Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction

Thomas Meyer^#^{1

2}, Matthias Boentert^#³, Julian Großkreutz⁴, Patrick Weydt^{5

6}, Sarah Bernsen^{5

6}, Peter Reilich⁷, Robert Steinbach⁸, Annekathrin Rödiger^{8

9}, Joachim Wolf¹⁰, Ute Weyen¹¹, Albert C Ludolph¹², Jochen Weishaupt^{12

13}, Susanne Petri^{14

15}, Paul Lingor^{16

17}, René Günther^{18

19}, Wolfgang Löscher²⁰, Markus Weber²¹, Christoph Münch^{22

23}, André Maier^#²², Torsten Grehl^#²⁴

Affiliations

¹ Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany. thomas.meyer@charite.de.
² APST Research GmbH, Berlin, Germany. thomas.meyer@charite.de.
³ Department of Neurology, Münster University Hospital, Münster, Germany.
⁴ Department of Neurology, Universitätsmedizin Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
⁵ Department for Neurodegenerative and Neuromuscular Disorders, Bonn University, Bonn, Germany.
⁶ Research Site Bonn, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
⁷ Department of Neurology, LMU University Hospital, Munich, Germany.
⁸ Department of Neurology, Jena University Hospital, Jena, Germany.
⁹ Zentrum für Seltene Erkrankungen (ZSE), Jena University Hospital, Jena, Germany.
¹⁰ Department of Neurology, Diako Mannheim, Mannheim, Germany.
¹¹ Department of Neurology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Germany.
¹² Department of Neurology, Ulm University, Ulm, Germany.
¹³ Research Site Ulm, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm, Germany.
¹⁴ Department of Neurology, Diakovere Henriettenstift and Friederikenstift, Hannover, Germany.
¹⁵ Department of Neurology, Hannover Medical School, Hannover, Germany.
¹⁶ Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
¹⁷ Research Site Munich, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
¹⁸ Department of Neurology, Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany.
¹⁹ Research Site Dresden, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
²⁰ Department of Neurology, Unit for Neuromuscular Disorders and Clinical Neurophysiology, Medical University of Innsbruck, Innsbruck, Austria.
²¹ Neuromuscular Diseases Unit/ALS Clinic, HOCH Health Ostschweiz, St. Gallen, Switzerland.
²² Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.
²³ APST Research GmbH, Berlin, Germany.
²⁴ Department of Neurology, Center for ALS and other Motor Neuron Disorders, Alfried Krupp Krankenhaus, Essen, Germany.

^# Contributed equally.

PMID: 40289140
PMCID: PMC12036282
DOI: 10.1186/s42466-025-00389-w

Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction

Thomas Meyer et al. Neurol Res Pract. 2025.

. 2025 Apr 28;7(1):27.

doi: 10.1186/s42466-025-00389-w.

Authors

Affiliations

¹ Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany. thomas.meyer@charite.de.
² APST Research GmbH, Berlin, Germany. thomas.meyer@charite.de.
³ Department of Neurology, Münster University Hospital, Münster, Germany.
⁴ Department of Neurology, Universitätsmedizin Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
⁵ Department for Neurodegenerative and Neuromuscular Disorders, Bonn University, Bonn, Germany.
⁶ Research Site Bonn, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
⁷ Department of Neurology, LMU University Hospital, Munich, Germany.
⁸ Department of Neurology, Jena University Hospital, Jena, Germany.
⁹ Zentrum für Seltene Erkrankungen (ZSE), Jena University Hospital, Jena, Germany.
¹⁰ Department of Neurology, Diako Mannheim, Mannheim, Germany.
¹¹ Department of Neurology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Germany.
¹² Department of Neurology, Ulm University, Ulm, Germany.
¹³ Research Site Ulm, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm, Germany.
¹⁴ Department of Neurology, Diakovere Henriettenstift and Friederikenstift, Hannover, Germany.
¹⁵ Department of Neurology, Hannover Medical School, Hannover, Germany.
¹⁶ Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
¹⁷ Research Site Munich, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
¹⁸ Department of Neurology, Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany.
¹⁹ Research Site Dresden, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
²⁰ Department of Neurology, Unit for Neuromuscular Disorders and Clinical Neurophysiology, Medical University of Innsbruck, Innsbruck, Austria.
²¹ Neuromuscular Diseases Unit/ALS Clinic, HOCH Health Ostschweiz, St. Gallen, Switzerland.
²² Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.
²³ APST Research GmbH, Berlin, Germany.
²⁴ Department of Neurology, Center for ALS and other Motor Neuron Disorders, Alfried Krupp Krankenhaus, Essen, Germany.

^# Contributed equally.

