Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis

Colombo, Eleonora; Poletti, Barbara; Maranzano, Alessio; Peverelli, Silvia; Solca, Federica; Colombrita, Claudia; Torre, Silvia; Tiloca, Cinzia; Verde, Federico; Bonetti, Ruggero; Carelli, Laura; Morelli, Claudia; Silani, Vincenzo; Ticozzi, Nicola

doi:10.1007/s00415-022-11433-z

Cited by 12 publications

(20 citation statements)

References 40 publications

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“…A number of studies have found a reduced survival time in patients with C9pALS compared with C9nALS,4 6–9 12 13 15 17 18 while others did not 10 19. When compared with patients carrying other ALS-causing mutations, C9ORF72 gene carriers had a similar survival time to patients who were SOD1 positive (median 3.2 and 3.8 years, respectively), with shorter survival time for FUS carriers (median 1.9 years) and longer for TARDBP carriers (median 5.0 years) 5.…”

Section: Introductionmentioning

confidence: 96%

“…Previous studies have found variations in the phenotype of patients with C9ORF72 gene-positive ALS (C9pALS) compared with C9ORF72 gene-negative ALS (C9nALS). In particular, there is a greater prevalence of cognitive impairment 4–13. Other aspects of the C9pALS phenotype are less well defined however.…”

Section: Introductionmentioning

confidence: 99%

“…Other aspects of the C9pALS phenotype are less well defined however. Some studies found an increased prevalence of bulbar disease for C9pALS compared with C9nALS,5 6 10 11 14 while others found no significant difference 4 8 12 15. One large study in Italy showed a higher burden of upper motor neuron (UMN) signs at presentation in patients with C9pALS compared with C9nALS,6 while another study showed no significant difference between cohorts 11.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies found an increased prevalence of bulbar disease for C9pALS compared with C9nALS,5 6 10 11 14 while others found no significant difference 4 8 12 15. One large study in Italy showed a higher burden of upper motor neuron (UMN) signs at presentation in patients with C9pALS compared with C9nALS,6 while another study showed no significant difference between cohorts 11. A number of studies have reported earlier age at disease onset in C9pALS versus C9nALS3 4 6–9 11 13 15–17; however, this finding has not been consistently replicated 10 12 14.…”

Section: Introductionmentioning

confidence: 99%

“…One large study in Italy showed a higher burden of upper motor neuron (UMN) signs at presentation in patients with C9pALS compared with C9nALS,6 while another study showed no significant difference between cohorts 11. A number of studies have reported earlier age at disease onset in C9pALS versus C9nALS3 4 6–9 11 13 15–17; however, this finding has not been consistently replicated 10 12 14. One study suggested that age at onset in C9pALS is similar to patients with other ALS-causing mutations, such as SOD1, TARDBP and FUS 5.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypical differences ofC9ORF72gene-positive and negative amyotrophic lateral sclerosis: a comparative case series

et al. 2023

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BackgroundHexanucleotide repeat expansions ofC9ORF72account for a significant proportion of autosomal dominant neurodegenerative diseases in the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia spectrum. In the absence of a family history, clinical identification of such patients remains difficult. We aimed to identify differences in demographics and clinical presentation between patients withC9ORF72gene-positive ALS (C9pALS) versusC9ORF72gene-negative ALS (C9nALS), to aid identification of these patients in the clinic and examine differences in outcomes including survival.MethodsWe retrospectively reviewed the clinical presentations of 32 patients with C9pALS and compared their characteristics with a cohort of 46 patients with C9nALS from the same tertiary neurosciences centre.ResultsPatients with C9pALS more commonly presented with mixed upper and lower motor signs (C9pALS 87.5%, C9nALS 65.2%; p=0.0352), but less frequently presented with purely upper motor neuron signs (C9pALS 3.1%, C9nALS 21.7%; p=0.0226). The C9pALS cohort had a higher frequency of cognitive impairment (C9pALS 31.3%, C9nALS 10.9%; p=0.0394) and bulbar disease (C9pALS 56.3%, C9nALS 28.3%; p=0.0186). There were no differences between cohorts in age at diagnosis, gender, limb weakness, respiratory symptoms, presentation with predominantly lower motor neuron signs or overall survival.DiscussionAnalysis of this ALS clinic cohort at a UK tertiary neurosciences centre adds to the small but growing understanding of the unique clinical features of patients with C9pALS. In the age of precision medicine with expanding opportunities to manage genetic diseases with disease-modifying therapies, clinical identification of such patients is increasingly important as focused therapeutic strategies become available.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phenotypical differences ofC9ORF72gene-positive and negative amyotrophic lateral sclerosis: a comparative case series

