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Nemaline Myopathy

Disease Pathophysiology Research Template

2026-02-19
Falcon MONDO:0018958 Model: Edison Scientific Literature 42 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Nemaline Myopathy
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Nemaline Myopathy. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Nemaline Myopathy (NM) – molecular and cellular mechanisms (2023–2024-focused)

  1. Disease identifiers, scope, and key definitions

Disease: Nemaline myopathy (NM) • MONDO: MONDO:0018958 (“nemaline myopathy”). (ziemian2025integrativeapproachesto pages 15-17) • Genetic category: Mendelian congenital myopathy; clinically heterogeneous with congenital-to-adult onset and variable severity. (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4)

Core definition and diagnostic lesion NM is histopathologically defined by “disorganization of the sarcomeric Z discs and the accumulation of nemaline bodies or rods in muscle fibers.” (Karimi et al., received 2023-12-22; accepted 2024-03-26; published 2024-04, Acta Neuropathologica; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Nemaline rods are “aggregates of Z-disc and thin filament-related proteins,” including “α-actinin, actin, tropomyosin, myotilin, γ-filamin, cofilin-2, telethonin and nebulin,” stain red on modified Gomori trichrome, and show an “electron-dense lattice-like structure on electron microscopy,” with “continuity … between rods and Z-discs.” (Nicolau et al., 2023-01, Acta Neuropathologica Communications; https://doi.org/10.1186/s40478-023-01518-9) (nicolau2023molecularsignaturesof pages 2-4) Visual evidence of rod distributions (subsarcolemmal, central aggregates, diffuse, rods filling atrophic fibers) is shown in a representative modified Gomori trichrome figure. (nicolau2023molecularsignaturesof media 60ef7b58)

Key concept: thin-filament / sarcomere disease Multiple authoritative sources converge on NM as primarily a thin-filament/Z-disc structural and regulatory disorder where altered thin-filament composition, length, mechanics, and/or turnover culminate in rod/aggregate pathology and impaired force generation. (karimi2024characterizationofneb pages 1-2, findlay2024dominantlyinheritedmuscle pages 14-15)

  1. Core pathophysiology (molecular and cellular mechanisms)

2.1 Final common pathway: thin-filament dysregulation → sarcomere/Z-disc disruption → weakness Across genetic subtypes, the common pathologic endpoint is altered thin-filament structure/regulation leading to Z-disc disruption and rod formation, with contractile weakness due to reduced effective actin–myosin force generation. (karimi2024characterizationofneb pages 1-2, findlay2024dominantlyinheritedmuscle pages 14-15) Findlay (2024-10, Disease Models & Mechanisms; https://doi.org/10.1242/dmm.050720) provides an expert review statement that rods “consist of aggregated actin and Z-disc material,” and emphasizes that altered nebulin can reduce thin-filament length and therefore thin–thick filament overlap, impairing force generation. (findlay2024dominantlyinheritedmuscle pages 14-15)

2.2 Nebulin (NEB) mechanisms: thin-filament length (TFL) regulation, cross-bridge cycling, alignment Nebulin is a core thin-filament component that contributes to “regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment.” (Karimi et al., 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Mechanistic links from patient samples (2024, Acta Neuropathologica) • Truncating NEB variants reduce NEB mRNA stability and can trigger nonsense-mediated decay. (karimi2024characterizationofneb pages 1-2) • Splice variants frequently induce cryptic splice activation and intronic inclusion, which the authors interpret as disrupting actin-binding-site spacing on nebulin (“insertion of an unstructured sequence into actin binding motifs” and “disrupts the proper domain spacing actin binding sites on nebulin”). (karimi2024characterizationofneb pages 16-17) • Importantly, NEB-NM pathomechanism can involve both shortened and elongated thin filaments: a pathogenic NEB duplication can yield “a much larger nebulin protein and longer TFL,” and “both a reduction and an increase in TFL are deleterious,” with “uniformity in TFL” emphasized. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) Functional correlation Karimi et al. report a “positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension).” (karimi2024characterizationofneb pages 1-2)