PMID: 40289140
PMCID: PMC12036282
DOI: 10.1186/s42466-025-00389-w

Abstract

Background: In amyotrophic lateral sclerosis (ALS), heterogeneity of motor phenotypes is a fundamental hallmark of the disease. Distinct ALS phenotypes were associated with a different progression and survival. Despite its relevance for clinical practice and research, there is no broader consensus on the classification of ALS phenotypes.

Methods: An expert consensus process for the classification of ALS motor phenotypes was performed from May 2023 to December 2024. A three-determinant anatomical classification was proposed which is based on the (1) region of onset (O), (2) the propagation of motor symptoms (P), and (3) the degree of upper (UMN) and/or lower motor neuron (LMN) dysfunction (M). Accordingly, this classification is referred to as the "OPM classification".

Results: Onset phenotypes differentiate the site of first motor symptoms: O1) head onset; O2d) distal arm onset; O2p) proximal arm onset; O3r) trunk respiratory onset; O3a) trunk axial onset; O4d) distal leg onset; O4p) proximal leg onset. Propagation phenotypes differentiate the temporal propagation of motor symptoms from the site of onset to another, vertically distant body region: PE) earlier propagation (within 12 months of symptom onset); PL) later propagation (without propagation within 12 months of symptom onset), including the established phenotypes of "progressive bulbar paralysis" (O1, PL), "flail-arm syndrome" (O2p, PL), and "flail-leg syndrome" (O4d, PL); PN) propagation not yet classifiable as time since symptom onset is less than 12 months. Phenotypes of motor neuron dysfunction differentiate the degree of UMN and/or LMN dysfunction: M0) balanced UMN and LMN dysfunction; M1d) dominant UMN dysfunction; M1p) pure UMN dysfunction ("primary lateral sclerosis", PLS); M2d) dominant LMN dysfunction; M2p) pure LMN dysfunction ("progressive muscle atrophy", PMA); M3) dissociated motor neuron dysfunction with dominant LMN and UMN dysfunction of the arms and legs ("brachial amyotrophic spastic paraparesis"), respectively.

Conclusion: This consensus process aimed to standardize the clinical description of ALS motor phenotypes in clinical practice and research - based on the onset region, propagation pattern, and motor neuron dysfunction. This "OPM classification" contributes to specifying the prognosis, to defining the inclusion or stratification criteria in clinical trials and to correlate phenotypes with the underlying disease mechanisms of ALS.

Keywords: Amyotrophic lateral sclerosis; Classification; Motor phenotypes; OPM.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors of the paper agree with the manuscript and meet the criteria for authorship. Competing interests: The authors declare that they have no competing interests.

Figures

**Fig. 1**
Assessment of ALS motor phenotypes. Phenotypes of the region of onset (O1-4) are assessed by patient history. Phenotypes of propagation (PE, PL, PN) pattern are determined by follow-up of the patient history and/or neurological investigation during the disease course. Some propagation phenotypes can be classified with certainty only after 12 months of follow-up. This includes the phenotypes of late propagation (PL), including the historic descriptions of progressive bulbar palsy (PBP), flail-arm syndrome (FAS) or flail-leg syndrome (FLS), respectively. Phenotypes of the motor neuron dysfunction (M0-M3) are assessed by neurological investigation of the degree of upper (UMN) and/or lower (LMN) neuron involvement. Some motor neuron dysfunction phenotypes can be classified with certainty only after 48 months of follow-up. This includes the phenotypes of pure UMN (M1p) and LMN dysfunction (M2p) in its historic descriptions of primary lateral sclerosis (PLS) and progressive muscle atrophy (PMA). In principle, phenotypes of the motor neuron dysfunction can be changing during the complete disease course. Therefore, motor neuron dysfunction phenotypes need to be re-evaluated as the disease progresses. O1) head onset; O2) arm onset; O3) trunk onset; O4) leg onset; PE) earlier propagation; PL) later propagation; PN) propagation not yet classifiable; M0) balanced UMN and LMN dysfunction; M1d) dominant UMN dysfunction; M1p) pure UMN dysfunction; M2d) dominant LMN dysfunction; M2p) pure LMN dysfunction; M3) dissociated motor neuron dysfunction with dominant LMN and UMN dysfunction of the arms and legs. Arrow, retrospective assessment period

**Fig. 2**
Classification of ALS motor phenotypes. Onset region (O): Phenotypes of onset differentiate the site of first symptoms including the bulbar region, arm, trunk and leg; phenotypes of propagation (P) differentiate the earlier (within 12 months), later (after 12 months) or unclassifiable (monitoring of 12 months not completed) propagation of motor neuron dysfunction from the region of onset to another, vertically distant body region; phenotypes of motor neuron dysfunction (M) differentiate the degree of clinical upper (UMN) and lower motor neuron (LMN) dysfunction

See this image and copyright information in PMC

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Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction

Affiliations

Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Research Materials

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