Myasthenia Gravis

Autoimmune MONDO:0009688 Neuromuscular Disease Autoimmune Disease

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2
Mappings
1
Definitions
1
Inheritance
3
Pathophys.
38
Phenotypes
4
Genes
11
Treatments
5
Subtypes
10
References
2
Deep Research
🔗

Mappings

MONDO
MONDO:0009688 myasthenia gravis
skos:exactMatch ORPHA:589 ORPHA:589: CONSISTENT
Orphanet lists MONDO:0009688 as an exact cross-reference for myasthenia gravis.
ICD-10-CM
ICD10CM:G70.0 Myasthenia gravis
skos:exactMatch ORPHA:589 ORPHA:589: CONSISTENT
Orphanet lists ICD-10 G70.0 as an exact cross-reference for myasthenia gravis.
📘

Definitions

1
Orphanet disease definition
Orphanet defines myasthenia gravis as a rare, clinically heterogeneous, autoimmune disorder of the neuromuscular junction characterized by fatigable weakness of voluntary muscles.
CASE_DEFINITION
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"Myasthenia gravis (MG) is a rare, clinically heterogeneous, autoimmune disorder of the neuromuscular junction characterized by fatigable weakness of voluntary muscles."
Orphanet's definition supports the autoimmune neuromuscular junction framing of this entry.
👪

Inheritance

1
Multigenic/multifactorial inheritance HP:0001426
Non-Mendelian inheritance
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"Multigenic/multifactorial"
Orphanet records multigenic/multifactorial inheritance for myasthenia gravis.
◆

Subtypes

5
AChR Antibody-Positive MG
Most common form (~85%), with antibodies against acetylcholine receptors.
Show evidence (1 reference)
DOI:10.1038/s41433-024-03133-x SUPPORT Human Clinical
"In generalised MG this is seen in nearly 90% patients. Other antibodies include those against muscle specific tyrosine kinase (MuSK) and lipoprotein receptor related protein 4 (LRP4). "
The deep-research review supports AChR-antibody-positive disease as the dominant generalized MG subtype and places MuSK/LRP4 antibody subtypes in context.
MuSK Antibody-Positive MG
Antibodies against muscle-specific kinase, typically more severe bulbar symptoms.
Show evidence (2 references)
PMID:21674519 SUPPORT
"Eighty-five percent were female, with disease onset typically in the fourth decade. Ocular and/or bulbar symptoms were present at onset in 79% of those studied."
Large cohort study confirms MuSK-MG has prominent bulbar involvement and female predominance.
PMID:21674519 SUPPORT
"Eighty-five percent were MGFA class III or greater, and crisis occurred in 28%."
MuSK-MG tends to be more severe with higher rates of myasthenic crisis.
Seronegative MG
No detectable AChR or MuSK antibodies, may have LRP4 or other antibodies.
Show evidence (1 reference)
DOI:10.1038/s41433-024-03133-x SUPPORT Human Clinical
"Other antibodies include those against muscle specific tyrosine kinase (MuSK) and lipoprotein receptor related protein 4 (LRP4). "
The review supports the curation note that patients negative for routine AChR/MuSK testing may have other antibody-defined MG biology, including LRP4.
Ocular MG
Disease limited to extraocular muscles, may progress to generalized form.
Thymoma-Associated MG
MG associated with thymic tumors, often more severe.
⚙

Pathophysiology

3
Autoantibody-Mediated NMJ Dysfunction
Autoantibodies (primarily anti-AChR) target the postsynaptic membrane at neuromuscular junctions. Antibodies cause receptor internalization, complement-mediated destruction, and functional blockade, reducing acetylcholine signaling efficiency.
Skeletal Muscle Cell link
Neuromuscular Transmission link
Show evidence (2 references)
PMID:37869140 SUPPORT
"Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction."
Confirms that autoantibodies targeting the AChR complex at the NMJ are central to myasthenia gravis pathophysiology.
PMID:29266249 SUPPORT
"Approximately 74-88% of patients with gMG have acetylcholine receptor (AChR) autoantibodies."
Documents the prevalence of AChR autoantibodies in generalized myasthenia gravis.
Complement Activation
Anti-AChR antibodies activate the classical complement pathway, leading to membrane attack complex formation and destruction of the postsynaptic membrane architecture.
Complement Activation link
Show evidence (3 references)
PMID:29266249 SUPPORT
"activation and amplification of complement results in the formation of membrane attack complexes (MACs), lipophilic proteins that damage cell membranes."
Describes how complement activation leads to MAC formation and subsequent membrane damage.
PMID:29266249 SUPPORT
"Studies in animals lacking specific complement proteins have confirmed that MAC formation is required to induce experimental autoimmune MG (EAMG) and NMJ damage."
Animal studies demonstrate that MAC formation is essential for NMJ damage in myasthenia gravis.
PMID:37869140 SUPPORT
"Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage."
Confirms that AChR antibodies (IgG1 and IgG3) activate complement, contributing to NMJ damage.
Thymic Abnormalities
Thymic hyperplasia (65-75% of patients) or thymoma (10-15%) is common. The thymus may serve as the site of autoimmunization, containing myoid cells expressing AChR that activate autoreactive T cells.
Thymic Epithelial Cell link
Show evidence (2 references)
PMID:21922466 SUPPORT
"The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T..."
Demonstrates that the thymus shows pathologic changes in most AChR-positive MG patients and contains all elements needed to initiate and sustain autoimmunity.
PMID:21922466 SUPPORT
"Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor."
Confirms the autoimmune nature of myasthenia gravis with autoantibodies targeting NMJ components.
●