2.3 ACTA1 mechanisms: actin polymerization/stability defects and dominant-negative effects ACTA1 encodes skeletal α-actin in the thin filament. Expert review synthesis highlights that many ACTA1 missense variants impair actin filament polymerization/stability and are “thought to cause pathology via a dominant-negative mechanism.” (Findlay 2024; https://doi.org/10.1242/dmm.050720) (findlay2024dominantlyinheritedmuscle pages 14-15) Clinically, ACTA1 disease is framed as “an actin-based thin filament disease” where thin-filament gene variants “result in sarcomeric dysfunction.” (Galli et al., 2024-02, J Gen Physiol; https://doi.org/10.1085/jgp.202313471) (galli2024tirasemtivenhancessubmaximal pages 1-2)

2.4 Protein homeostasis / ubiquitin–proteasome and inter-organelle communication (KLHL40) A major recent mechanistic advance (2023) expands NM pathophysiology beyond myofilament biophysics to include ubiquitylation-regulated membrane trafficking and extracellular matrix (ECM) secretion. KLHL40 as a CUL3 adaptor and proteostasis regulator • KLHL40 is described as “a substrate-specific adaptor of CUL3 E3 ubiquitin ligase,” and the authors propose that “inter-organelle communication between sarcomeric and endomembrane compartments, is dynamically regulated by ubiquitylation” and that defects underlie pathology. (Mansur et al., 2023-07, eLife; https://doi.org/10.1101/2022.07.21.501000) (mansur2023dynamicregulationof pages 4-8) SAR1A/COPII trafficking mechanism • KLHL40 acts as a negative regulator of ER→Golgi anterograde trafficking by promoting “ubiquitin-mediated protein degradation of secretion associated Ras related GTPase1a (Sar1a)” (SAR1A; COPII vesicle formation). (mansur2023dynamicregulationof pages 1-4) • In KLHL40 deficiency, “SAR1a is abnormally localized to the ER and contributes to membrane tubulation defects and disruption of the trafficking of ECM proteins,” with downstream ultrastructural abnormalities (vesicle accumulation near SR/ER, fragmented Golgi, ECM gaps, mitochondrial changes). (mansur2023dynamicregulationof pages 4-8) This provides a plausible disease-progression axis: KLHL40 loss → altered ubiquitylation → ER exit/COPII dysfunction → impaired ECM secretion and membrane homeostasis → secondary sarcomere growth/maintenance failure and myofiber damage. (mansur2023dynamicregulationof pages 4-8)

2.5 Disease modifiers and sarcomere remodeling (NRAP) In NEB deficiency, NRAP upregulation behaves as a disease modifier: NRAP reduction in neb−/− zebrafish “restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function,” and notably eliminated observable nemaline bodies in the rescue genotype. (Casey et al., 2023-01, Human Molecular Genetics; https://doi.org/10.1093/hmg/ddad011) (casey2023nrapreductionrescues pages 1-2, casey2023nrapreductionrescues pages 3-6) Quantitative ultrastructure: neb−/− sarcomere height was reduced (510 ± 107 nm vs 755 ± 192 nm control), with slightly increased sarcomere length (1475 ± 55 nm vs 1400 ± 96 nm control), both improved by partial nrap reduction. (casey2023nrapreductionrescues pages 3-6)

  1. Key molecular players (genes/proteins, pathways, cells, anatomy, chemicals)

3.1 Causal/implicated genes and encoded functional modules A contemporary gene list emphasized in recent pathology-centric work includes thin filament and turnover genes: ACTA1, NEB, LMOD3, TPM3, TPM2, TNNT1, TNNT3, CFL2, MYPN, KBTBD13, KLHL40, KLHL41, and MYO18B. (Karimi 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) Rod composition proteins (as biochemical/pathology anchors) include α-actinin, actin, tropomyosin, cofilin-2, telethonin and nebulin. (nicolau2023molecularsignaturesof pages 2-4)

