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 x 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.

Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis / E. Colombo, B. Poletti, A. Maranzano, S. Peverelli, F. Solca, C. Colombrita, S. Torre, C. Tiloca, F. Verde, R. Bonetti, L. Carelli, C. Morelli, A. Ratti, V. Silani, N. Ticozzi. - In: JOURNAL OF NEUROLOGY. - ISSN 0340-5354. - (2022 Oct 29), pp. 1-11. [Epub ahead of print] [10.1007/s00415-022-11433-z]

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

A. Maranzano;S. Peverelli;C. Colombrita;C. Tiloca;F. Verde;R. Bonetti;C. Morelli;A. Ratti;V. Silani;N. Ticozzi
2022

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 x 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.
ALS; Frontotemporal dementia; Genetics; Motor neuron disease
Settore MED/26 - Neurologia
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
PSRL321NTICO_01 - Piano Sviluppo Unimi - Linea 3 - Bando SOE 2020 - Progetto GENDER-ALS - TICOZZI, NICOLA - PSR_LINEA3_ / Piano di sviluppo di ricerca - Bando SoE-SEED- Linea 3 - 2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/945635
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