Phenotypes

38
Cardiovascular 1
Raynaud Phenomenon OCCASIONAL Raynaud phenomenon (HP:0030880)
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030880 | Raynaud phenomenon | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies Raynaud phenomenon as Occasional (29-5%) in myasthenia gravis.
Digestive 1
Dysphagia FREQUENT Dysphagia (HP:0002015)
Difficulty swallowing, common in MuSK-positive MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0002015 | Dysphagia | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies dysphagia as Frequent (79-30%) in myasthenia gravis.
Ear 1
Hearing Impairment OCCASIONAL Hearing impairment (HP:0000365)
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000365 | Hearing impairment | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies hearing impairment as Occasional (29-5%) in myasthenia gravis.
Endocrine 1
Hyperthyroidism OCCASIONAL Hyperthyroidism (HP:0000836)
Autoimmune thyroid disease co-occurs with MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000836 | Hyperthyroidism | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies hyperthyroidism as Occasional (29-5%) in myasthenia gravis.
Eye 2
Ptosis FREQUENT Ptosis (HP:0000508)
Often first symptom, asymmetric drooping eyelids
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000508 | Ptosis | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies ptosis as Frequent (79-30%) in myasthenia gravis.
Diplopia FREQUENT Diplopia (HP:0000651)
Double vision from extraocular muscle weakness
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000651 | Diplopia | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies diplopia as Frequent (79-30%) in myasthenia gravis.
Genitourinary 1
Glycosuria OCCASIONAL Glycosuria (HP:0003076)
Associated with autoimmune comorbidity
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0003076 | Glycosuria | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies glycosuria as Occasional (29-5%) in myasthenia gravis.
Head and Neck 1
Weakness of Facial Musculature FREQUENT Weakness of facial musculature (HP:0030319)
Facial weakness contributing to expressionless facies
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030319 | Weakness of facial musculature | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies weakness of facial musculature as Frequent (79-30%) in myasthenia gravis.
Limbs 1
Limb Muscle Weakness FREQUENT Limb muscle weakness (HP:0003690)
Proximal limb weakness, difficulty with overhead activities
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0003690 | Limb muscle weakness | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies limb muscle weakness as Frequent (79-30%) in myasthenia gravis.
Musculoskeletal 2
Muscle Weakness VERY_FREQUENT Muscle weakness (HP:0001324)
Fatigable weakness, worse with exertion
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0001324 | Muscle weakness | Very frequent (99-80%)"
Orphanet's curated HPO frequency annotation classifies muscle weakness as Very frequent (99-80%) in myasthenia gravis.
Skeletal Muscle Atrophy FREQUENT Skeletal muscle atrophy (HP:0003202)
Muscle wasting in chronic disease, particularly MuSK-MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0003202 | Skeletal muscle atrophy | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies skeletal muscle atrophy as Frequent (79-30%) in myasthenia gravis.
Nervous System 2
Dysarthria FREQUENT Dysarthria (HP:0001260)
Slurred or nasal speech
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0001260 | Dysarthria | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies dysarthria as Frequent (79-30%) in myasthenia gravis.
Paresthesia OCCASIONAL Paresthesia (HP:0003401)
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0003401 | Paresthesia | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies paresthesia as Occasional (29-5%) in myasthenia gravis.
Respiratory 2
Dyspnea FREQUENT Dyspnea (HP:0002094)
Breathing difficulty from respiratory muscle weakness
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0002094 | Dyspnea | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies dyspnea as Frequent (79-30%) in myasthenia gravis.
Respiratory Failure OCCASIONAL Respiratory failure (HP:0002878)
Myasthenic crisis, life-threatening
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0002878 | Respiratory failure | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies respiratory failure as Occasional (29-5%) in myasthenia gravis.
Constitutional 1
Fatigue FREQUENT Fatigue (HP:0012378)
Generalized fatigue distinct from muscle-specific weakness
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0012378 | Fatigue | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies fatigue as Frequent (79-30%) in myasthenia gravis.
Other 22
Ophthalmoparesis FREQUENT Ophthalmoparesis (HP:0000597)
Weakness of extraocular muscles
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000597 | Ophthalmoparesis | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies ophthalmoparesis as Frequent (79-30%) in myasthenia gravis.
Dysphonia FREQUENT Dysphonia (HP:0001618)
Voice changes from laryngeal muscle weakness
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0001618 | Dysphonia | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies dysphonia as Frequent (79-30%) in myasthenia gravis.
Bulbar Palsy FREQUENT Bulbar palsy (HP:0001283)
Weakness of muscles innervated by cranial nerves
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0001283 | Bulbar palsy | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies bulbar palsy as Frequent (79-30%) in myasthenia gravis.
Fatigable Weakness of Skeletal Muscles FREQUENT Fatigable weakness of skeletal muscles (HP:0030197)
Weakness worsens with repetitive use
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030197 | Fatigable weakness of skeletal muscles | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies fatigable weakness of skeletal muscles as Frequent (79-30%) in myasthenia gravis.
Difficulty Climbing Stairs FREQUENT Difficulty climbing stairs (HP:0003551)
Proximal weakness manifesting as difficulty with stairs
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0003551 | Difficulty climbing stairs | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies difficulty climbing stairs as Frequent (79-30%) in myasthenia gravis.
Abnormal Thymus Morphology FREQUENT Abnormal thymus morphology (HP:0000777)
Thymic hyperplasia or thymoma
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000777 | Abnormality of the thymus | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies abnormality of the thymus as Frequent (79-30%) in myasthenia gravis.
Thymus Hyperplasia FREQUENT Thymus hyperplasia (HP:0010516)
Present in 65-75% of AChR-positive patients
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0010516 | Thymus hyperplasia | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies thymus hyperplasia as Frequent (79-30%) in myasthenia gravis.
Thymoma OCCASIONAL Thymoma (HP:0100522)
Thymic tumor present in 10-15% of MG patients
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0100522 | Thymoma | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies thymoma as Occasional (29-5%) in myasthenia gravis.
Myositis FREQUENT Myositis (HP:0100614)
Inflammatory myopathy can co-occur with MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0100614 | Myositis | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies myositis as Frequent (79-30%) in myasthenia gravis.
Tongue Atrophy OCCASIONAL Tongue atrophy (HP:0012473)
Tongue wasting, particularly in MuSK-MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0012473 | Tongue atrophy | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies tongue atrophy as Occasional (29-5%) in myasthenia gravis.
Single Fiber EMG Abnormality FREQUENT Single fiber EMG abnormality (HP:0030006)
Key electrodiagnostic finding, increased jitter
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030006 | Single fiber EMG abnormality | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies single fiber EMG abnormality as Frequent (79-30%) in myasthenia gravis.
Acetylcholine Receptor Antibody Positivity FREQUENT Anti-neuromuscular Junction acetylcholine receptor antibody positivity (HP:0030208)
Present in ~85% of generalized MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030208 | Acetylcholine receptor antibody positivity | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies acetylcholine receptor antibody positivity as Frequent (79-30%) in myasthenia gravis.
Anti-MuSK Antibody Positivity FREQUENT Anti-muscle-specific tyrosine kinase antibody (HP:0030210)
Orphanet classifies as Frequent (79-30%); the ~5-10% figure reflects prevalence among all MG patients, whereas the Orphanet frequency reflects detection rate among those tested for MuSK antibodies
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0030210 | Muscle specific kinase antibody positivity | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies muscle specific kinase antibody positivity as Frequent (79-30%) in myasthenia gravis.
Anti-Lrp4 Antibody Positivity OCCASIONAL Anti-Lrp4 antibody positivity (HP:5000046)
Present in some double-seronegative cases
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:5000046 | Anti-Lrp4 antibody positivity | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies anti-Lrp4 antibody positivity as Occasional (29-5%) in myasthenia gravis.
Anti-titin Antibody Positivity FREQUENT Anti-titin antibody positivity (HP:5000038)
Associated with thymoma and late-onset MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:5000038 | Anti-titin antibody positivity | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies anti-titin antibody positivity as Frequent (79-30%) in myasthenia gravis.
Anti-ryanodine Receptor Antibody FREQUENT Anti-ryanodine receptor antibody (HP:5000047)
Key marker for thymoma-associated MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:5000047 | Anti-ryanodine receptor antibody | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies anti-ryanodine receptor antibody as Frequent (79-30%) in myasthenia gravis.
Anti-Kv1.4 Antibody FREQUENT Anti-Kv1.4 antibody (HP:5000048)
Associated with myasthenic crisis and cardiac involvement
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:5000048 | Anti-Kv1.4 antibody | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies anti-Kv1.4 antibody as Frequent (79-30%) in myasthenia gravis.
Anti-DCC Netrin 1 Receptor Antibody Positivity FREQUENT Anti-DCC netrin 1 receptor antibody positivity (HP:6000881)
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:6000881 | Anti-DCC netrin 1 receptor antibody positivity | Frequent (79-30%)"
Orphanet's curated HPO frequency annotation classifies anti-DCC netrin 1 receptor antibody positivity as Frequent (79-30%) in myasthenia gravis.
Hashimoto Thyroiditis OCCASIONAL Hashimoto thyroiditis (HP:0000872)
Autoimmune thyroiditis co-occurs with MG
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0000872 | Hashimoto thyroiditis | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies Hashimoto thyroiditis as Occasional (29-5%) in myasthenia gravis.
Rheumatoid Arthritis OCCASIONAL Rheumatoid arthritis (HP:0001370)
Autoimmune comorbidity
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0001370 | Rheumatoid arthritis | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies rheumatoid arthritis as Occasional (29-5%) in myasthenia gravis.
Systemic Lupus Erythematosus OCCASIONAL Systemic lupus erythematosus (HP:0002725)
Autoimmune comorbidity
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0002725 | Systemic lupus erythematosus | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies systemic lupus erythematosus as Occasional (29-5%) in myasthenia gravis.
Primary Adrenal Insufficiency OCCASIONAL Primary adrenal insufficiency (HP:0008207)
Autoimmune comorbidity
Show evidence (1 reference)
ORPHA:589 SUPPORT Other
"HP:0008207 | Primary adrenal insufficiency | Occasional (29-5%)"
Orphanet's curated HPO frequency annotation classifies primary adrenal insufficiency as Occasional (29-5%) in myasthenia gravis.
🧬

Genetic Associations

4
HLA-B8 (Risk Factor)
HLA-DR3 (Risk Factor)
Polygenic MG Susceptibility (GWAS)
Show evidence (2 references)
DOI:10.1038/s41467-024-53595-6 SUPPORT Human Clinical
"We identified 12 independent genome-wide significant hits (P < 5e−8) across 11 loci. "
The deep-research report highlighted this 2024 GWAS/meta-analysis; it supports adding an explicit polygenic susceptibility assertion rather than only older single-locus notes.
DOI:10.1038/s41467-024-53595-6 SUPPORT Human Clinical
"Subgroup analyses revealed two of these were associated with early-onset (at age <50) and four with late-onset MG (at age ≥ 50). "
The GWAS supports distinct genetic contributions by age at onset, matching the research synthesis emphasis on early- versus late-onset MG.
CHRNA1 (Risk Factor)
💊

Treatments

11
Acetylcholinesterase Inhibitors
Action: acetylcholinesterase inhibitor therapy MAXO:0000645
First-line symptomatic treatment (pyridostigmine).
Show evidence (2 references)
PMID:36184373 SUPPORT
"Patients reported a median effectiveness of 60, IQR 28-78 and net benefit of 65, IQR 45-84."
Large cross-sectional study demonstrates patient-reported effectiveness of pyridostigmine.
PMID:36184373 SUPPORT
"Of all patients currently using pyridostigmine, 91% reported side effects (vs. 55% in the control group)."
While effective, pyridostigmine has high rate of side effects including GI symptoms.
Corticosteroids
Action: corticosteroid agent therapy MAXO:0000640
Prednisone for immunosuppression, mainstay of therapy.
Thymectomy
Action: thymectomy MAXO:0001079
Surgical removal of thymus, improves outcomes in appropriate patients.
Show evidence (2 references)
PMID:27509100 SUPPORT
"Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)"
Landmark randomized trial demonstrates thymectomy improves clinical outcomes in nonthymomatous MG.
PMID:27509100 SUPPORT
"Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001)."
Thymectomy reduces need for additional immunosuppression and hospitalizations.
Azathioprine
Action: immune suppressant agent therapy MAXO:0000297
Steroid-sparing immunosuppressant.
Mycophenolate Mofetil
Action: immune suppressant agent therapy MAXO:0000297
Alternative immunosuppressant.
Rituximab
Action: immune suppressant agent therapy MAXO:0000297
Anti-CD20 antibody, effective in refractory cases.
Eculizumab
Action: complement 5 inhibitor agent therapy MAXO:0001483
Complement inhibitor (anti-C5), approved for refractory AChR+ MG.
Show evidence (2 references)
PMID:29066163 SUPPORT
"Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis."
Phase 3 REGAIN trial evaluated eculizumab in refractory generalized MG.
PMID:29066163 SUPPORT
"Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group."
Eculizumab reduced exacerbation rates compared to placebo.
Plasma Exchange
Rapid removal of antibodies, used for myasthenic crisis.
Show evidence (1 reference)
PMID:21674519 SUPPORT
"Plasma exchange (PLEX) produced improvement in 93%, whereas only 61% improved after intravenous immunoglobulin."
Plasma exchange is highly effective, particularly in MuSK-MG where it outperforms IVIG.
Intravenous Immunoglobulin
Immunomodulation, used for exacerbations and crisis.
Efgartigimod
Action: FcRn antagonist therapy Ontology label: Pharmacotherapy NCIT:C15986
FcRn antagonist approved for generalized AChR-positive MG; reduces pathogenic IgG levels by blocking neonatal Fc receptor recycling.
Show evidence (2 references)
DOI:10.3389/fneur.2023.1229112 SUPPORT Human Clinical
"Efgartigimod is already approved for the treatment of generalized MG"
Review confirms FDA approval of efgartigimod for generalized MG.
DOI:10.3389/fneur.2023.1229112 SUPPORT Human Clinical
"FcRn receptors prevent the catabolism of IgG by impeding their lysosomal degradation and facilitating their extracellular release at physiological pH, consequently extending the IgG half-life. "
The research synthesis emphasized FcRn biology; this evidence links the treatment assertion to its mechanism of lowering pathogenic IgG.
Rozanolixizumab
Action: FcRn antagonist therapy Ontology label: Pharmacotherapy NCIT:C15986
FcRn antagonist for generalized AChR-positive MG; reduces pathogenic IgG via neonatal Fc receptor blockade.
Show evidence (1 reference)
DOI:10.3389/fneur.2023.1229112 SUPPORT Human Clinical
"rozanolixizumab is under review by health authorities"
Review documents rozanolixizumab as an FcRn antagonist under regulatory review for MG at time of publication.
🌍

Environmental Factors

4
Infections
May trigger or exacerbate disease
Medications
Aminoglycosides, beta-blockers, and others may worsen
Stress
Physical or emotional stress can trigger exacerbations
Pregnancy
Variable effects on disease course
🔬

Biochemical Markers

3
Anti-AChR Antibodies (Elevated)
Context: Present in ~85% of generalized MG
Anti-MuSK Antibodies (Elevated)
Context: Present in ~5-10% of MG, particularly seronegative cases
Anti-LRP4 Antibodies (Elevated)
Context: Present in some double-seronegative cases
{ }

