Journal Article

DZNE-2026-01000

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genetic ALS-Progressive Sleep Defects Precede the Onset of Clinical Disease.

Lang, C. (First author)DZNE* ; Guillot, S. J. ; Knehr, A. ; Weydt, P.DZNE* ; Dorst, J.Extern* ; Tumani, H.Extern* ; Ludolph, A.Extern* ; Dupuis, L. ; Bolborea, M.

2026
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1111/ene.70755

Abstract: The onset of amyotrophic lateral sclerosis (ALS) is preceded by non-motor signs detectable many years before motor symptom onset. We recently showed that early ALS patients and presymptomatic carriers of ALS-associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non-REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS-associated gene mutations.This longitudinal observational cohort study included presymptomatic first-degree relatives of ALS patients carrying pathogenic gene mutations (n = 18) and noncarrier family members (n = 3). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow-up examination after 2.3 ± 1.5 years.In all carriers, sleep alterations were more severe at follow-up compared to the initial examination, for both macro- and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.Sleep macro- and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography-derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: physiopathology (MeSH) ; Amyotrophic Lateral Sclerosis: complications (MeSH) ; Female (MeSH) ; Male (MeSH) ; Polysomnography (MeSH) ; Disease Progression (MeSH) ; Middle Aged (MeSH) ; Sleep Wake Disorders: genetics (MeSH) ; Sleep Wake Disorders: physiopathology (MeSH) ; Sleep Wake Disorders: etiology (MeSH) ; Electroencephalography (MeSH) ; Longitudinal Studies (MeSH) ; Adult (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Mutation (MeSH) ; C9orf72 Protein: genetics (MeSH) ; Aged (MeSH) ; Cohort Studies (MeSH) ; C9orf72 ; SOD1 ; electroencephalography ; polysomnography ; Superoxide Dismutase-1 ; C9orf72 Protein ; C9orf72 protein, human ; SOD1 protein, human

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Contributing Institute(s):

1. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))
2. Clinical Research Coordination (Clinical Research (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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