3.2 Dysregulated pathways / cellular processes (current understanding) The most strongly supported dysregulated processes from the provided 2023–2024 mechanistic sources are: • Sarcomere assembly/maintenance and thin-filament length regulation (NEB, ACTA1, LMOD3; and associated regulatory complexes). (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Ubiquitin-mediated proteostasis and specific ubiquitylation control of vesicle trafficking (KLHL40–CUL3 → SAR1A/COPII). (mansur2023dynamicregulationof pages 1-4, mansur2023dynamicregulationof pages 4-8) • Sarcomere remodeling/aggregate biology involving modifiers such as NRAP. (casey2023nrapreductionrescues pages 1-2) A broader expert synthesis also highlights proteostasis roles for BTB-Kelch family members and KBTBD13 (CUL3 complex), although detailed KBTBD13 ubiquitin substrates were not provided in the retrieved primary excerpts. (ziemian2025integrativeapproachesto pages 15-17, karimi2024characterizationofneb pages 1-2)

3.3 Primary affected cell types and anatomical locations • Primary cell type: skeletal muscle fiber / skeletal myofiber (CL:0000187, “skeletal muscle cell”; mapping provided for knowledge-base use). Mechanistic evidence is from patient skeletal muscle biopsies and in vivo skeletal muscle models (zebrafish). (karimi2024characterizationofneb pages 1-2, mansur2023dynamicregulationof pages 4-8) • Primary anatomy: skeletal muscle tissue (UBERON:0001134, “skeletal muscle tissue”) with frequent respiratory muscle involvement clinically (diaphragm and accessory muscles inferred via respiratory endpoints). (NCT03728803 chunk 1, moreno2023clinicalmanifestationof pages 7-9)

3.4 Chemical entities (therapeutic and mechanistic) Drug/compound candidates with mechanistic rationale and evidence: • Omecamtiv mecarbil (cardiac myosin activator): in NEB-NM type 1 fibers from patients, OM “substantially increased submaximal tension … ranging from 87 to 318%,” with larger effects in those with lower nebulin. (Karimi 2024; https://doi.org/10.1007/s00401-024-02726-w) (karimi2024characterizationofneb pages 1-2) • Tirasemtiv (CK-2017357; fast skeletal troponin activator): in an Acta1 NM mouse model, “acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies,” with respiratory efficiency effects described. (Galli 2024; https://doi.org/10.1085/jgp.202313471) (galli2024tirasemtivenhancessubmaximal pages 1-2) Mechanistic tool compound: • MG132 (proteasome inhibitor) is used experimentally to support a ubiquitin–proteasome mechanism in KLHL40-mediated regulation (increasing stability of a target protein, SAR1A, in the Mansur et al. study). (mansur2023dynamicregulationof pages 15-19) (For CHEBI mapping in a knowledge base: omecamtiv mecarbil, tirasemtiv, MG132 are chemically name-identifiable but CHEBI IDs were not available in the retrieved excerpts and are therefore not asserted.)

  1. Gene-to-mechanism annotations (ontology-ready; representative)

Below are representative, evidence-supported annotations suitable for a knowledge base (not exhaustive).

NEB (HGNC symbol: NEB; protein: nebulin) • Function/pathophysiology: regulates thin-filament length, cross-bridge cycling, and myofibril alignment; NEB variants can cause both shortened and elongated thin filaments; reduced nebulin correlates with reduced tension. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Example disrupted processes (GO): – GO:0030017 sarcomere organization – GO:0007015 actin filament organization – GO:0006936 muscle contraction – GO:0045214 sarcomere organization (related)

ACTA1 (HGNC symbol: ACTA1; protein: skeletal muscle α-actin) • Function/pathophysiology: thin filament core component; pathogenic missense variants can impair actin polymerization/stability with dominant-negative effects; contributes to contractile weakness. (findlay2024dominantlyinheritedmuscle pages 14-15, galli2024tirasemtivenhancessubmaximal pages 1-2) • Example disrupted processes (GO): – GO:0030048 actin filament-based movement – GO:0007015 actin filament organization

KLHL40 (HGNC symbol: KLHL40; BTB-Kelch protein) • Function/pathophysiology: CUL3 E3 ligase adaptor; regulates ubiquitylation and proteasomal degradation of targets including SAR1A to control ER exit/COPII and ECM trafficking; loss causes vesicle/Golgi/ECM and sarcomere-size defects. (mansur2023dynamicregulationof pages 1-4, mansur2023dynamicregulationof pages 4-8) • Example disrupted processes (GO): – GO:0016567 protein ubiquitination – GO:0032440 protein polyubiquitination – GO:0006888 ER to Golgi vesicle-mediated transport – GO:0030705 cytoplasmic vesicle budding from endoplasmic reticulum

