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@ARTICLE{Schmitt:282906,
author = {Schmitt, Philipp and Schumann, Peggy and Koerbs, Alexander
and Lin, Hsuen-Ju and Grehl, Torsten and Weyen, Ute and
Petri, Susanne and Rödiger, Annekathrin and Steinbach,
Robert and Großkreutz, Julian and Bernsen, Sarah and Weydt,
Patrick and Wolf, Joachim and Günther, René and Baum,
Petra and Metelmann, Moritz and Weishaupt, Jochen H and
Streubel, Berthold and Kasper, David C and Koc, Yasemin and
Kettemann, Dagmar and Norden, Jenny and Walter, Bertram and
Münch, Christoph and Spittel, Susanne and Maier, André and
Körtvelyessy, Peter and Meyer, Thomas},
title = {{M}otor phenotypes and neurofilament light chain in genetic
amyotrophic lateral sclerosis-results from a multicenter
screening program.},
journal = {Journal of neurology},
volume = {273},
number = {1},
issn = {0367-004X},
address = {[Darmstadt]},
publisher = {Steinkopff},
reportid = {DZNE-2025-01367},
pages = {22},
year = {2025},
abstract = {In genetic amyotrophic lateral sclerosis (ALS), the
clinical phenotypes, disease progression and neurofilament
light chain (NfL) levels are incompletely characterized.In a
total cohort of 1988 ALS patients, a subcohort of genetic
ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n =
27), and FUS (n = 19) was investigated. The phenotypes of
onset region, propagation and motor neuron involvement were
analyzed according to the OPM classification. Serum NfL
(sNfL) was measured and related to ALS progression (ALSPR,
monthly change of ALS Functional Rating Scale-Revised). To
quantify NfL elevation relative to ALSPR, the logNfL(index),
the log-transformed ratio of sNfL to ALSPR was
calculated.C9orf72-associated ALS showed frequent bulbar
onset (n = $42.6\%),$ higher ALSPR (0.95, SD 0.84), highest
NfL (116.3, SD 72.7 pg/mL) and logNfL(index) (5.02, SD
0.88). SOD1-ALS had mostly limb onset (n = $96.1\%),$ slower
ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4 pg/mL) and a
comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS
exhibited mostly limb onset $(82.4\%),$ lower motor neuron
dysfunction $(70.6\%),$ a wide range of faster $(22.2\%)$ to
slower ALSPR $(55.6\%),$ lower NfL (66.2, SD 32.9) and
logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR
(0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and
the lowest logNfL(index) (4.40, SD 0.7).In C9orf72-ALS, the
phenotype and NfL profile are close to typical ALS. The
finding of distinct phenotypes and NfL patterns in SOD1-,
FUS- and TARDBP-associated ALS underscores the relevance of
genetic ALS for prognostic counseling, clinical trial
design, treatment expectations and unraveling of pathogenic
mechanisms in ALS.},
keywords = {Humans / Amyotrophic Lateral Sclerosis: genetics /
Amyotrophic Lateral Sclerosis: blood / Amyotrophic Lateral
Sclerosis: physiopathology / Amyotrophic Lateral Sclerosis:
diagnosis / Neurofilament Proteins: blood / Male / Female /
Middle Aged / C9orf72 Protein: genetics / Phenotype / Aged /
RNA-Binding Protein FUS: genetics / Superoxide Dismutase-1:
genetics / Adult / Disease Progression / Cohort Studies /
DNA-Binding Proteins: genetics / ALS progression (Other) /
Genetic ALS (Other) / Neurofilament (Other) / Phenotype
(Other) / Neurofilament Proteins (NLM Chemicals) /
neurofilament protein L (NLM Chemicals) / C9orf72 Protein
(NLM Chemicals) / C9orf72 protein, human (NLM Chemicals) /
RNA-Binding Protein FUS (NLM Chemicals) / Superoxide
Dismutase-1 (NLM Chemicals) / TARDBP protein, human (NLM
Chemicals) / FUS protein, human (NLM Chemicals) / SOD1
protein, human (NLM Chemicals) / DNA-Binding Proteins (NLM
Chemicals)},
cin = {AG Radbruch / Clinical Research (Bonn) / AG Falkenburger},
ddc = {610},
cid = {I:(DE-2719)5000075 / I:(DE-2719)1011001 /
I:(DE-2719)1710012},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41388206},
pmc = {pmc:PMC12700978},
doi = {10.1007/s00415-025-13555-6},
url = {https://pub.dzne.de/record/282906},
}