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Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations

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Abstract

In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood–brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.

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Acknowledgments

A special thank to the Italian ALS patients and their caregivers. Generous support was provided by the Italian Ministry of Health (Malattie Neurodegenerative, ex Art.56, n.533F/N1) and by AriSLA—Agenzia Italiana per la Ricerca sulla Sclerosi Laterale Amiotrofica (grant EXOMEFALS 2009, co-financed with the support of “5 × 1000” —Healthcare Research of the Ministry of Health).

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy

    Nicola Ticozzi, Cinzia Tiloca, Niccolò E. Mencacci, Claudia Morelli, Alberto Doretti, Claudia Colombrita, Davide Sangalli, Federico Verde, Stefano Messina, Antonia Ratti & Vincenzo Silani

  2. Doctoral School in Molecular Medicine, Università degli Studi di Milano, 20122, Milan, Italy

    Cinzia Tiloca

  3. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, ‘Dino Ferrari’ Center, Università degli Studi di Milano, 20122, Milan, Italy

    Niccolò E. Mencacci, Alberto Doretti, Antonia Ratti & Vincenzo Silani

  4. Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Cusano Milanino, Milan, Italy

    Daniela Rusconi & Palma Finelli

  5. Department of Biology and Genetics for Medical Sciences, Università degli Studi di Milano, 20133, Milan, Italy

    Palma Finelli

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  1. Nicola Ticozzi
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  2. Cinzia Tiloca
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Correspondence to Nicola Ticozzi.

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N. Ticozzi and C. Tiloca contributed equally to this manuscript.

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Ticozzi, N., Tiloca, C., Mencacci, N.E. et al. Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations. J Neurol 260, 85–92 (2013). https://doi.org/10.1007/s00415-012-6589-0

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