Academic Journal
Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.
| Τίτλος: | Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients. |
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| Συγγραφείς: | Couto CM; Neurology Department, SARAH Network of Rehabilitation Hospitals, Rio de Janeiro, Brazil.; Postgraduate Program in Neurology and Neurosciences, Faculty of Medicine, Fluminense Federal University (UFF), Rio de Janeiro, Brazil., de Melo Queiroz E; Neurology Department, SARAH Network of Rehabilitation Hospitals, Rio de Janeiro, Brazil.; Translational Neuroscience Graduate Program (PGNET), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil., da Cunha MC; Neurology Department, SARAH Network of Rehabilitation Hospitals, Rio de Janeiro, Brazil., Santos SCL; Molecular Biology Laboratory, SARAH Network of Rehabilitation Hospitals, Brasília, Brazil., Ferreira AR; Molecular Biology Laboratory, SARAH Network of Rehabilitation Hospitals, Brasília, Brazil., Nascimento OJM; Postgraduate Program in Neurology and Neurosciences, Faculty of Medicine, Fluminense Federal University (UFF), Rio de Janeiro, Brazil. |
| Πηγή: | Frontiers in neurology [Front Neurol] 2026 Aug 05; Vol. 17, pp. 1883977. Date of Electronic Publication: 2026 Aug 05 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Multicenter Study |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101546899 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-2295 (Electronic) Linking ISSN: 16642295 NLM ISO Abbreviation: Front Neurol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation, 2010]- |
| Ιατρικοί όροι (MeSH): | Motor Neuron Disease*/genetics , Motor Neuron Disease*/epidemiology , Amyotrophic Lateral Sclerosis*/genetics , Amyotrophic Lateral Sclerosis*/epidemiology , Genetic Profile*, Brazil/epidemiology ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Humans ; Female ; Male ; Retrospective Studies ; Middle Aged ; Genetic Testing ; Aged ; Cohort Studies ; Adult |
| Περίληψη: | Background: Genetic testing in amyotrophic lateral sclerosis (ALS) is increasingly recommended for all patients, but real-world implementation in middle-income countries remains heterogeneous. Brazilian motor neuron disease genetics has largely been characterized through protocol-based cohorts focused on the founder VAPB p.Pro56Ser variant (amyotrophic lateral sclerosis type 8, ALS8). The broader genetic landscape beyond ALS8 in Brazilian clinical populations has not been described in a large multiregional cohort. We aimed to characterize this profile. Methods: We retrospectively analyzed 1,911 patients with motor neuron disease followed at six SARAH Network rehabilitation hospitals across Brazil between 2007 and 2024. Genetic testing was clinically directed; ALS8 cases (n = 78) were characterized separately. We assessed characteristics of genetically tested versus untested patients, the temporal evolution of testing modalities, and the diagnostic yield by gene and by Byrne family history classification. Results: Of 1,833 patients without ALS8, 318 (17.3%) underwent genetic testing, with selection bias toward younger age, higher educational attainment, and positive family history of ALS or frontotemporal dementia (all p < 0.001). Testing expanded markedly after 2020, particularly C9orf72 screening and next-generation sequencing panels. Panel/exome sequencing identified pathogenic or likely pathogenic variants in 13 of 66 patients (19.7%), consistent with international literature for mixed familial-sporadic cohorts. Across all modalities, 30 patients without ALS8 carried pathogenic or likely pathogenic variants in six genes: SOD1 (n = 15), C9orf72 (n = 11; 7.0% of 157 tested), and VCP, FUS, TBK1, and SETX (n = 1 each). ATXN2 intermediate-length CAG repeats were identified in 15 of 230 patients tested (6.5%), replicating the 6.3% previously reported in a Brazilian multicenter sample. Yield by Byrne classification followed a marked gradient (Definite: 89.7%, Probable: 24.0%, Possible: 15.4%, Sporadic: 4.9%; p < 0.001). The SOD1 spectrum included recurrent variants of likely Iberian/European origin. Conclusion: This 18-year cohort defines a real-world genetic profile of motor neuron disease beyond ALS8, with diagnostic yield comparable to the literature and a Byrne gradient supporting universal testing. Beyond family history, socioeconomic factors appeared to shape access to testing, reinforcing the importance of equitable genetic testing for diagnostic precision, family counseling, and access to gene-targeted therapy. (Copyright © 2026 Couto, de Melo Queiroz, da Cunha, Santos, Ferreira and Nascimento.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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| Contributed Indexing: | Keywords: ATXN2; Brazilian cohort; C9orf72; SOD1; amyotrophic lateral sclerosis; genetic testing; motor neuron disease; real-world evidence |
| Substance Nomenclature: | 0 (C9orf72 Protein) 0 (C9orf72 protein, human) EC 1.15.1.1 (Superoxide Dismutase-1) |
| Entry Date(s): | Date Created: 20260820 Date Completed: 20260820 Latest Revision: 20260909 |
| Update Code: | 20260909 |
| PubMed Central ID: | PMC13487208 |
| DOI: | 10.3389/fneur.2026.1883977 |
| PMID: | 42621206 |
| Βάση Δεδομένων: | MEDLINE |
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