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. 2023 Aug;270(8):3970-3980.
doi: 10.1007/s00415-023-11746-7. Epub 2023 May 3.

Genetic characterization of primary lateral sclerosis

Eva M J de Boer  1 , Balint S de Vries  1 , Maartje Pennings  2 , Erik-Jan Kamsteeg  2 , Jan H Veldink  1 , Leonard H van den Berg  1 , Michael A van Es  3
Affiliations

Genetic characterization of primary lateral sclerosis

Eva M J de Boer et al. J Neurol. 2023 Aug.

Abstract

Background and objectives: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.

Methods: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.

Results: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11).

Discussion: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.

Keywords: Amyotrophic lateral sclerosis; Genetics; Hereditary spastic paraplegia; Primary lateral sclerosis.

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Conflict of interest statement

Jan Veldink reports to have sponsored research agreements with Biogen and Astra Zeneca. Leonard van den Berg declares fees to his institution from Biogen, Wave, Amylyx, Ferrer, and Cytokinetics for being on a scientific advisory board; fees to his institution from Amylyx for a lecture; an unrestricted educational grant from Takeda, and is the Chair of ENCALS and TRICALS. Michael van Es has consulted for Biogen, and has received travel grants from Shire (formerly Baxalta), performs work as a medical monitor for an on-going trial from Ferrer (NCT05178810).

Figures

Fig. 1
Fig. 1
Distribution of genetic variants found. Phenotypes were determined using the gene database of the National Centre for Biotechnology Information on 25-08-2022 [29]. A Whole cohort with all variants found; B pathogenic and likely pathogenic variants. ALS genes: FUS, NEK1, ANG, ERBB4; ALS-FTD genes: C9orf72, TBK1, CHMP2B; pure HSP genes: SPG7, SPAST, ZFVE27, FA2H, UBAP1, ALDH18A1; MSP genes: VCP, OPTN, ANXA11; “ALS-HSP-CMT overlap” genes: SPG11, DCTN1, FIG4, SETX, NIPA1, NEFL; SCA genes: ATXN2, PPP2R2B; X-ALD genes: ABCD1. ALS amyotrophic lateral sclerosis, CMT Charcot–Marie–Tooth, FTD frontotemporal dementia, HSP hereditary spastic paraplegia, MSP multisystem proteinopathy, SCA spinocerebellar ataxia, X-ALD X-linked adrenoleukodystrophy
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References

    1. Statland JM, Barohn RJ, Dimachkie MM, Floeter MK, Mitsumoto H. Primary lateral sclerosis. Neurol Clin. 2015;33:749–760. doi: 10.1016/j.ncl.2015.07.007. - DOI - PMC - PubMed
    1. van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, et al. Amyotrophic lateral sclerosis. The Lancet. 2017;390:2084–2098. doi: 10.1016/S0140-6736(17)31287-4. - DOI - PubMed
    1. De Vries BS, Rustemeijer LMM, Bakker LA, Schröder CD, Veldink JH, Van Den Berg LH, et al. Cognitive and behavioural changes in PLS and PMA: challenging the concept of restricted phenotypes. J Neurol Neurosurg Psychiatry. 2019;90:141–147. doi: 10.1136/jnnp-2018-318788. - DOI - PubMed
    1. de Vries BS, Spreij LA, Rustemeijer LMM, Bakker LA, Veldink JH, van den Berg LH, et al. A neuropsychological and behavioral study of PLS. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20:376–384. doi: 10.1080/21678421.2019.1620284. - DOI - PubMed
    1. Finegan E, Chipika RH, Shing SLH, Hardiman O, Bede P. Primary lateral sclerosis: a distinct entity or part of the ALS spectrum? Amyotroph Lateral Scler Frontotemporal Degener. 2019;20:133–145. doi: 10.1080/21678421.2018.1550518. - DOI - PubMed