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. 2023 Feb;270(2):898-908.
doi: 10.1007/s00415-022-11433-z. Epub 2022 Oct 29.

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

Eleonora Colombo  1 , Barbara Poletti  1 , Alessio Maranzano  1   2 , Silvia Peverelli  1 , Federica Solca  1 , Claudia Colombrita  1 , Silvia Torre  1 , Cinzia Tiloca  1 , Federico Verde  1   2 , Ruggero Bonetti  1   2 , Laura Carelli  1 , Claudia Morelli  1 , Antonia Ratti  1   3 , Vincenzo Silani  1   2 , Nicola Ticozzi  4   5
Affiliations

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

Eleonora Colombo et al. J Neurol. 2023 Feb.

Erratum in

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor.

Methods: We studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively.

Results: C9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10-4), lower degrees of depression (P = 0.015) and anxiety (P = 0.008) compared to C9Neg cases.

Conclusions: Our study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype.

Keywords: ALS; Frontotemporal dementia; Genetics; Motor neuron disease.

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Conflict of interest statement

E.Colombo, B. Poletti, A. Maranzano, S. Peverelli, F. Solca, C. Colombrita, S. Torre, C. Tiloca, F. Verde, R. Bonetti, L. Carelli, C. Morelli report no disclosures. A. Ratti received research funding from AriSLA. V. Silani received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb Srl, and Novartis Pharma AG. He receives or has received research support from the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is on the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. N. Ticozzi received compensation for consulting services from Amylyx Pharmaceuticals and Zambon Biotech SA. He received research funding from the Italian Ministry of Health and AriSLA. He is Associate Editor for Frontiers in Aging Neuroscience.

Figures

Fig. 1
Fig. 1
Kaplan–Meier plots of survival probabilities. Patients carrying the pathogenic C9orf72 repeat expansion (C9Pos, red line) display shorter survival time compared to patients without the genetic mutations (C9Neg, grey line); + : censored cases
Fig. 2
Fig. 2
Representative Southern blot images of 12 different C9Pos blood DNA samples. A C9Neg sample was also included as negative control. The mode value within the smear range in each lane was considered for HRE size (Asterisks). Arrowheads indicate the C9orf72 wild-type allele (2.3 Kb). C9Pos, patients carrying C9orf72 repeat expansion; C9Neg, patients without C9orf72 repeat expansion
Fig. 3
Fig. 3
Correlation between hexanucleotide repeat expansion size and cognitive features. Simple dispersion with adjustment curve of hexanucleotide repeat expansion length, respectively for Edinburgh Cognitive and Behavioural ALS Screen (ECAS) total (R2 = 0.261, P = 0.036) (A), ECAS ALS-specific (R2 = 0.275, P = 0.031) (B), ECAS ALS-nonspecific (R2 = 0.048, P = NS) (C), ECAS language (R2 = 0.202, P = NS) (D), ECAS fluency (R2 = 0.125, P = NS) (E), ECAS executive (R2 = 0.320, P = 0.018) (F), ECAS memory (R2 = 0.035, P = NS) (G), ECAS visuospatial (R2 = 0.029, P = NS) (H) scores. Each dot represents an ALS patient. HRE hexanucleotide repeat expansion, ECAS Edinburgh Cognitive and Behavioural ALS Screen
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