KBTBD13 (HGNC symbol: KBTBD13; BTB-Kelch family) • Mechanism evidence in retrieved set: Karimi et al. categorize KBTBD13 among NM genes “likely involved in protein turnover … via the ubiquitin–proteasome pathway,” and clinical data show markedly reduced relaxation rate in KBTBD13-related NM. (karimi2024characterizationofneb pages 1-2, kleef2024nemalinemyopathytype pages 1-2)

Rod/nemaline body cellular component context • Rods show continuity with Z-discs and are composed of Z-disc/thin-filament proteins. (nicolau2023molecularsignaturesof pages 2-4) • Example cellular component (GO CC): – GO:0030018 Z disc – GO:0030017 sarcomere

  1. Disease progression model (sequence of events)

A synthesis consistent with the 2023–2024 evidence is: 1) Initiating event: pathogenic variant in a thin-filament structural/regulatory gene (e.g., NEB, ACTA1, TPM2/3, TNNT1) or in proteostasis/assembly regulators (e.g., KLHL40, KBTBD13). (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4) 2) Early molecular consequences: • Thin filament: altered actin polymerization/stability (ACTA1) and/or altered nebulin abundance and thin-filament length uniformity (NEB), with direct effects on cross-bridge recruitment/overlap and force. (findlay2024dominantlyinheritedmuscle pages 14-15, karimi2024characterizationofneb pages 1-2) • Proteostasis/trafficking: altered KLHL40–CUL3 ubiquitylation and destabilized ER exit/COPII trafficking of ECM proteins, impacting membrane homeostasis and myofiber microenvironment. (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4) 3) Structural pathology: • Z-disc disorganization and accumulation of nemaline rods (protein aggregates) composed of thin-filament/Z-disc proteins; rods can appear subsarcolemmal, central, or diffuse. (karimi2024characterizationofneb pages 1-2, nicolau2023molecularsignaturesof pages 2-4, nicolau2023molecularsignaturesof media 60ef7b58) 4) Functional decline: • Reduced maximal and/or submaximal tension and impaired relaxation dynamics (subtype-dependent), leading to clinical weakness and fatigability; respiratory and bulbar muscles frequently affected. (karimi2024characterizationofneb pages 1-2, kleef2024nemalinemyopathytype pages 1-2, moreno2023clinicalmanifestationof pages 7-9) 5) Domain-specific progression: • For NEB-associated NM, cross-sectional age stratification suggests progression in respiratory dysfunction and skeletal deformities (e.g., scoliosis) even if motor/swallowing may appear more stable in some groups. (moreno2023clinicalmanifestationof pages 1-2)

  1. Phenotypic manifestations (HPO mapping; representative)

NEB-associated NM (cohort evidence; 2023) • Ventilatory support requirement: 55% used ventilatory support; progressive uptake with age in some analyses. (HP:0002093 Respiratory insufficiency; HP:0011949 Assisted ventilation) (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9) • Feeding impairment: gastrostomy tube use 32% (bulbar dysfunction). (HP:0002020 Dysphagia; HP:0004396 Feeding difficulties) (moreno2023clinicalmanifestationof pages 1-2) • Weakness and impaired ambulation (HP:0001324 Muscle weakness; HP:0003677 Walking disability). (moreno2023clinicalmanifestationof pages 1-2) • Scoliosis/axial deformities (HP:0002650 Scoliosis; HP:0003307 Rigid spine). (moreno2023clinicalmanifestationof pages 3-5)

KBTBD13-associated NEM6 (2024) • Slowness of movements and delayed relaxation (phenotype aligned with “reduced muscle relaxation rate”). (HP:0003394 Muscle stiffness; HP:0001251 Ataxia not implied; do not assert) (kleef2024nemalinemyopathytype pages 1-2) • Falls: 33% fell ≥1 time over 100 days; 21% ≥2 times. (HP:0002527 Falls) (kleef2024nemalinemyopathytype pages 1-2)

  1. Recent developments (prioritizing 2023–2024)

7.1 Mechanistic diversification beyond “sarcomere-only” models The KLHL40 ubiquitylation → SAR1A/COPII → ECM secretion mechanism introduces a disease-onset model where endomembrane trafficking and ECM homeostasis are upstream contributors to muscle pathology, linking proteostasis and organelle communication to later structural damage. (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4)