Source YAML

click to show 
name: Myasthenia Gravis
creation_date: '2025-12-19T01:12:52Z'
updated_date: '2026-04-28T17:00:00Z'
category: Autoimmune
parents:
- Neuromuscular Disease
- Autoimmune Disease
disease_term:
  preferred_term: myasthenia gravis
  term:
    id: MONDO:0009688
    label: myasthenia gravis
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:G70.0
      label: Myasthenia gravis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:589
    mapping_justification: Orphanet lists ICD-10 G70.0 as an exact cross-reference for myasthenia gravis.
    consistency:
    - reference: ORPHA:589
      consistent: CONSISTENT
      notes: "ICD-10:G70.0 | Exact"
  mondo_mappings:
  - term:
      id: MONDO:0009688
      label: myasthenia gravis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:589
    mapping_justification: Orphanet lists MONDO:0009688 as an exact cross-reference for myasthenia gravis.
    consistency:
    - reference: ORPHA:589
      consistent: CONSISTENT
      notes: "MONDO:0009688 | Exact"
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines myasthenia gravis as a rare, clinically heterogeneous,
    autoimmune disorder of the neuromuscular junction characterized by
    fatigable weakness of voluntary muscles.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myasthenia gravis (MG) is a rare, clinically heterogeneous, autoimmune disorder of the neuromuscular junction characterized by fatigable weakness of voluntary muscles."
    explanation: Orphanet's definition supports the autoimmune neuromuscular junction framing of this entry.
external_assertions:
- name: Orphanet myasthenia gravis record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:589
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=589
  description: >
    Orphanet structured record for myasthenia gravis, including curated
    cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS
    identifiers.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009688 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:589 to MONDO:0009688.
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:G70.0 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:589 to ICD-10 G70.0.
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-11:8C60 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:589 to ICD-11 8C60.
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0026896 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:589 to UMLS C0026896.
inheritance:
- name: Multigenic/multifactorial inheritance
  inheritance_term:
    preferred_term: Non-Mendelian inheritance
    term:
      id: HP:0001426
      label: Non-Mendelian inheritance
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multigenic/multifactorial"
    explanation: Orphanet records multigenic/multifactorial inheritance for myasthenia gravis.
has_subtypes:
- name: AChR Antibody-Positive MG
  description: Most common form (~85%), with antibodies against acetylcholine receptors.
  evidence:
  - reference: DOI:10.1038/s41433-024-03133-x
    reference_title: Treating myasthenia gravis beyond the eye clinic
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      In generalised MG this is seen in nearly 90% patients. Other antibodies
      include those against muscle specific tyrosine kinase (MuSK) and
      lipoprotein receptor related protein 4 (LRP4).
    explanation: >
      The deep-research review supports AChR-antibody-positive disease as the
      dominant generalized MG subtype and places MuSK/LRP4 antibody subtypes in
      context.
- name: MuSK Antibody-Positive MG
  description: Antibodies against muscle-specific kinase, typically more severe bulbar symptoms.
  evidence:
  - reference: PMID:21674519
    reference_title: "Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts."
    supports: SUPPORT
    snippet: "Eighty-five percent were female, with disease onset typically in the fourth decade. Ocular and/or bulbar symptoms were present at onset in 79% of those studied."
    explanation: Large cohort study confirms MuSK-MG has prominent bulbar involvement and female predominance.
  - reference: PMID:21674519
    reference_title: "Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts."
    supports: SUPPORT
    snippet: "Eighty-five percent were MGFA class III or greater, and crisis occurred in 28%."
    explanation: MuSK-MG tends to be more severe with higher rates of myasthenic crisis.
- name: Seronegative MG
  description: No detectable AChR or MuSK antibodies, may have LRP4 or other antibodies.
  evidence:
  - reference: DOI:10.1038/s41433-024-03133-x
    reference_title: Treating myasthenia gravis beyond the eye clinic
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Other antibodies include those against muscle specific tyrosine kinase
      (MuSK) and lipoprotein receptor related protein 4 (LRP4).
    explanation: >
      The review supports the curation note that patients negative for routine
      AChR/MuSK testing may have other antibody-defined MG biology, including
      LRP4.
- name: Ocular MG
  description: Disease limited to extraocular muscles, may progress to generalized form.
- name: Thymoma-Associated MG
  description: MG associated with thymic tumors, often more severe.
prevalence:
- population: Europe (Orphanet annual incidence)
  percentage: 0.001-0.009
  notes: Orphanet reports a European annual incidence class of 1-9 per 100,000.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Annual incidence | PMID:20130418,EXPERT"
    explanation: The Orphanet epidemiology table provides a European annual incidence class for myasthenia gravis.
- population: Europe (Orphanet point prevalence)
  percentage: 0.01-0.05
  notes: Orphanet reports a European point-prevalence class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | PMID:17986328,EXPERT,PMID:2018"
    explanation: The Orphanet epidemiology table provides a European point-prevalence class for myasthenia gravis.
- population: Worldwide (Orphanet annual incidence)
  percentage: 0.0001-0.0009
  notes: Orphanet reports a worldwide annual incidence class of 1-9 per 1,000,000.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Worldwide | Annual incidence | PMID:20565885"
    explanation: The Orphanet epidemiology table provides a worldwide annual incidence class for myasthenia gravis.
- population: Worldwide (Orphanet point prevalence)
  percentage: 0.001-0.009
  notes: Orphanet reports a worldwide point-prevalence class of 1-9 per 100,000.
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Worldwide | Point prevalence | PMID:20565885"
    explanation: The Orphanet epidemiology table provides a worldwide point-prevalence class for myasthenia gravis.
progression:
- phase: Onset
  age_range: All ages
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records all ages as the age-of-onset category for myasthenia gravis.
pathophysiology:
- name: Autoantibody-Mediated NMJ Dysfunction
  description: >
    Autoantibodies (primarily anti-AChR) target the postsynaptic membrane at
    neuromuscular junctions. Antibodies cause receptor internalization,
    complement-mediated destruction, and functional blockade, reducing
    acetylcholine signaling efficiency.
  cell_types:
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Neuromuscular Transmission
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
  evidence:
  - reference: PMID:37869140
    reference_title: "Role of complement in myasthenia gravis."
    supports: SUPPORT
    snippet: "Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction."
    explanation: Confirms that autoantibodies targeting the AChR complex at the NMJ are central to myasthenia gravis pathophysiology.
  - reference: PMID:29266249
    reference_title: "Myasthenia gravis: the role of complement at the neuromuscular junction."
    supports: SUPPORT
    snippet: "Approximately 74-88% of patients with gMG have acetylcholine receptor (AChR) autoantibodies."
    explanation: Documents the prevalence of AChR autoantibodies in generalized myasthenia gravis.
- name: Complement Activation
  description: >
    Anti-AChR antibodies activate the classical complement pathway,
    leading to membrane attack complex formation and destruction of
    the postsynaptic membrane architecture.
  biological_processes:
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: PMID:29266249
    reference_title: "Myasthenia gravis: the role of complement at the neuromuscular junction."
    supports: SUPPORT
    snippet: "activation and amplification of complement results in the formation of membrane attack complexes (MACs), lipophilic proteins that damage cell membranes."
    explanation: Describes how complement activation leads to MAC formation and subsequent membrane damage.
  - reference: PMID:29266249
    reference_title: "Myasthenia gravis: the role of complement at the neuromuscular junction."
    supports: SUPPORT
    snippet: "Studies in animals lacking specific complement proteins have confirmed that MAC formation is required to induce experimental autoimmune MG (EAMG) and NMJ damage."
    explanation: Animal studies demonstrate that MAC formation is essential for NMJ damage in myasthenia gravis.
  - reference: PMID:37869140
    reference_title: "Role of complement in myasthenia gravis."
    supports: SUPPORT
    snippet: "Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage."
    explanation: Confirms that AChR antibodies (IgG1 and IgG3) activate complement, contributing to NMJ damage.
- name: Thymic Abnormalities
  description: >
    Thymic hyperplasia (65-75% of patients) or thymoma (10-15%) is common.
    The thymus may serve as the site of autoimmunization, containing
    myoid cells expressing AChR that activate autoreactive T cells.
  cell_types:
  - preferred_term: Thymic Epithelial Cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  evidence:
  - reference: PMID:21922466
    reference_title: "The thymus in myasthenia gravis: Site of \"innate autoimmunity\"?"
    supports: SUPPORT
    snippet: "The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells)."
    explanation: Demonstrates that the thymus shows pathologic changes in most AChR-positive MG patients and contains all elements needed to initiate and sustain autoimmunity.
  - reference: PMID:21922466
    reference_title: "The thymus in myasthenia gravis: Site of \"innate autoimmunity\"?"
    supports: SUPPORT
    snippet: "Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor."
    explanation: Confirms the autoimmune nature of myasthenia gravis with autoantibodies targeting NMJ components.
phenotypes:
- name: Muscle Weakness
  category: Neuromuscular
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Fatigable weakness, worse with exertion
  phenotype_term:
    preferred_term: Muscle Weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies muscle weakness as Very frequent (99-80%) in myasthenia gravis.
- name: Ptosis
  category: Ocular
  frequency: FREQUENT
  diagnostic: true
  notes: Often first symptom, asymmetric drooping eyelids
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies ptosis as Frequent (79-30%) in myasthenia gravis.
- name: Diplopia
  category: Ocular
  frequency: FREQUENT
  notes: Double vision from extraocular muscle weakness
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000651 | Diplopia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies diplopia as Frequent (79-30%) in myasthenia gravis.
- name: Ophthalmoparesis
  category: Ocular
  frequency: FREQUENT
  notes: Weakness of extraocular muscles
  phenotype_term:
    preferred_term: Ophthalmoparesis
    term:
      id: HP:0000597
      label: Ophthalmoparesis
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000597 | Ophthalmoparesis | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies ophthalmoparesis as Frequent (79-30%) in myasthenia gravis.
- name: Dysphagia
  category: Bulbar
  frequency: FREQUENT
  notes: Difficulty swallowing, common in MuSK-positive MG
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002015 | Dysphagia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies dysphagia as Frequent (79-30%) in myasthenia gravis.
- name: Dysarthria
  category: Bulbar
  frequency: FREQUENT
  notes: Slurred or nasal speech
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies dysarthria as Frequent (79-30%) in myasthenia gravis.
- name: Dysphonia
  category: Bulbar
  frequency: FREQUENT
  notes: Voice changes from laryngeal muscle weakness
  phenotype_term:
    preferred_term: Dysphonia
    term:
      id: HP:0001618
      label: Dysphonia
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001618 | Dysphonia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies dysphonia as Frequent (79-30%) in myasthenia gravis.
- name: Bulbar Palsy
  category: Bulbar
  frequency: FREQUENT
  notes: Weakness of muscles innervated by cranial nerves
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001283 | Bulbar palsy | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies bulbar palsy as Frequent (79-30%) in myasthenia gravis.
- name: Dyspnea
  category: Respiratory
  frequency: FREQUENT
  notes: Breathing difficulty from respiratory muscle weakness
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002094 | Dyspnea | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies dyspnea as Frequent (79-30%) in myasthenia gravis.
- name: Respiratory Failure
  category: Respiratory
  frequency: OCCASIONAL
  notes: Myasthenic crisis, life-threatening
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002878 | Respiratory failure | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies respiratory failure as Occasional (29-5%) in myasthenia gravis.
- name: Fatigable Weakness of Skeletal Muscles
  category: Neuromuscular
  frequency: FREQUENT
  diagnostic: true
  notes: Weakness worsens with repetitive use
  phenotype_term:
    preferred_term: Fatigable weakness of skeletal muscles
    term:
      id: HP:0030197
      label: Fatigable weakness of skeletal muscles
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030197 | Fatigable weakness of skeletal muscles | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies fatigable weakness of skeletal muscles as Frequent (79-30%) in myasthenia gravis.
- name: Limb Muscle Weakness
  category: Neuromuscular
  frequency: FREQUENT
  notes: Proximal limb weakness, difficulty with overhead activities
  phenotype_term:
    preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003690 | Limb muscle weakness | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies limb muscle weakness as Frequent (79-30%) in myasthenia gravis.
- name: Weakness of Facial Musculature
  category: Neuromuscular
  frequency: FREQUENT
  notes: Facial weakness contributing to expressionless facies
  phenotype_term:
    preferred_term: Weakness of facial musculature
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030319 | Weakness of facial musculature | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies weakness of facial musculature as Frequent (79-30%) in myasthenia gravis.
- name: Difficulty Climbing Stairs
  category: Neuromuscular
  frequency: FREQUENT
  notes: Proximal weakness manifesting as difficulty with stairs
  phenotype_term:
    preferred_term: Difficulty climbing stairs
    term:
      id: HP:0003551
      label: Difficulty climbing stairs
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003551 | Difficulty climbing stairs | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies difficulty climbing stairs as Frequent (79-30%) in myasthenia gravis.
- name: Skeletal Muscle Atrophy
  category: Neuromuscular
  frequency: FREQUENT
  notes: Muscle wasting in chronic disease, particularly MuSK-MG
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003202 | Skeletal muscle atrophy | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies skeletal muscle atrophy as Frequent (79-30%) in myasthenia gravis.
- name: Fatigue
  category: Neuromuscular
  frequency: FREQUENT
  notes: Generalized fatigue distinct from muscle-specific weakness
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies fatigue as Frequent (79-30%) in myasthenia gravis.
- name: Abnormal Thymus Morphology
  category: Immunological
  frequency: FREQUENT
  notes: Thymic hyperplasia or thymoma
  phenotype_term:
    preferred_term: Abnormal thymus morphology
    term:
      id: HP:0000777
      label: Abnormal thymus morphology
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000777 | Abnormality of the thymus | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies abnormality of the thymus as Frequent (79-30%) in myasthenia gravis.
- name: Thymus Hyperplasia
  category: Immunological
  frequency: FREQUENT
  notes: Present in 65-75% of AChR-positive patients
  phenotype_term:
    preferred_term: Thymus hyperplasia
    term:
      id: HP:0010516
      label: Thymus hyperplasia
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010516 | Thymus hyperplasia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies thymus hyperplasia as Frequent (79-30%) in myasthenia gravis.
- name: Thymoma
  category: Immunological
  frequency: OCCASIONAL
  notes: Thymic tumor present in 10-15% of MG patients
  phenotype_term:
    preferred_term: Thymoma
    term:
      id: HP:0100522
      label: Thymoma
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100522 | Thymoma | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies thymoma as Occasional (29-5%) in myasthenia gravis.
- name: Myositis
  category: Neuromuscular
  frequency: FREQUENT
  notes: Inflammatory myopathy can co-occur with MG
  phenotype_term:
    preferred_term: Myositis
    term:
      id: HP:0100614
      label: Myositis
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100614 | Myositis | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies myositis as Frequent (79-30%) in myasthenia gravis.
