Survival and Prognostic Factors in <i>C9orf72</i> Repeat Expansion Carriers

Glasmacher, Stella A.; Wong, Charis; Pearson, Iona; Pal, Suvankar

doi:10.1001/jamaneurol.2019.3924

Cited by 34 publications

(28 citation statements)

References 68 publications

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“…In a population-based study by Chiò et al [6], genetic mutations did not modify the effect of sex on clinical phenotype, neither motor nor cognitive. Similarly, Glasmacher et al [109] did not find an association between sex and survival in C9orf72 repeat expansion carriers. With regard to evidence of potential sex-genetics interplay in C9orf72 repeat expansion (C9+) carriers, a recent meta-analysis on sex differences in genetic mutations in ALS and FTD showed that in women there has been a higher prevalence of expanded C9orf72-related ALS [104].…”

Section: Interplay Between Sex and Genetics In Als Pathogenesismentioning

confidence: 90%

“…In a population-based study by Chiò et al [6], genetic mutations did not modify the effect of sex on clinical phenotype, neither motor nor cognitive. Similarly, Glasmacher et al [109] did not find an association between sex and survival in C9orf72 repeat expansion carriers. gender-specific differences for age of onset in C9orf72-linked ALS: male subjects are more likely to express the disease at a younger age…”

Section: Interplay Between Sex and Genetics In Als Pathogenesismentioning

confidence: 90%

See 1 more Smart Citation

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Trojsi

D’Alvano

Bonavita

et al. 2020

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

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Section: Interplay Between Sex and Genetics In Als Pathogenesismentioning

confidence: 90%

“…In a population-based study by Chiò et al [6], genetic mutations did not modify the effect of sex on clinical phenotype, neither motor nor cognitive. Similarly, Glasmacher et al [109] did not find an association between sex and survival in C9orf72 repeat expansion carriers. gender-specific differences for age of onset in C9orf72-linked ALS: male subjects are more likely to express the disease at a younger age…”

Section: Interplay Between Sex and Genetics In Als Pathogenesismentioning

confidence: 90%

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Trojsi

D’Alvano

Bonavita

et al. 2020

IJMS

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“…12 The association between age and survival is variably reported amongst FTLD subtypes. Older age appears to portend shorter survival from disease onset in bvFTD 13 and FTD-ALS 14 with variable reports in PSP 15,16,17 . A series of 100 patients with SD found no association between age and survival.…”

Section: Demographic Factorsmentioning

confidence: 95%

Predictors of survival in frontotemporal lobar degeneration syndromes

El-Wahsh

Finger

Piguet

et al. 2021

J Neurol Neurosurg Psychiatry

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After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.

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“…9 13 14 The initial presentation and disease course also vary widely (box 1, table 1); survival after symptom onset ranges from 2 months in rapidly progressive ALS to over 30 years in slowly progressive behavioural variant FTD (bvFTD). 14…”

Section: Epidemiology Of C9orf72 Repeat Expansionsmentioning

confidence: 99%

“…Other motor neuron diseases, including progressive muscular atrophy and primary lateral sclerosis, are rare in C9orf72 expansion carriers. 14…”

Section: Neurodegeneration Motor Neuron Diseasesmentioning

confidence: 99%

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

Ende

Jackson

White

et al. 2021

J Neurol Neurosurg Psychiatry

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Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases.

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Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers

Cited by 34 publications

References 68 publications

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Predictors of survival in frontotemporal lobar degeneration syndromes

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

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