7.2 Variant-class mechanisms in NEB: NMD, cryptic splicing, and “long TFL” disease Karimi et al. (2024) provide direct patient-based evidence that NEB-NM pathomechanism includes not only reduced nebulin/short TFL but also “longer than normal” TFL due to pathogenic duplication, arguing for thin-filament length homeostasis (and uniformity) as a central disease variable. (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17)

7.3 Pharmacologic contractility augmentation as a rational strategy (proof-of-concept) • OM (myosin activator) enhanced submaximal tension in patient type 1 fibers by 87–318% (NEB-NM), suggesting that correcting submaximal force generation is a mechanistically coherent route. (karimi2024characterizationofneb pages 1-2) • Tirasemtiv (troponin activator) improved submaximal stimulation force in an ACTA1 NM mouse model, supporting “myofilament activators” as a class. (galli2024tirasemtivenhancessubmaximal pages 1-2) These advances do not establish clinical efficacy in NM, but they strengthen the therapeutic logic and motivate outcome measures emphasizing submaximal force/respiratory efficiency. (galli2024tirasemtivenhancessubmaximal pages 1-2, NCT03728803 chunk 1)

  1. Current applications and real-world implementations

8.1 Diagnostics in practice Muscle pathology • NM rods “appear red on the Gomori trichrome stain” and have an “electron-dense lattice-like structure on electron microscopy,” with rods categorized by distribution (central/subsarcolemmal/diffuse). (nicolau2023molecularsignaturesof pages 2-4) Genetic testing • A targeted panel approach (example: “Sequencing of 123 genes … known to cause inherited myopathies”) is used in practice for distinguishing inherited vs acquired nemaline myopathies. (nicolau2023molecularsignaturesof pages 2-4) • Case-based literature highlights expanded next-generation sequencing panels and emphasizes the value of electron microscopy when multiple biopsy abnormalities coexist. (piga2024casereporta pages 1-2) • In neonatal hypotonia contexts, rapid genetic testing is advocated to expedite diagnosis and potentially reduce invasive biopsy. (vu2024nemalinemyopathyin pages 1-2)

8.2 Management and supportive care Cohort and case reports emphasize multidisciplinary, supportive management focusing on respiratory and feeding support (noninvasive/invasive ventilation, tracheostomy, gastrostomy), plus rehabilitation and airway clearance. (vu2024nemalinemyopathyin pages 1-2, moreno2023clinicalmanifestationof pages 1-2)

8.3 Clinical trials and real-world research infrastructure Inspiratory muscle training (IMT) as a respiratory physiology intervention • NCT03728803 (NEMTRAIN; Radboud UMC). Completed; started 2018-10-10; primary completion 2021-03-25; enrollment 42. Primary endpoint: maximal inspiratory pressure (MIP). Secondary endpoints include diaphragm ultrasound measures, cough flow, spirometry, and functional outcomes (MFM, 6MWT, balance/falls) that align with NM respiratory pathophysiology. URL: https://clinicaltrials.gov/study/NCT03728803 (NCT03728803 chunk 1, NCT03728803 chunk 2) Natural history studies (trial readiness) • Belgium Acti-Nemaline natural history: NCT07201636, not-yet-recruiting (estimated start 2025-12). Primary endpoints: MFM32 change and ventilation hours/day over 3 years; wearable-derived falls and gait metrics included. URL: https://clinicaltrials.gov/study/NCT07201636 (NCT07201636 chunk 1, NCT07201636 chunk 2) • UK NM natural history network: NCT06670378 (mixed recruiting status by site in retrieved excerpt). URL: https://clinicaltrials.gov/study/NCT06670378 (NCT06670378 chunk 2) These initiatives operationalize clinically meaningful outcome domains (motor, ventilation burden, falls, QoL) that directly reflect NM pathophysiology. (NCT07201636 chunk 2, NCT03728803 chunk 2)