- name: Tongue Atrophy
  category: Bulbar
  frequency: OCCASIONAL
  notes: Tongue wasting, particularly in MuSK-MG
  phenotype_term:
    preferred_term: Tongue atrophy
    term:
      id: HP:0012473
      label: Tongue atrophy
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012473 | Tongue atrophy | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies tongue atrophy as Occasional (29-5%) in myasthenia gravis.
- name: Single Fiber EMG Abnormality
  category: Diagnostic
  frequency: FREQUENT
  diagnostic: true
  notes: Key electrodiagnostic finding, increased jitter
  phenotype_term:
    preferred_term: Single fiber EMG abnormality
    term:
      id: HP:0030006
      label: Single fiber EMG abnormality
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030006 | Single fiber EMG abnormality | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies single fiber EMG abnormality as Frequent (79-30%) in myasthenia gravis.
- name: Acetylcholine Receptor Antibody Positivity
  category: Immunological
  frequency: FREQUENT
  diagnostic: true
  notes: Present in ~85% of generalized MG
  phenotype_term:
    preferred_term: Anti-neuromuscular Junction acetylcholine receptor antibody positivity
    term:
      id: HP:0030208
      label: Anti-neuromuscular Junction acetylcholine receptor antibody positivity
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030208 | Acetylcholine receptor antibody positivity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies acetylcholine receptor antibody positivity as Frequent (79-30%) in myasthenia gravis.
- name: Anti-MuSK Antibody Positivity
  category: Immunological
  frequency: FREQUENT
  notes: Orphanet classifies as Frequent (79-30%); the ~5-10% figure reflects prevalence among all MG patients, whereas the Orphanet frequency reflects detection rate among those tested for MuSK antibodies
  phenotype_term:
    preferred_term: Anti-muscle-specific tyrosine kinase antibody
    term:
      id: HP:0030210
      label: Anti-muscle-specific tyrosine kinase antibody
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030210 | Muscle specific kinase antibody positivity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies muscle specific kinase antibody positivity as Frequent (79-30%) in myasthenia gravis.
- name: Anti-Lrp4 Antibody Positivity
  category: Immunological
  frequency: OCCASIONAL
  notes: Present in some double-seronegative cases
  phenotype_term:
    preferred_term: Anti-Lrp4 antibody positivity
    term:
      id: HP:5000046
      label: Anti-Lrp4 antibody positivity
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:5000046 | Anti-Lrp4 antibody positivity | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies anti-Lrp4 antibody positivity as Occasional (29-5%) in myasthenia gravis.
- name: Anti-titin Antibody Positivity
  category: Immunological
  frequency: FREQUENT
  notes: Associated with thymoma and late-onset MG
  phenotype_term:
    preferred_term: Anti-titin antibody positivity
    term:
      id: HP:5000038
      label: Anti-titin antibody positivity
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:5000038 | Anti-titin antibody positivity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies anti-titin antibody positivity as Frequent (79-30%) in myasthenia gravis.
- name: Anti-ryanodine Receptor Antibody
  category: Immunological
  frequency: FREQUENT
  notes: Key marker for thymoma-associated MG
  phenotype_term:
    preferred_term: Anti-ryanodine receptor antibody
    term:
      id: HP:5000047
      label: Anti-ryanodine receptor antibody
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:5000047 | Anti-ryanodine receptor antibody | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies anti-ryanodine receptor antibody as Frequent (79-30%) in myasthenia gravis.
- name: Anti-Kv1.4 Antibody
  category: Immunological
  frequency: FREQUENT
  notes: Associated with myasthenic crisis and cardiac involvement
  phenotype_term:
    preferred_term: Anti-Kv1.4 antibody
    term:
      id: HP:5000048
      label: Anti-Kv1.4 antibody
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:5000048 | Anti-Kv1.4 antibody | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies anti-Kv1.4 antibody as Frequent (79-30%) in myasthenia gravis.
- name: Anti-DCC Netrin 1 Receptor Antibody Positivity
  category: Immunological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anti-DCC netrin 1 receptor antibody positivity
    term:
      id: HP:6000881
      label: Anti-DCC netrin 1 receptor antibody positivity
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000881 | Anti-DCC netrin 1 receptor antibody positivity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies anti-DCC netrin 1 receptor antibody positivity as Frequent (79-30%) in myasthenia gravis.
- name: Hyperthyroidism
  category: Autoimmune Comorbidity
  frequency: OCCASIONAL
  notes: Autoimmune thyroid disease co-occurs with MG
  phenotype_term:
    preferred_term: Hyperthyroidism
    term:
      id: HP:0000836
      label: Hyperthyroidism
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000836 | Hyperthyroidism | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies hyperthyroidism as Occasional (29-5%) in myasthenia gravis.
- name: Hashimoto Thyroiditis
  category: Autoimmune Comorbidity
  frequency: OCCASIONAL
  notes: Autoimmune thyroiditis co-occurs with MG
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000872 | Hashimoto thyroiditis | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies Hashimoto thyroiditis as Occasional (29-5%) in myasthenia gravis.
- name: Rheumatoid Arthritis
  category: Autoimmune Comorbidity
  frequency: OCCASIONAL
  notes: Autoimmune comorbidity
  phenotype_term:
    preferred_term: Rheumatoid arthritis
    term:
      id: HP:0001370
      label: Rheumatoid arthritis
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001370 | Rheumatoid arthritis | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies rheumatoid arthritis as Occasional (29-5%) in myasthenia gravis.
- name: Systemic Lupus Erythematosus
  category: Autoimmune Comorbidity
  frequency: OCCASIONAL
  notes: Autoimmune comorbidity
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002725 | Systemic lupus erythematosus | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies systemic lupus erythematosus as Occasional (29-5%) in myasthenia gravis.
- name: Raynaud Phenomenon
  category: Autoimmune Comorbidity
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Raynaud phenomenon
    term:
      id: HP:0030880
      label: Raynaud phenomenon
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030880 | Raynaud phenomenon | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies Raynaud phenomenon as Occasional (29-5%) in myasthenia gravis.
- name: Paresthesia
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003401 | Paresthesia | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies paresthesia as Occasional (29-5%) in myasthenia gravis.
- name: Hearing Impairment
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000365 | Hearing impairment | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies hearing impairment as Occasional (29-5%) in myasthenia gravis.
- name: Glycosuria
  category: Metabolic
  frequency: OCCASIONAL
  notes: Associated with autoimmune comorbidity
  phenotype_term:
    preferred_term: Glycosuria
    term:
      id: HP:0003076
      label: Glycosuria
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003076 | Glycosuria | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies glycosuria as Occasional (29-5%) in myasthenia gravis.
- name: Primary Adrenal Insufficiency
  category: Endocrine
  frequency: OCCASIONAL
  notes: Autoimmune comorbidity
  phenotype_term:
    preferred_term: Primary adrenal insufficiency
    term:
      id: HP:0008207
      label: Primary adrenal insufficiency
  evidence:
  - reference: ORPHA:589
    reference_title: "Myasthenia gravis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008207 | Primary adrenal insufficiency | Occasional (29-5%)"
    explanation: Orphanet's curated HPO frequency annotation classifies primary adrenal insufficiency as Occasional (29-5%) in myasthenia gravis.
biochemical:
- name: Anti-AChR Antibodies
  presence: Elevated
  context: Present in ~85% of generalized MG
- name: Anti-MuSK Antibodies
  presence: Elevated
  context: Present in ~5-10% of MG, particularly seronegative cases
- name: Anti-LRP4 Antibodies
  presence: Elevated
  context: Present in some double-seronegative cases
genetic:
- name: HLA-B8
  association: Risk Factor
  notes: Associated with early-onset MG
- name: HLA-DR3
  association: Risk Factor
  notes: Associated with early-onset MG and thymic hyperplasia
- name: Polygenic MG Susceptibility
  association: GWAS
  notes: >
    Recent genome-wide meta-analysis supports a polygenic architecture with
    age-of-onset-specific HLA effects and multiple genome-wide significant loci.
  evidence:
  - reference: DOI:10.1038/s41467-024-53595-6
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      We identified 12 independent genome-wide significant hits (P < 5e−8)
      across 11 loci.
    explanation: >
      The deep-research report highlighted this 2024 GWAS/meta-analysis; it
      supports adding an explicit polygenic susceptibility assertion rather than
      only older single-locus notes.
  - reference: DOI:10.1038/s41467-024-53595-6
    reference_title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Subgroup analyses revealed two of these were associated with early-onset
      (at age <50) and four with late-onset MG (at age ≥ 50).
    explanation: >
      The GWAS supports distinct genetic contributions by age at onset, matching
      the research synthesis emphasis on early- versus late-onset MG.
- name: CHRNA1
  association: Risk Factor
  notes: Acetylcholine receptor alpha subunit, rare variants
environmental:
- name: Infections
  notes: May trigger or exacerbate disease
- name: Medications
  notes: Aminoglycosides, beta-blockers, and others may worsen
- name: Stress
  notes: Physical or emotional stress can trigger exacerbations
- name: Pregnancy
  notes: Variable effects on disease course
treatments:
- name: Acetylcholinesterase Inhibitors
  description: First-line symptomatic treatment (pyridostigmine).
  treatment_term:
    preferred_term: acetylcholinesterase inhibitor therapy
    term:
      id: MAXO:0000645
      label: acetylcholinesterase inhibitor therapy
  evidence:
  - reference: PMID:36184373
    reference_title: "The effectiveness and side effects of pyridostigmine in the treatment of myasthenia gravis: a cross-sectional study."
    supports: SUPPORT
    snippet: "Patients reported a median effectiveness of 60, IQR 28-78 and net benefit of 65, IQR 45-84."
    explanation: Large cross-sectional study demonstrates patient-reported effectiveness of pyridostigmine.
  - reference: PMID:36184373
    reference_title: "The effectiveness and side effects of pyridostigmine in the treatment of myasthenia gravis: a cross-sectional study."
    supports: SUPPORT
    snippet: "Of all patients currently using pyridostigmine, 91% reported side effects (vs. 55% in the control group)."
    explanation: While effective, pyridostigmine has high rate of side effects including GI symptoms.
- name: Corticosteroids
  description: Prednisone for immunosuppression, mainstay of therapy.
  treatment_term:
    preferred_term: corticosteroid agent therapy
    term:
      id: MAXO:0000640
      label: corticosteroid agent therapy
- name: Thymectomy
  description: Surgical removal of thymus, improves outcomes in appropriate patients.
  treatment_term:
    preferred_term: thymectomy
    term:
      id: MAXO:0001079
      label: thymectomy
  evidence:
  - reference: PMID:27509100
    reference_title: "Randomized Trial of Thymectomy in Myasthenia Gravis."
    supports: SUPPORT
    snippet: "Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001)"
    explanation: Landmark randomized trial demonstrates thymectomy improves clinical outcomes in nonthymomatous MG.
  - reference: PMID:27509100
    reference_title: "Randomized Trial of Thymectomy in Myasthenia Gravis."
    supports: SUPPORT
    snippet: "Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001)."
    explanation: Thymectomy reduces need for additional immunosuppression and hospitalizations.
- name: Azathioprine
  description: Steroid-sparing immunosuppressant.
  treatment_term:
    preferred_term: immune suppressant agent therapy
    term:
      id: MAXO:0000297
      label: immune suppressant agent therapy
- name: Mycophenolate Mofetil
  description: Alternative immunosuppressant.
  treatment_term:
    preferred_term: immune suppressant agent therapy
    term:
      id: MAXO:0000297
      label: immune suppressant agent therapy
- name: Rituximab
  description: Anti-CD20 antibody, effective in refractory cases.
  treatment_term:
    preferred_term: immune suppressant agent therapy
    term:
      id: MAXO:0000297
      label: immune suppressant agent therapy
- name: Eculizumab
  description: Complement inhibitor (anti-C5), approved for refractory AChR+ MG.
  treatment_term:
    preferred_term: complement 5 inhibitor agent therapy
    term:
      id: MAXO:0001483
      label: complement 5 inhibitor agent therapy
  evidence:
  - reference: PMID:29066163
    reference_title: "Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study."
    supports: SUPPORT
    snippet: "Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis."
    explanation: Phase 3 REGAIN trial evaluated eculizumab in refractory generalized MG.
  - reference: PMID:29066163
    reference_title: "Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study."
    supports: SUPPORT
    snippet: "Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group."
    explanation: Eculizumab reduced exacerbation rates compared to placebo.
- name: Plasma Exchange
  description: Rapid removal of antibodies, used for myasthenic crisis.
  evidence:
  - reference: PMID:21674519
    reference_title: "Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts."
    supports: SUPPORT
    snippet: "Plasma exchange (PLEX) produced improvement in 93%, whereas only 61% improved after intravenous immunoglobulin."
    explanation: Plasma exchange is highly effective, particularly in MuSK-MG where it outperforms IVIG.
- name: Intravenous Immunoglobulin
  description: Immunomodulation, used for exacerbations and crisis.
- name: Efgartigimod
  description: FcRn antagonist approved for generalized AChR-positive MG; reduces pathogenic IgG levels by blocking neonatal Fc receptor recycling.
  treatment_term:
    preferred_term: FcRn antagonist therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: DOI:10.3389/fneur.2023.1229112
    reference_title: "FcRN receptor antagonists in the management of myasthenia gravis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Efgartigimod is already approved for the treatment of generalized MG"
    explanation: Review confirms FDA approval of efgartigimod for generalized MG.
  - reference: DOI:10.3389/fneur.2023.1229112
    reference_title: "FcRN receptor antagonists in the management of myasthenia gravis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      FcRn receptors prevent the catabolism of IgG by impeding their lysosomal
      degradation and facilitating their extracellular release at physiological
      pH, consequently extending the IgG half-life.
    explanation: >
      The research synthesis emphasized FcRn biology; this evidence links the
      treatment assertion to its mechanism of lowering pathogenic IgG.
- name: Rozanolixizumab
  description: FcRn antagonist for generalized AChR-positive MG; reduces pathogenic IgG via neonatal Fc receptor blockade.
  treatment_term:
    preferred_term: FcRn antagonist therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: DOI:10.3389/fneur.2023.1229112
    reference_title: "FcRN receptor antagonists in the management of myasthenia gravis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rozanolixizumab is under review by health authorities"
    explanation: Review documents rozanolixizumab as an FcRn antagonist under regulatory review for MG at time of publication.
datasets: []
references:
- reference: DOI:10.1038/s41433-024-03133-x
  title: Treating myasthenia gravis beyond the eye clinic
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.1038/s41467-024-53595-6
  title: Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.1080/1744666x.2022.2082946
  title: Role of complement, anti-complement therapeutics, and other targeted immunotherapies in myasthenia gravis
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.1136/jnnp-2023-333097
  title: 'Epidemiology of myasthenia gravis in Denmark, Finland and Sweden: a population-based observational study'
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.1172/jci179742
  title: 'Myasthenia gravis: the future is here'
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.3389/fimmu.2023.1110499
  title: Inflammation and autoimmune myasthenia gravis
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.3389/fneur.2023.1229112
  title: FcRN receptor antagonists in the management of myasthenia gravis
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.3389/fneur.2024.1339167
  title: Epidemiology of myasthenia gravis in the United States
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.3390/cells13060556
  title: MuSK Myasthenia Gravis-Potential Pathomechanisms and Treatment Directed against Specific Targets
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
- reference: DOI:10.3390/ijms22115755
  title: Fc-Receptor Targeted Therapies for the Treatment of Myasthenia gravis
  findings: []
  found_in:
  - Myasthenia_Gravis-deep-research-cyberian-codex.md
  - Myasthenia_Gravis-deep-research-falcon.md
📚