et al. 2023

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High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants

Calvo,

Moglia,

Canosa

et al. 2024

Annals of Neurology

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ObjectiveWhile the cognitive‐behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive‐behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS‐related genes (wild‐type [WT]‐ALS) and healthy controls.MethodsAll ALS patients seen at the Turin ALS expert center in the 2009–2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1‐ALS) and WT‐ALS (n = 829) were enrolled in the study. A series of 129 controls was also included.ResultsAmong the 28 SOD1‐ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS‐FTD. SOD1‐ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1‐ALS patients had similar scores in all tests compared to WT‐ALS, except the Story‐based Empathy Task (SET), where they performed worse.InterpretationCognitive‐behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1‐ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1‐ALS. ANN NEUROL 2024

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The value of routine blood work-up in clinical stratification and prognosis of patients with amyotrophic lateral sclerosis

Gentile,

Maranzano,

Verde

et al. 2023

J Neurol

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Background There is an unmet need in amyotrophic lateral sclerosis (ALS) to provide specific biomarkers for the disease. Due to their easy availability, we aimed to investigate whether routine blood parameters provide useful clues for phenotypic classification and disease prognosis. Methods We analyzed a large inpatient cohort of 836 ALS patients who underwent deep phenotyping with evaluation of the clinical and neurophysiological burden of upper (UMN) and lower (LMN) motor neuron signs. Disability and progression rate were measured through the revised ALS Functional Rating Scale (ALSFRS-R) and its changes during time. Cox regression analysis was performed to assess survival associations. Results Creatinine significantly correlated with LMN damage (r = 0.38), active (r = 0.18) and chronic (r = 0.24) denervation and baseline ALSFRS-R (r = 0.33). Creatine kinase (CK), alanine (ALT) and aspartate (AST) transaminases correlated with active (r = 0.35, r = 0.27, r = 0.24) and chronic (r = 0.37, r = 0.20, r = 0.19) denervation, while albumin and C-reactive protein significantly correlated with LMN score (r = 0.20 and r = 0.17). Disease progression rate showed correlations with chloride (r = −0.19) and potassium levels (r = −0.16). After adjustment for known prognostic factors, total protein [HR 0.70 (95% CI 0.57–0.86)], creatinine [HR 0.86 (95% CI 0.81–0.92)], chloride [HR 0.95 (95% CI 0.92–0.99)], lactate dehydrogenase [HR 0.99 (95% CI 0.99–0.99)], and AST [HR 1.02 (95% CI 1.01–1.02)] were independently associated with survival. Conclusions Creatinine is a reliable biomarker for ALS, associated with clinical features, disability and survival. Markers of nutrition/inflammation may offer additional prognostic information and partially correlate with clinical features. AST and chloride could further assist in predicting progression rate and survival.

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Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis

Cited by 12 publications

References 40 publications

Phenotypical differences ofC9ORF72gene-positive and negative amyotrophic lateral sclerosis: a comparative case series

Phenotypical differences ofC9ORF72gene-positive and negative amyotrophic lateral sclerosis: a comparative case series

High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants

The value of routine blood work-up in clinical stratification and prognosis of patients with amyotrophic lateral sclerosis

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