and the role of repeat length in <i>C9ORF72</i> repeat expansions

Ende, Emma L. van der; Jackson, Jazmyne L.; White, Adrianna; Seelaar, Harro; Blitterswijk, Marka van; Swieten, John C. van

doi:10.1136/jnnp-2020-325377

Cited by 45 publications

(38 citation statements)

References 59 publications

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“…The behavioral variant of FTD (bvFTD), characterized by behavior and social cognition alterations associated with semantic access and speech fluidity impairment, is the most frequent C9orf72 -related form of FTD [ 33 ], while the aphasic presentation of FTD is rarer but anyway possible in association with this mutation.…”

Section: Biomarkers and Outcome Measuresmentioning

confidence: 99%

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Querin

Biferi

2022

JND

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The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.

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Section: Biomarkers and Outcome Measuresmentioning

confidence: 99%

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Querin

Biferi

2022

JND

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“… 76 By contrast, age at onset of parents (or other family members) does not reliably predict FTD age of onset (except among MAPT mutation carriers) 87 or of ALS; neither does C9orf72 repeat expansion length. 106 Discovery of biomarkers that predict age of onset in ALS and FTD could transform the study of the pre-symptomatic stage of these diseases.…”

Section: Pre-symptomatic Neurodegenerative Diseasesmentioning

confidence: 99%

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Benatar

Wuu

McHutchison

et al. 2021

Brain

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Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy, and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in ALS. The development of biomarkers reflecting amyloid and tau has led to a shift in defining AD based on inferred underlying histopathology. PD is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM-sleep behavior disorder. HD benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. SMA clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in FTD illustrate the differential role of biomarkers based on genotype. Similar advances in ALS would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic ALS relies upon a clear conceptual framework for defining the earliest stages of disease. Clinically manifest ALS may emerge abruptly, especially among those who harbor genetic mutations associated with rapidly progressive ALS. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioral impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioral impairment before progression to ALS. Biomarkers are critically important to studying pre-symptomatic ALS and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counseling, informed consent, communication of results, and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counseling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building upon what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from ALS gene mutation carriers—we present a roadmap to early intervention, and perhaps even disease prevention, for all forms of ALS.

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“…The C9pos patients may rarely have other clinical presentations than ALS or FTD such as movement disorders, psychiatric symptoms, and idiopathic normal pressure hydrocephalus. 5 , 6 A younger than average age at onset and shorter survival have been relatively uniformly reported among the C9pos patients with ALS, although the penetrance of this expansion is variable. 7 A higher proportion of bulbar onset has been inconsistently reported.…”

Section: Introductionmentioning

confidence: 99%

ALS in Finland

et al. 2022

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Background and ObjectivesTo analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without the C9orf72 hexanucleotide repeat expansion.MethodsA cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes.ResultsOf the 815 patients, 25% had FALS-A and 45% FALS-NP. C9orf72 expansion (C9pos) was found in 256 (31%) of all patients, in 58% of FALS-A category, in 48% of FALS-NP category, and in 23 or 17% of sporadic cases using the FALS-A or FALS-NP definition. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between C9pos and patients with unknown cause of ALS (Unk). We found that the age at onset was significantly earlier and survival markedly shorter in the C9pos vs Unk patients with ALS. The shortest survival was found in bulbar-onset male C9pos patients, whereas the longest survival was found in Unk limb-onset males. Older age at onset associated consistently with shorter survival in C9pos and Unk patients in both limb-onset and bulbar-onset groups. There were no significant differences in the frequencies of bulbar-onset and limb-onset patients in C9pos and Unk groups. ALS-frontotemporal dementia (FTD) was more common in C9pos (17%) than in Unk (4%) patients, and of all patients with ALS-FTD, 70% were C9pos.DiscussionThese results provide further evidence for the short survival of C9orf72-associated ALS. A prominent role of the C9orf72 and SOD1 variants was found in the Finnish population. An unusually high frequency of C9pos was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.

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Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions

Cited by 45 publications

References 59 publications

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

ALS in Finland

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