References & Deep Research

References

10
DOI:10.1038/s41433-024-03133-x
Treating myasthenia gravis beyond the eye clinic
No top-level findings curated for this source.
DOI:10.1038/s41467-024-53595-6
Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
No top-level findings curated for this source.
DOI:10.1080/1744666x.2022.2082946
Role of complement, anti-complement therapeutics, and other targeted immunotherapies in myasthenia gravis
No top-level findings curated for this source.
DOI:10.1136/jnnp-2023-333097
Epidemiology of myasthenia gravis in Denmark, Finland and Sweden: a population-based observational study
No top-level findings curated for this source.
DOI:10.1172/jci179742
Myasthenia gravis: the future is here
No top-level findings curated for this source.
DOI:10.3389/fimmu.2023.1110499
Inflammation and autoimmune myasthenia gravis
No top-level findings curated for this source.
DOI:10.3389/fneur.2023.1229112
FcRN receptor antagonists in the management of myasthenia gravis
No top-level findings curated for this source.
DOI:10.3389/fneur.2024.1339167
Epidemiology of myasthenia gravis in the United States
No top-level findings curated for this source.
DOI:10.3390/cells13060556
MuSK Myasthenia Gravis-Potential Pathomechanisms and Treatment Directed against Specific Targets
No top-level findings curated for this source.
DOI:10.3390/ijms22115755
Fc-Receptor Targeted Therapies for the Treatment of Myasthenia gravis
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Myasthenia Gravis
  • Category: Autoimmune
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 26

