Genetic characterization of primary lateral sclerosis.

Autor: de Boer EMJ; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., de Vries BS; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Pennings M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Kamsteeg EJ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Veldink JH; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., van den Berg LH; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., van Es MA; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. m.a.vanes@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2023 Aug; Vol. 270 (8), pp. 3970-3980. Date of Electronic Publication: 2023 May 03.
DOI: 10.1007/s00415-023-11746-7
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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