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Objective <p>In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.</p> Methods <p>In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to <i>C9orf72</i> (n = 137)<i>, SOD1</i> (n = 54), <i>TARDBP</i> (n = 27), and <i>FUS</i> (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL)&#xa0;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.</p> Results <p><i>C9orf72</i>-associated ALS showed frequent bulbar onset (n = 42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7&#xa0;pg/mL) and logNfL(index) (5.02, SD 0.88). <i>SOD1-</i>ALS had mostly limb onset (n = 96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4&#xa0;pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). <i>FUS</i>-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). <i>TARDBP-</i>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).</p> Conclusion <p>In <i>C9orf72</i>-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in <i>SOD1</i>-, <i>FUS</i>- and <i>TARDBP-</i>associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.</p>

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Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis—results from a multicenter screening program

  • 期刊论文

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  • 发表日期：

    2025年12月12日

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  • Philipp Schmitt,
  • Peggy Schumann,
  • Alexander Koerbs,
  • Hsuen-Ju Lin,
  • Torsten Grehl,
  • Ute Weyen,
  • Susanne Petri,
  • Annekathrin Rödiger,
  • Robert Steinbach,
  • Julian Großkreutz,
  • Sarah Bernsen,
  • Patrick Weydt,
  • Joachim Wolf,
  • René Günther,
  • Petra Baum,
  • Moritz Metelmann,
  • Jochen H. Weishaupt,
  • Berthold Streubel,
  • David C. Kasper,
  • Yasemin Koc,
  • Dagmar Kettemann,
  • Jenny Norden,
  • Bertram Walter,
  • Christoph Münch,
  • Susanne Spittel,
  • André Maier,
  • Péter Körtvélyessy,
  • Thomas Meyer

摘要

Objective

In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

Methods

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.

Results

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).

Conclusion

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.