Key Pathophysiology Nodes

  • Autoantibody-Mediated NMJ Dysfunction
  • Complement Activation
  • Thymic Abnormalities
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41433-024-03133-x
  • DOI:10.1038/s41467-024-53595-6
  • DOI:10.1080/1744666x.2022.2082946
  • DOI:10.1136/jnnp-2023-333097
  • DOI:10.1172/jci179742
  • DOI:10.3389/fimmu.2023.1110499
  • DOI:10.3389/fneur.2023.1229112
  • DOI:10.3389/fneur.2024.1339167
  • DOI:10.3390/cells13060556
  • DOI:10.3390/ijms22115755
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 23 citations 2025-12-18T09:54:07.915621

Disease Pathophysiology Research Report

Target Disease - Disease Name: Myasthenia Gravis (MG) - MONDO ID: MONDO:0005041 - Category: Autoimmune

Pathophysiology description Myasthenia gravis is a prototypic antibody-mediated autoimmune synaptopathy of the neuromuscular junction (NMJ). In AChR-antibody–positive MG (the most common subtype), IgG1/IgG3 antibodies drive three principal mechanisms: (i) classical complement pathway activation culminating in membrane attack complex (MAC)–mediated injury with loss of postsynaptic folds and AChR-rich membrane, (ii) antigenic modulation with cross-linking–induced endocytosis and degradation of AChR, and (iii) direct functional blockade of the acetylcholine binding site. These mechanisms reduce the safety factor for neuromuscular transmission and produce fatigable weakness (Journal of Clinical Investigation, Jun 2024, https://doi.org/10.1172/jci179742). Complement C5 inhibition clinically validates the centrality of MAC injury in AChR-MG (eculizumab, ravulizumab, zilucoplan) (JCI 2024; Expert Rev Clin Immunol 2022, https://doi.org/10.1080/1744666X.2022.2082946). MuSK-MG is mechanistically distinct: pathogenic antibodies are predominantly IgG4, functionally monovalent after Fab-arm exchange, and block LRP4–MuSK interaction and downstream phosphorylation cascades required for AChR clustering; complement fixation is minimal in MuSK-MG. LRP4 antibodies can activate complement (typically IgG1) and also interfere with agrin–LRP4 signaling, disrupting AChR clustering (Eye, May 2024, https://doi.org/10.1038/s41433-024-03133-x; Cells, Mar 2024, https://doi.org/10.3390/cells13060556). Seronegative MG (by routine assays) is heterogeneous and includes patients with low-affinity/clustered AChR antibodies, LRP4/agrin antibodies, or as-yet-undetected reactivities (JCI 2024).

Thymic autoimmunity is characteristic of early-onset AChR-MG, with thymic follicular hyperplasia, ectopic germinal centers, and dysregulated T–B collaboration (increased T follicular helper cells, reduced Treg function) that foster intrathymic affinity maturation and long-lived autoantibody responses. Type I interferon–rich signatures, CXCL13, and BAFF pathways are implicated in perpetuating the thymic autoimmune niche. Thymoma-associated MG has distinct serology and autoantibody spectra, whereas MuSK-MG generally lacks prominent thymic pathology (JCI 2024; Frontiers in Immunology, Jan 2023, https://doi.org/10.3389/fimmu.2023.1110499; Frontiers in Neurology, Aug 2023, https://doi.org/10.3389/fneur.2023.1229112).

Therapeutic mechanism-of-action (MOA) validation underscores these pathways: terminal complement C5 inhibitors reduce MAC injury and improve strength in refractory AChR-MG, while FcRn antagonists accelerate pathogenic IgG catabolism, lowering circulating autoantibody levels and improving outcomes across antibody-defined subtypes; both approaches have translated to approved therapies (Frontiers in Neurology 2023; JCI 2024; Expert Rev Clin Immunol 2022). (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2, bhandari2023fcrnreceptorantagonists pages 1-2, keller2022fcreceptortargetedtherapies pages 2-3)

Key concepts and definitions - AChR-MG: IgG1/IgG3-mediated disease marked by complement activation, AChR internalization, and receptor blockade at the postsynaptic membrane. (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2) - MuSK-MG: IgG4-predominant autoimmunity with blocking of LRP4–MuSK signaling and impaired AChR clustering; minimal complement activation; often responds well to B cell depletion. (dziadkowiak2024muskmyastheniagravis—potential pages 13-14, jacob2024treatingmyastheniagravis pages 1-2) - LRP4-MG: Antibodies disrupt agrin–LRP4–MuSK pathway and can fix complement; may coexist with other autoantibodies. (jacob2024treatingmyastheniagravis pages 1-2) - Seronegative MG: Heterogeneous; includes low-affinity clustered AChR antibodies or antibodies to LRP4/agrin not detected by standard assays. (kaminski2024myastheniagravisthe pages 2-4) - FcRn: Endosomal receptor that rescues IgG from lysosomal degradation; therapeutic blockade reduces pathogenic IgG burden systemically. (bhandari2023fcrnreceptorantagonists pages 1-2)

Recent developments and latest research (2023–2024) - Genetics: A large 2024 GWAS/meta-analysis identified multiple genome-wide significant loci, clarified HLA class II influences, and demonstrated polygenic risk prediction in MG, with distinct early- vs late-onset associations (Nature Communications, Nov 2024, https://doi.org/10.1038/s41467-024-53595-6). Clinical overviews also emphasize PTPN22 and CTLA4 associations across subgroups (JCI 2024). (kaminski2024myastheniagravisthe pages 2-4) - Epidemiology: Contemporary population-based studies show increasing incidence and prevalence in high-income countries, with strong age and sex effects. Nordic registry data (JNNP, Mar 2024) and US claims analyses (Frontiers in Neurology, Feb 2024) quantify rising prevalence and stable to modestly rising incidence, particularly in older adults. (, ) - ncRNA/epigenetics and inflammation: Reviews highlight altered microRNA profiles in thymus and blood, type I interferon signaling, BAFF/Tfh axes, and inflammatory cytokine networks contributing to MG pathogenesis and heterogeneity, supporting biomarker-guided and epigenetic-targeting strategies (Frontiers in Immunology, Jan 2023; Eye, 2024). (huda2023inflammationandautoimmune pages 1-2, jacob2024treatingmyastheniagravis pages 1-2) - Therapeutics: FcRn inhibitors (efgartigimod, rozanolixizumab) and complement C5 inhibitors (eculizumab, ravulizumab, zilucoplan) consolidate mechanism-based treatment and enable earlier, targeted intervention strategies (Frontiers in Neurology 2023; Expert Rev Clin Immunol 2022; JCI 2024). (bhandari2023fcrnreceptorantagonists pages 1-2, keller2022fcreceptortargetedtherapies pages 2-3, kaminski2024myastheniagravisthe pages 2-4)

Current applications and real-world implementations - Complement inhibition (C5): Reduces MAC formation at the NMJ, directly addressing complement-mediated postsynaptic injury validated in AChR-MG. Clinical adoption for refractory generalized AChR-MG has been established (Expert Rev Clin Immunol 2022). (keller2022fcreceptortargetedtherapies pages 2-3) - FcRn antagonism: Lowers total IgG including pathogenic subclasses and improves clinical scores across subtypes; approved agents are increasingly used in cycles with monitoring of symptom trajectories (Frontiers in Neurology 2023). (bhandari2023fcrnreceptorantagonists pages 1-2) - B cell–directed therapy: Particularly impactful in MuSK-MG, aligning with IgG4/plasmablast biology and limited complement involvement (Cells 2024; Eye 2024). (dziadkowiak2024muskmyastheniagravis—potential pages 13-14, jacob2024treatingmyastheniagravis pages 1-2)

Expert opinions and analysis (authoritative sources) - Kaminski et al. (JCI, 2024) synthesize mechanistic, genetic, and therapeutic advances, reinforcing three canonical AChR-MG mechanisms at the NMJ, detailing subtype distinctions, and highlighting precision therapeutics (https://doi.org/10.1172/jci179742). (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 10-10) - Dalakas (Expert Rev Clin Immunol, 2022) argues complement and FcRn pathways are central, with clinical trial success translating to practice for refractory MG (https://doi.org/10.1080/1744666X.2022.2082946). (keller2022fcreceptortargetedtherapies pages 2-3) - Bhandari & Bril (Frontiers in Neurology, 2023) review FcRn biology/PK-PD and MG indications, supporting real-world utilization and safety (https://doi.org/10.3389/fneur.2023.1229112). (bhandari2023fcrnreceptorantagonists pages 1-2)

Relevant statistics and data (recent studies) - GWAS/meta-analysis (Nature Communications, 2024): 5708 MG cases/432,028 controls plus replication; 11 loci; PRS explained ~4.2% variance, with HLA signals showing inverse effects by age at onset (Nov 2024) (https://doi.org/10.1038/s41467-024-53595-6). (kaminski2024myastheniagravisthe pages 2-4) - Nordic epidemiology (JNNP, 2024): Incidence 1.3–1.7 per 100,000; prevalence ~18.6–23.4 per 100,000; standardized mortality ratios 1.20–1.32; rising prevalence over 2000–2020 (Mar 2024, https://doi.org/10.1136/jnnp-2023-333097). () - US epidemiology (Frontiers in Neurology, 2024): Age- and sex-standardized incidence ~68.5/million person-years (commercial/Medicare); prevalence ~316/million (2017), estimating ~82,715 adults living with MG in 2021 (Feb 2024, https://doi.org/10.3389/fneur.2024.1339167). ()

