Objective: To investigate the clinical and molecular characteristics of amyotrophic lateral sclerosis (ALS) families carrying variants in the RTN2 gene (SPG12), associated with hereditary spastic paraplegia (HSP).

Background: Genetic overlaps among neurodegenerative disorders are increasingly recognized, suggesting that variants in genes linked to one condition may contribute to broader phenotypic spectra. While RTN2 mutations are known to cause hereditary spastic paraplegia through mechanisms related to axonal maintenance, their role in ALS remains poorly defined.

Method: We performed clinical and molecular characterization of 10 unrelated ALS pedigrees from Italy, Brazil, and Japan. Genetic analyses included variant identification by Next-Generation Sequencing and segregation studies within families. Variant pathogenicity was assessed using population databases and in-silico prediction tools. Functional characterization of a novel truncating variant was performed using transfection-based assays to evaluate its effect on protein expression.

Results: Ten RTN2 variants were identified across the 10 ALS families. All variants segregated with disease within pedigrees and were absent from control population databases, supporting their pathogenic role. Functional analysis of the novel truncating variant demonstrated altered protein expression. Clinical and molecular features were consistent with ALS phenotypes, extending the disease spectrum associated with RTN2 beyond hereditary spastic paraplegia.

Conclusion: Our findings support a role for RTN2 variants in ALS and further highlight genetic pleiotropy across neurodegenerative disorders. These results expand the genotype–phenotype spectrum associated with RTN2, and underscore shared pathogenic mechanisms between ALS and hereditary spastic paraplegia.

References: [1] Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, Munhoz RP, Rogaeva EA, St George-Hyslop PH, Bernardi G, Kawarai T: SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 2010, 133: 591-598. [2] Montenegro G, Rebelo AP, Connell J, …, Orlacchio A, Reid E, Züchner S: Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest 2012, 122: 538-544. [3] Panza E, Meyyazhagan A, Orlacchio A: Hereditary spastic paraplegia: Genetic heterogeneity and common pathways. Experimental Neurology 2022, 357: 114203.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rtn2-variants-expand-the-als-hereditary-spastic-paraplegia-disease-spectrum/