  1. Recent statistics and quantitative data (selected)

Epidemiology • Pediatric systematic review states NM “affects 1 in 50 000 live births.” (Christophers et al., 2022-06; https://doi.org/10.1177/08830738221096316) (christophers2022pediatricnemalinemyopathy pages 1-3) • Karimi et al. (2024) cite an “estimated incidence of two cases per 100,000 live births.” (karimi2024characterizationofneb pages 1-2) (These figures differ by source/definition and should be harmonized in future epidemiologic studies.) (christophers2022pediatricnemalinemyopathy pages 1-3, karimi2024characterizationofneb pages 1-2)

NEB-associated NM (33-patient cohort) • 55% ventilatory support; 32% gastrostomy tube; 35% unable to walk without support; progressive respiratory involvement in time-to-event analysis (e.g., 50% began VS before age 20; ~85% by age 40 in one analysis). (Moreno et al., 2023-02; https://doi.org/10.1212/nxg.0000000000200056) (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9)

KBTBD13-associated NEM6 (24-patient cohort) • Falls: 33% ≥1 fall in 100 days; 21% ≥2 falls. (van Kleef et al., 2024-12; https://doi.org/10.1212/nxg.0000000000200214) (kleef2024nemalinemyopathytype pages 1-2) • Muscle relaxation: median peak relaxation rate 6.5 s−1 (IQR 4.9–8.1) vs lower limit of normal 10.1 s−1. (kleef2024nemalinemyopathytype pages 1-2)

Therapy-linked functional effects (ex vivo/in vivo) • OM increased submaximal tension 87–318% in NEB-NM patient type-1 fibers. (karimi2024characterizationofneb pages 1-2) • NRAP reduction rescued neb−/− sarcomere height deficit (510 ± 107 nm vs 755 ± 192 nm control) and eliminated observable nemaline bodies. (casey2023nrapreductionrescues pages 3-6)

  1. Evidence items (PMID/DOI, date, URL) – curated list

• Karimi E et al. “Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.” Acta Neuropathologica. Accepted 2024-03-26; published 2024-04. DOI:10.1007/s00401-024-02726-w. URL: https://doi.org/10.1007/s00401-024-02726-w (karimi2024characterizationofneb pages 1-2, karimi2024characterizationofneb pages 16-17) • Mansur A et al. “Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset.” eLife. 2023-07. DOI:10.1101/2022.07.21.501000. URL: https://doi.org/10.1101/2022.07.21.501000 (mansur2023dynamicregulationof pages 4-8, mansur2023dynamicregulationof pages 1-4) • Nicolau S et al. “Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies.” Acta Neuropathol Commun. 2023-01. DOI:10.1186/s40478-023-01518-9. URL: https://doi.org/10.1186/s40478-023-01518-9 (nicolau2023molecularsignaturesof pages 2-4, nicolau2023molecularsignaturesof media 60ef7b58) • Findlay AR. “Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.” Dis Model Mech. 2024-10. DOI:10.1242/dmm.050720. URL: https://doi.org/10.1242/dmm.050720 (findlay2024dominantlyinheritedmuscle pages 14-15) • Galli RA et al. “Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.” J Gen Physiol. 2024-02. DOI:10.1085/jgp.202313471. URL: https://doi.org/10.1085/jgp.202313471 (galli2024tirasemtivenhancessubmaximal pages 1-2) • Casey JG et al. “NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.” Hum Mol Genet. 2023-01. DOI:10.1093/hmg/ddad011. URL: https://doi.org/10.1093/hmg/ddad011 (casey2023nrapreductionrescues pages 1-2, casey2023nrapreductionrescues pages 3-6) • Moreno CAM et al. “Clinical manifestation of nebulin-associated nemaline myopathy.” Neurology Genetics. 2023-02. DOI:10.1212/nxg.0000000000200056. URL: https://doi.org/10.1212/nxg.0000000000200056 (moreno2023clinicalmanifestationof pages 1-2, moreno2023clinicalmanifestationof pages 7-9) • van Kleef ESB et al. “Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene.” Neurology: Genetics. 2024-12. DOI:10.1212/nxg.0000000000200214. URL: https://doi.org/10.1212/nxg.0000000000200214 (kleef2024nemalinemyopathytype pages 1-2) • ClinicalTrials.gov NCT03728803 (Inspiratory Muscle Training in Nemaline Myopathy). URL: https://clinicaltrials.gov/study/NCT03728803 (NCT03728803 chunk 1) • ClinicalTrials.gov NCT07201636 (Natural History Study for Patients With Nemaline Myopathy in Belgium). URL: https://clinicaltrials.gov/study/NCT07201636 (NCT07201636 chunk 1)