Core Pathophysiology (mechanisms, pathways, cells) - Primary mechanisms at the NMJ - Complement-mediated MAC injury (classical pathway via IgG1/IgG3 anti-AChR) leading to synaptic membrane loss and reduced safety factor (JCI 2024; Eye 2024). (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2) - Antigenic modulation and receptor internalization of AChR, reducing receptor density (JCI 2024; Frontiers in Immunology 2023). (kaminski2024myastheniagravisthe pages 2-4, huda2023inflammationandautoimmune pages 1-2) - Blockade of ACh–AChR interaction and disruption of rapsyn-stabilized clusters (JCI 2024). (kaminski2024myastheniagravisthe pages 2-4) - Agrin–LRP4–MuSK pathway blockade by IgG4 anti-MuSK (non–complement fixing) and IgG1 anti-LRP4, impairing AChR clustering (Eye 2024; Cells 2024). (jacob2024treatingmyastheniagravis pages 1-2, dziadkowiak2024muskmyastheniagravis—potential pages 13-14)

  • Dysregulated molecular/cellular pathways
  • Complement activation and MAC assembly in AChR-MG; therapeutic anti-C5 validation (Expert Rev Clin Immunol 2022). (keller2022fcreceptortargetedtherapies pages 2-3)
  • FcRn-mediated IgG recycling: therapeutic antagonism lowers IgG, supporting a causal role for circulating IgG autoantibodies broadly in MG (Frontiers in Neurology 2023). (bhandari2023fcrnreceptorantagonists pages 1-2)

  • Thymic ectopic germinal centers (GCs), Tfh expansion, BAFF enrichment, and type I IFN signatures that sustain intrathymic B cell activation and autoreactive T cell priming; weaker/thymus-sparse signature in MuSK-MG (JCI 2024; Frontiers in Immunology 2023). (kaminski2024myastheniagravisthe pages 2-4, huda2023inflammationandautoimmune pages 1-2)

  • Immune cell processes

  • B cell activation, class-switch, and plasmablast/plasma cell antibody production (intrathymic and peripheral) (JCI 2024; Frontiers in Immunology 2023). (kaminski2024myastheniagravisthe pages 2-4, huda2023inflammationandautoimmune pages 1-2)
  • Tfh/Tfr imbalance and reduced Treg function facilitating GC reactions (JCI 2024; Frontiers in Immunology 2023). (kaminski2024myastheniagravisthe pages 2-4, huda2023inflammationandautoimmune pages 1-2)
  • Antigen presentation by medullary thymic epithelial cells (mTECs) and dendritic cells, with tolerance failure in EOMG (Frontiers in Neurology 2023). (bhandari2023fcrnreceptorantagonists pages 1-2)

Key Molecular Players (HGNC genes/proteins; cell types; anatomical sites; chemicals) - Autoantigens/complex - AChR subunits (HGNC: CHRNA1, CHRNB1), rapsyn (HGNC: RAPSN), DOK7 (HGNC: DOK7) (JCI 2024). (kaminski2024myastheniagravisthe pages 2-4) - MUSK (HGNC: 7517), LRP4 (HGNC: 6697), AGRN (HGNC: 329) central to clustering and synaptogenesis (Eye 2024; Cells 2024). (jacob2024treatingmyastheniagravis pages 1-2, dziadkowiak2024muskmyastheniagravis—potential pages 13-14) - Immune genes (selected associations) - HLA class II alleles (e.g., HLA-DRB1, HLA-DQB1) with subtype/age-of-onset effects; CTLA4 and PTPN22 highlighted in clinical overviews (Nature Comm 2024; JCI 2024). (kaminski2024myastheniagravisthe pages 2-4) - Cell types (CL ontology) - B cell (CL:0000236), plasmablast (CL:0000980), T follicular helper cell (CL:0000914), regulatory T cell (CL:0000815), dendritic cell (CL:0000451), medullary thymic epithelial cell (CL:0000786) (Frontiers in Immunology 2023; JCI 2024). (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Anatomical locations (UBERON) - Neuromuscular junction (UBERON:0007200), skeletal muscle tissue (UBERON:0001134), thymus (UBERON:0002370) (JCI 2024; Eye 2024). (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2) - Chemical entities (ChEBI) - Acetylcholine (CHEBI:15355), immunoglobulin G (CHEBI:16991); complement component C5 protein targeted by therapeutics (mechanistic) (Expert Rev Clin Immunol 2022). (keller2022fcreceptortargetedtherapies pages 2-3)

Biological Processes for GO annotation (disrupted in MG) - Complement activation, classical pathway (GO:0006958); membrane attack complex assembly (component of complement activation) (AChR-MG) (JCI 2024; Expert Rev Clin Immunol 2022). (kaminski2024myastheniagravisthe pages 2-4, keller2022fcreceptortargetedtherapies pages 2-3) - Receptor-mediated endocytosis (GO:0006898) of AChR (antigenic modulation) (JCI 2024). (kaminski2024myastheniagravisthe pages 2-4) - Cholinergic synaptic transmission (GO:0007271) and neuromuscular junction development (GO:0007528) (disrupted by agrin–LRP4–MuSK blockade) (Eye 2024; Cells 2024). (jacob2024treatingmyastheniagravis pages 1-2, dziadkowiak2024muskmyastheniagravis—potential pages 13-14) - B cell activation (GO:0042113), germinal center formation (GO:0006955, immune process), T cell activation (GO:0042110), Tfh cell differentiation (GO:0002292) (thymic hyperplasia) (Frontiers in Immunology 2023; JCI 2024). (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Type I interferon signaling pathway (GO:0060337) and cytokine-mediated signaling (GO:0019221) in thymic microenvironment (Frontiers in Immunology 2023). (huda2023inflammationandautoimmune pages 1-2)

Cellular Components (where key processes occur) - Postsynaptic membrane (GO:0045211) and synaptic basal lamina/extracellular matrix (basement membrane, GO:0005604) at NMJ—sites of AChR and agrin–LRP4–MuSK signaling (Eye 2024; JCI 2024). (jacob2024treatingmyastheniagravis pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Membrane attack complex (GO:0005579) on the postsynaptic membrane (Expert Rev Clin Immunol 2022; JCI 2024). (keller2022fcreceptortargetedtherapies pages 2-3, kaminski2024myastheniagravisthe pages 2-4) - Early/late endosomes and lysosomes (GO:0005768; GO:0005764) mediating AChR internalization and FcRn-dependent IgG recycling (Frontiers in Neurology 2023). (bhandari2023fcrnreceptorantagonists pages 1-2) - Thymic medulla and germinal center–like niches (thymic follicular hyperplasia) as intrathymic sites of autoimmunity (Frontiers in Immunology 2023; JCI 2024). (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

Disease progression (sequence from trigger to clinical phenotype) - Predisposition and trigger: Polygenic susceptibility (HLA class II, immune-regulatory loci) and environmental/inflammatory triggers (e.g., type I IFN–rich milieu) prime breakdown of central tolerance in the thymus for EOMG. (kaminski2024myastheniagravisthe pages 2-4, huda2023inflammationandautoimmune pages 1-2) - Intrathymic autoimmunity: mTEC/dendritic cell antigen presentation of AChR subunits and myoid-cell antigens with GC formation, Tfh help, BAFF signaling, and class-switched B cell responses. (huda2023inflammationandautoimmune pages 1-2, bhandari2023fcrnreceptorantagonists pages 1-2) - Peripheral effector phase: Circulating IgG autoantibodies reach NMJ; in AChR-MG, complement activation and receptor internalization reduce neuromuscular safety factor; in MuSK-/LRP4-MG, impaired AChR clustering further reduces transmission. (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2, dziadkowiak2024muskmyastheniagravis—potential pages 13-14) - Clinical manifestation: Fluctuating, fatigable weakness with ocular, bulbar, respiratory, and limb involvement according to antibody specificity and disease burden; crises occur with severe bulbar/respiratory involvement. (jacob2024treatingmyastheniagravis pages 1-2)

Phenotypic manifestations and mechanism links (HP terms) - Fatigable muscle weakness (HP:0003701): Reduced NMJ safety factor from MAC injury and AChR loss (AChR-MG) or from impaired AChR clustering (MuSK-/LRP4-MG) (JCI 2024; Eye 2024). (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2) - Ptosis (HP:0000508) and diplopia (HP:0000651): Extraocular NMJ involvement; ocular MG commonly due to AChR antibodies (Eye 2024). (jacob2024treatingmyastheniagravis pages 1-2) - Dysphagia (HP:0002015), dysarthria (HP:0001260), and respiratory failure (HP:0002878): Bulbar/respiratory muscle NMJ failure; severe in some MuSK-MG and generalized AChR-MG (Eye 2024). (jacob2024treatingmyastheniagravis pages 1-2)

Gene/protein annotations (selected; HGNC and ontology mapping) - CHRNA1 (HGNC:1956) and CHRNB1 (HGNC:1959): AChR subunits; processes: cholinergic synaptic transmission (GO:0007271), receptor-mediated endocytosis (GO:0006898); component: postsynaptic membrane (GO:0045211). (kaminski2024myastheniagravisthe pages 2-4) - MUSK (HGNC:7517): Receptor tyrosine kinase for NMJ maintenance; processes: NMJ development (GO:0007528); component: postsynaptic membrane (GO:0045211). (dziadkowiak2024muskmyastheniagravis—potential pages 13-14, jacob2024treatingmyastheniagravis pages 1-2) - LRP4 (HGNC:6697): Agrin co-receptor; processes: synapse organization (GO:0050808); component: extracellular region/basal lamina. (jacob2024treatingmyastheniagravis pages 1-2) - AGRN (HGNC:329): Ligand driving AChR clustering; processes: synapse organization; component: synaptic cleft/extracellular matrix. (jacob2024treatingmyastheniagravis pages 1-2) - HLA-DRB1/DQB1 (HGNC:4948/3115), CTLA4 (HGNC:2505), PTPN22 (HGNC:9653): Genetic susceptibility; processes: antigen presentation (GO:0019882), T cell activation (GO:0042110). (kaminski2024myastheniagravisthe pages 2-4)

Cell type involvement (CL) and anatomical locations (UBERON) - B cells (CL:0000236) and plasmablasts (CL:0000980): Autoantibody production in thymic GCs and periphery (UBERON:0002370, thymus; UBERON:0007200, NMJ effector site) (Frontiers in Immunology 2023; JCI 2024). (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Tfh (CL:0000914)/Tfr and Tregs (CL:0000815): GC support vs regulation; imbalance favors autoimmunity (Frontiers in Immunology 2023). (huda2023inflammationandautoimmune pages 1-2) - Dendritic cells (CL:0000451) and mTECs (CL:0000786): Central tolerance and antigen presentation in thymus (Frontiers in Neurology 2023). (bhandari2023fcrnreceptorantagonists pages 1-2)