Limitations of this report (evidence scope) • Several mechanistic topics requested (e.g., autophagy in NM specifically; comprehensive mitochondrial/oxidative stress statistics in skeletal muscle tissue; gene-by-gene mechanistic depth for TPM2/3, TNNT1, CFL2, LMOD3, KLHL41) are only partially supported by the retrieved 2023–2024 full-text excerpts. Where mechanisms are not explicitly supported in the cited excerpts, they are not asserted. • PMIDs were not consistently available in the provided full-text excerpts; DOIs/ClinicalTrials.gov identifiers and URLs are therefore provided as the primary reference anchors.

Figure citation • Modified Gomori trichrome figure showing multiple rod distribution patterns (subsarcolemmal, central, diffuse, atrophic fibers). (nicolau2023molecularsignaturesof media 60ef7b58)

References

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  2. (karimi2024characterizationofneb pages 1-2): Esmat Karimi, Jochen Gohlke, Mila van der Borgh, Johan Lindqvist, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W. Lawlor, Coen Ottenheijm, and Henk Granzier. Characterization of neb pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects. Acta Neuropathologica, Apr 2024. URL: https://doi.org/10.1007/s00401-024-02726-w, doi:10.1007/s00401-024-02726-w. This article has 5 citations and is from a highest quality peer-reviewed journal.

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  5. (findlay2024dominantlyinheritedmuscle pages 14-15): Andrew R. Findlay. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms, Oct 2024. URL: https://doi.org/10.1242/dmm.050720, doi:10.1242/dmm.050720. This article has 7 citations and is from a domain leading peer-reviewed journal.

  6. (karimi2024characterizationofneb pages 16-17): Esmat Karimi, Jochen Gohlke, Mila van der Borgh, Johan Lindqvist, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W. Lawlor, Coen Ottenheijm, and Henk Granzier. Characterization of neb pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects. Acta Neuropathologica, Apr 2024. URL: https://doi.org/10.1007/s00401-024-02726-w, doi:10.1007/s00401-024-02726-w. This article has 5 citations and is from a highest quality peer-reviewed journal.

  7. (galli2024tirasemtivenhancessubmaximal pages 1-2): Ricardo A. Galli, Tamara C. Borsboom, Charlotte Gineste, Lorenza Brocca, Maira Rossi, Darren T. Hwee, Fady I. Malik, Roberto Bottinelli, Julien Gondin, Maria-Antonietta Pellegrino, Josine M. de Winter, and Coen A.C. Ottenheijm. Tirasemtiv enhances submaximal muscle tension in an acta1:p.asp286gly mouse model of nemaline myopathy. The Journal of General Physiology, Feb 2024. URL: https://doi.org/10.1085/jgp.202313471, doi:10.1085/jgp.202313471. This article has 3 citations.

  8. (mansur2023dynamicregulationof pages 4-8): A. Mansur, Remi Joseph, E. Kim, Pierre M. Jean-Beltran, N. Udeshi, Cadence Pearce, Hanjie Jiang, Reina Iwase, Miroslav P. Milev, Hashem Almousa, E. McNamara, J. Widrick, C. Perez, G. Ravenscroft, M. Sacher, Philip A. Cole, Steve Carr, and Vandana Gupta. Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset. eLife, Jul 2023. URL: https://doi.org/10.1101/2022.07.21.501000, doi:10.1101/2022.07.21.501000. This article has 17 citations and is from a domain leading peer-reviewed journal.

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  10. (casey2023nrapreductionrescues pages 1-2): Jennifer G Casey, Eurick S. Kim, Remi Joseph, Frank Li, H. Granzier, and Vandana A Gupta. Nrap reduction rescues sarcomere defects in nebulin-related nemaline myopathy. Human molecular genetics, 32:1711-1721, Jan 2023. URL: https://doi.org/10.1093/hmg/ddad011, doi:10.1093/hmg/ddad011. This article has 10 citations and is from a domain leading peer-reviewed journal.