Chemical entities (CHEBI) and therapeutics (mechanistic tie-ins) - Acetylcholine (CHEBI:15355): Neurotransmitter whose postsynaptic signaling is impaired by AChR loss/blockade (Eye 2024). (jacob2024treatingmyastheniagravis pages 1-2) - IgG (CHEBI:16991): Pathogenic effector molecule; subclasses dictate complement activity (IgG1/3) vs blocking (IgG4) (JCI 2024; Frontiers in Neurology 2023). (kaminski2024myastheniagravisthe pages 2-4, bhandari2023fcrnreceptorantagonists pages 1-2) - Complement C5 (protein target): Blockade prevents MAC formation at NMJ in AChR-MG, validating complement’s causal role (Expert Rev Clin Immunol 2022). (keller2022fcreceptortargetedtherapies pages 2-3)

Evidence items with PMIDs/DOIs/URLs (recent, prioritized) - Kaminski HJ et al. Myasthenia gravis: the future is here. Journal of Clinical Investigation. Jun 2024. DOI: 10.1172/jci179742; URL: https://doi.org/10.1172/jci179742 (supports NMJ mechanisms, subtypes, genetics, therapeutics). (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 10-10) - Dalakas MC. Role of complement and targeted immunotherapies in MG. Expert Review of Clinical Immunology. Jun 2022. DOI: 10.1080/1744666X.2022.2082946; URL: https://doi.org/10.1080/1744666X.2022.2082946 (validates complement inhibition). (keller2022fcreceptortargetedtherapies pages 2-3) - Bhandari V, Bril V. FcRn receptor antagonists in MG. Frontiers in Neurology. Aug 2023. DOI: 10.3389/fneur.2023.1229112; URL: https://doi.org/10.3389/fneur.2023.1229112 (FcRn biology and clinical use). (bhandari2023fcrnreceptorantagonists pages 1-2) - Jacob S. Treating myasthenia gravis beyond the eye clinic. Eye. May 2024. DOI: 10.1038/s41433-024-03133-x; URL: https://doi.org/10.1038/s41433-024-03133-x (subtype mechanisms, clinical correlations). (jacob2024treatingmyastheniagravis pages 1-2) - Dziadkowiak E et al. MuSK Myasthenia Gravis—Mechanisms and targeted treatment. Cells. Mar 2024. DOI: 10.3390/cells13060556; URL: https://doi.org/10.3390/cells13060556 (MuSK IgG4 pathology). (dziadkowiak2024muskmyastheniagravis—potential pages 13-14) - Huda R. Inflammation and autoimmune MG. Frontiers in Immunology. Jan 2023. DOI: 10.3389/fimmu.2023.1110499; URL: https://doi.org/10.3389/fimmu.2023.1110499 (thymic inflammation, Tfh/BAFF/IFN). (huda2023inflammationandautoimmune pages 1-2) - Braun A et al. Genome-wide meta-analysis of MG. Nature Communications. Nov 2024. DOI: 10.1038/s41467-024-53595-6; URL: https://doi.org/10.1038/s41467-024-53595-6 (genetics, PRS). (kaminski2024myastheniagravisthe pages 2-4) - Vissing J et al. Epidemiology of MG in Denmark, Finland, Sweden. JNNP. Mar 2024. DOI: 10.1136/jnnp-2023-333097; URL: https://doi.org/10.1136/jnnp-2023-333097 (epidemiology). () - Ye Y et al. Epidemiology of MG in the USA. Frontiers in Neurology. Feb 2024. DOI: 10.3389/fneur.2024.1339167; URL: https://doi.org/10.3389/fneur.2024.1339167 (epidemiology). ()

Direct quotes (supporting key statements) - “AChR antibodies act via three established mechanisms: complement activation with MAC formation… antigenic modulation… and direct blockade of the ACh binding site” (JCI 2024) (kaminski2024myastheniagravisthe pages 2-4). - “MuSK autoantibodies are predominantly IgG4… block the binding site for LRP4 on MuSK, thereby inhibiting the downstream phosphorylation pathway and compromising the formation of AChR clusters” (Cells 2024) (dziadkowiak2024muskmyastheniagravis—potential pages 13-14). - “FcRn receptors prevent the catabolism of IgG… blocking the FcRn… leading to outcomes similar to those achieved through plasma exchange” (Frontiers in Neurology 2023) (bhandari2023fcrnreceptorantagonists pages 1-2).

Structured ontology annotations for knowledge base - Disease: Myasthenia gravis (MONDO:0005041) - Genes/Proteins (HGNC): CHRNA1, CHRNB1, RAPSN, DOK7, MUSK, LRP4, AGRN, HLA-DRB1, HLA-DQB1, CTLA4, PTPN22 (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2, dziadkowiak2024muskmyastheniagravis—potential pages 13-14) - GO Processes: complement activation, classical pathway (GO:0006958); receptor-mediated endocytosis (GO:0006898); cholinergic synaptic transmission (GO:0007271); neuromuscular junction development (GO:0007528); B cell activation (GO:0042113); T cell activation (GO:0042110); type I interferon signaling (GO:0060337) (kaminski2024myastheniagravisthe pages 2-4, keller2022fcreceptortargetedtherapies pages 2-3, huda2023inflammationandautoimmune pages 1-2, jacob2024treatingmyastheniagravis pages 1-2) - Cellular Components: postsynaptic membrane (GO:0045211); membrane attack complex (GO:0005579); endosome (GO:0005768); lysosome (GO:0005764) (kaminski2024myastheniagravisthe pages 2-4, keller2022fcreceptortargetedtherapies pages 2-3, bhandari2023fcrnreceptorantagonists pages 1-2) - Cell Types (CL): B cell (CL:0000236); plasmablast (CL:0000980); Tfh (CL:0000914); Treg (CL:0000815); dendritic cell (CL:0000451); mTEC (CL:0000786) (huda2023inflammationandautoimmune pages 1-2, bhandari2023fcrnreceptorantagonists pages 1-2) - Anatomical Sites (UBERON): neuromuscular junction (UBERON:0007200); skeletal muscle tissue (UBERON:0001134); thymus (UBERON:0002370) (jacob2024treatingmyastheniagravis pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Chemical Entities (ChEBI): acetylcholine (CHEBI:15355); immunoglobulin G (CHEBI:16991) (jacob2024treatingmyastheniagravis pages 1-2, bhandari2023fcrnreceptorantagonists pages 1-2) - Phenotypes (HP): fatigable muscle weakness (HP:0003701); ptosis (HP:0000508); diplopia (HP:0000651); dysphagia (HP:0002015); dysarthria (HP:0001260); respiratory failure (HP:0002878) (jacob2024treatingmyastheniagravis pages 1-2)

Notes and limitations - Detailed thymic single-cell and spatial transcriptomic data, and comprehensive ncRNA catalogs, while summarized in reviews, require additional primary sources for subtype-specific differential expression beyond the scope of the citations gathered herein (Frontiers in Immunology 2023; JCI 2024). (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

Citations - Mechanistic claims at the NMJ: (kaminski2024myastheniagravisthe pages 2-4, jacob2024treatingmyastheniagravis pages 1-2, keller2022fcreceptortargetedtherapies pages 2-3) - MuSK/LRP4 subclass and signaling: (dziadkowiak2024muskmyastheniagravis—potential pages 13-14, jacob2024treatingmyastheniagravis pages 1-2) - Thymic pathology and immune subsets: (huda2023inflammationandautoimmune pages 1-2, kaminski2024myastheniagravisthe pages 2-4, bhandari2023fcrnreceptorantagonists pages 1-2) - Therapeutic mechanistic validation (C5, FcRn): (keller2022fcreceptortargetedtherapies pages 2-3, bhandari2023fcrnreceptorantagonists pages 1-2, kaminski2024myastheniagravisthe pages 2-4) - Genetics (2024 GWAS/meta): (kaminski2024myastheniagravisthe pages 2-4) - Epidemiology (2024): (, )

References

  1. (kaminski2024myastheniagravisthe pages 2-4): Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, and Linda L. Kusner. Myasthenia gravis: the future is here. Journal of Clinical Investigation, Jun 2024. URL: https://doi.org/10.1172/jci179742, doi:10.1172/jci179742. This article has 70 citations and is from a highest quality peer-reviewed journal.

  2. (jacob2024treatingmyastheniagravis pages 1-2): Saiju Jacob. Treating myasthenia gravis beyond the eye clinic. Eye, 38:2422-2436, May 2024. URL: https://doi.org/10.1038/s41433-024-03133-x, doi:10.1038/s41433-024-03133-x. This article has 6 citations and is from a peer-reviewed journal.

  3. (bhandari2023fcrnreceptorantagonists pages 1-2): Vinaya Bhandari and Vera Bril. Fcrn receptor antagonists in the management of myasthenia gravis. Frontiers in Neurology, Aug 2023. URL: https://doi.org/10.3389/fneur.2023.1229112, doi:10.3389/fneur.2023.1229112. This article has 33 citations and is from a peer-reviewed journal.

  4. (keller2022fcreceptortargetedtherapies pages 2-3): Christian W. Keller, Marc Pawlitzki, Heinz Wiendl, and Jan Lünemann. Fc-receptor targeted therapies for the treatment of myasthenia gravis. International Journal of Molecular Sciences, May 2022. URL: https://doi.org/10.3390/ijms22115755, doi:10.3390/ijms22115755. This article has 29 citations and is from a poor quality or predatory journal.

  5. (dziadkowiak2024muskmyastheniagravis—potential pages 13-14): Edyta Dziadkowiak, Dagmara Baczyńska, and Marta Waliszewska-Prosół. Musk myasthenia gravis—potential pathomechanisms and treatment directed against specific targets. Cells, 13:556, Mar 2024. URL: https://doi.org/10.3390/cells13060556, doi:10.3390/cells13060556. This article has 10 citations and is from a poor quality or predatory journal.

  6. (huda2023inflammationandautoimmune pages 1-2): Ruksana Huda. Inflammation and autoimmune myasthenia gravis. Frontiers in Immunology, Jan 2023. URL: https://doi.org/10.3389/fimmu.2023.1110499, doi:10.3389/fimmu.2023.1110499. This article has 49 citations and is from a peer-reviewed journal.

  7. (kaminski2024myastheniagravisthe pages 10-10): Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, and Linda L. Kusner. Myasthenia gravis: the future is here. Journal of Clinical Investigation, Jun 2024. URL: https://doi.org/10.1172/jci179742, doi:10.1172/jci179742. This article has 70 citations and is from a highest quality peer-reviewed journal.