  11. (casey2023nrapreductionrescues pages 3-6): Jennifer G Casey, Eurick S. Kim, Remi Joseph, Frank Li, H. Granzier, and Vandana A Gupta. Nrap reduction rescues sarcomere defects in nebulin-related nemaline myopathy. Human molecular genetics, 32:1711-1721, Jan 2023. URL: https://doi.org/10.1093/hmg/ddad011, doi:10.1093/hmg/ddad011. This article has 10 citations and is from a domain leading peer-reviewed journal.

  12. (NCT03728803 chunk 1): Inspiratory Muscle Training in Nemaline Myopathy. Radboud University Medical Center. 2018. ClinicalTrials.gov Identifier: NCT03728803

  13. (moreno2023clinicalmanifestationof pages 7-9): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.

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  15. (kleef2024nemalinemyopathytype pages 1-2): Esmee S.B. van Kleef, Karlijn Bouman, Joery P.F. Molenaar, Benno Küsters, Jan T. Groothuis, Montse Olivé, Edoardo Malfatti, Erik-Jan Kamsteeg, Baziel G.M. Van Engelen, Coen A.C. Ottenheijm, Jonne Doorduin, and Nicol C. Voermans. Nemaline myopathy type 6 caused by variants in the kbtbd13 gene. Neurology: Genetics, Dec 2024. URL: https://doi.org/10.1212/nxg.0000000000200214, doi:10.1212/nxg.0000000000200214. This article has 1 citations.

  16. (moreno2023clinicalmanifestationof pages 1-2): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.

  17. (moreno2023clinicalmanifestationof pages 3-5): Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, and Edmar Zanoteli. Clinical manifestation of nebulin-associated nemaline myopathy. Neurology Genetics, Feb 2023. URL: https://doi.org/10.1212/nxg.0000000000200056, doi:10.1212/nxg.0000000000200056. This article has 15 citations.

  18. (piga2024casereporta pages 1-2): Daniela Piga, Martina Rimoldi, Francesca Magri, Simona Zanotti, Laura Napoli, Michela Ripolone, Serena Pagliarani, Patrizia Ciscato, Daniele Velardo, Adele D’Amico, Enrico Bertini, Giacomo Pietro Comi, Dario Ronchi, and Stefania Corti. Case report: a novel acta1 variant in a patient with nemaline rods and increased glycogen deposition. Frontiers in Neurology, Mar 2024. URL: https://doi.org/10.3389/fneur.2024.1340693, doi:10.3389/fneur.2024.1340693. This article has 3 citations and is from a peer-reviewed journal.

  19. (vu2024nemalinemyopathyin pages 1-2): Annie Vu, Subah Nanda, and Todd Chassee. Nemaline myopathy in a hypotonic neonate: diagnostic approach for early detection and management. Cureus, Mar 2024. URL: https://doi.org/10.7759/cureus.56866, doi:10.7759/cureus.56866. This article has 0 citations.

  20. (NCT03728803 chunk 2): Inspiratory Muscle Training in Nemaline Myopathy. Radboud University Medical Center. 2018. ClinicalTrials.gov Identifier: NCT03728803

  21. (NCT07201636 chunk 1): Manon HUSTINX. Natural History Study for Patients With Nemaline Myopathy in Belgium. Centre Hospitalier Universitaire de Liege. 2025. ClinicalTrials.gov Identifier: NCT07201636

  22. (NCT07201636 chunk 2): Manon HUSTINX. Natural History Study for Patients With Nemaline Myopathy in Belgium. Centre Hospitalier Universitaire de Liege. 2025. ClinicalTrials.gov Identifier: NCT07201636

  23. (NCT06670378 chunk 2): Natural History Study for Patients With Nemaline Myopathy in the UK. University of Oxford. 2024. ClinicalTrials.gov Identifier: NCT06670378

  24. (christophers2022pediatricnemalinemyopathy pages 1-3): Briana Christophers, Michael A. Lopez, Vandana A. Gupta, Hannes Vogel, and Mary Baylies. Pediatric nemaline myopathy: a systematic review using individual patient data. Journal of Child Neurology, 37:652-663, Jun 2022. URL: https://doi.org/10.1177/08830738221096316, doi:10.1177/08830738221096316. This article has 20 citations and is from a peer-reviewed journal.