Adult-Onset Myasthenia Gravis

Autoimmune MONDO:0018324 Pathograph 9 Show in embeddings browser Myasthenia Gravis Neuromuscular Disease Autoimmune Disease

Adult-onset myasthenia gravis is acquired autoimmune myasthenia gravis whose symptoms begin after puberty. It shares the postsynaptic neuromuscular-junction effector mechanism of myasthenia gravis generally — autoantibody binding, complement-mediated damage to the endplate, and fatigable weakness — but is defined by an additional axis that the serotype axis does not capture: age at onset. Early-onset disease (EOMG, conventionally onset before 50 years) is female-predominant and is driven by a hyperplastic thymus that behaves as a tertiary lymphoid organ, with ectopic germinal centres, intrathymic acetylcholine-receptor antigen presentation, and a very strong HLA-B*08/DRB1*03 class I-anchored susceptibility signal. Late-onset disease (LOMG, onset at or after 50 years, with a very-late-onset tier beyond 65 years) is male-predominant, arises against an atrophic involuted thymus, carries striational (anti-titin and anti-ryanodine-receptor) autoantibodies, and has an HLA architecture that is weaker and in places directionally opposite to EOMG. LOMG incidence has risen substantially in ageing populations while EOMG incidence has stayed flat, and the thymectomy evidence base is restricted to the adult non-thymomatous population.

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3
Mappings
1
Definitions
6
Pathophys.
10
Phenotypes
2
Hypotheses
2
Gaps
9
Pathograph
7
Genes
3
Medical Actions
3
Subtypes
5
References
1
Deep Research
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Mappings

MONDO
MONDO:0018324 adult-onset myasthenia gravis
skos:exactMatch ORPHA:391490 ORPHA:391490: CONSISTENT
Orphanet lists MONDO:0018324 as an exact cross-reference for ORPHA:391490.
MONDO:0009688 myasthenia gravis DisMech
skos:broadMatch ORPHA:391490
Orphanet classes ORPHA:391490 as a clinical subtype of a disorder, and MONDO asserts MONDO:0018324 is_a MONDO:0009688; the general myasthenia gravis concept is therefore broader than this entry. Curated as `skos:broadMatch` so it is not mistaken for a mapping that would retire MONDO:0009688 from the curation queue — that concept is curated separately in `Myasthenia_Gravis.yaml`.
ICD-10-CM
ICD10CM:G70.0 Myasthenia gravis
skos:broadMatch ORPHA:391490 ORPHA:391490: CONSISTENT
Orphanet records ICD-10 G70.0 as a *narrower* cross-reference direction for ORPHA:391490 — i.e. the ORPHA subtype is narrower than the ICD code — so from this entry's perspective the ICD code is the broader concept.
📘

Definitions

1
Orphanet disease definition
Orphanet defines adult-onset myasthenia gravis as a rare autoimmune disorder of the neuromuscular junction with fatigable muscle weakness, frequent ocular signs and/or generalized weakness, and occasional thymoma association.
CASE_DEFINITION
Show evidence (1 reference)
ORPHA:391490 SUPPORT Other
"A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma."
Orphanet's definition for the adult-onset subtype anchors the scope of this entry.
◆

Subtypes

3
Early-Onset MG (onset before ~50 years)
Adult-onset disease beginning before approximately 50 years of age. Female-predominant, strongly associated with thymic follicular hyperplasia containing ectopic germinal centres, and carrying the strongest HLA signal in myasthenia gravis (HLA-B*08 / DRB1*03).
Show evidence (1 reference)
PMID:40675735 SUPPORT Human Clinical
"EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."
Defines the early-onset subgroup by its immunogenetic profile, sex skew, and thymic pathology.
Late-Onset MG (onset at or after ~50 years)
Adult-onset disease beginning at or after approximately 50 years of age. Male-predominant, typically arising against an atrophic (age-involuted) thymus, frequently anti-AChR and anti-titin positive, and with a genetically distinct susceptibility architecture from EOMG.
Show evidence (2 references)
PMID:33458590 SUPPORT Human Clinical
"LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high."
Gives the conventional ≥50-year onset boundary together with the male skew and antibody profile that define the subgroup.
PMID:40675735 SUPPORT Human Clinical
"In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."
Contrasts late-onset thymic and genetic biology with the early-onset subgroup.
Very Late-Onset MG (onset after ~65 years)
A further tier within late-onset disease, conventionally onset after about 65 years. Incidence in this age band has risen continuously, with a clear male predominance. Presentation is typically focal (ocular or bulbar), and diagnosis is described as requiring a high index of suspicion.
Show evidence (2 references)
PMID:23893883 SUPPORT Human Clinical
"We define late-onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance."
Documents the ≥65-year boundary used for the very-late-onset tier — and, by differing from the ≥50-year boundary used elsewhere, shows that the cut-point itself is a convention rather than a measured discontinuity.
PMID:23893883 SUPPORT Human Clinical
"Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis."
Supports focal presentation and diagnostic delay as characteristic of the oldest-onset group.
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Mechanistic Hypotheses

2
Intrathymic autoimmunization drives early-onset disease
thymic_autoimmunization_eomg CANONICAL EOMG
Evidence balance 1 support
In early-onset disease the hyperplastic thymus is the site of autoimmunization: it converts to a tertiary lymphoid organ, presents acetylcholine receptor locally, and generates the anti-AChR response. This model predicts — and is supported by — the benefit of thymectomy in the early-onset, non-thymomatous, AChR-positive population.
Pathograph links
Age-at-Onset Stratification of Myasthenia Gravis -> Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation DIRECT Early onset is the branch in which the thymus itself becomes the autoimmunizing organ.
Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation -> Autoantibody-Mediated Neuromuscular Junction Failure DIRECT Intrathymic germinal centres supply the anti-AChR antibody that damages the endplate.
Show evidence (1 reference)
PMID:27273086 SUPPORT Human Clinical
"Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients."
Explicitly connects the thymic-autoimmunization model to the therapeutic benefit observed in early-onset patients.
Late-onset disease arises without a thymic germinal-centre reaction
extrathymic_lomg ALTERNATIVE LOMG VLOMG
Evidence balance 2 support
In late- and very-late-onset disease the thymus is atrophic and the germinal-centre mechanism is largely unavailable, so autoimmunization is presumed to occur elsewhere. The genetic architecture is distinct from — and in the MHC partly directionally opposite to — early-onset disease, and the incidence trajectories of the two subgroups have diverged over decades. What the initiating event actually is in the involuted thymus remains unidentified; this is recorded as an open knowledge gap rather than asserted.
Pathograph links
Age-at-Onset Stratification of Myasthenia Gravis -> Late-Onset Autoimmunity Against an Involuted Thymus DIRECT Late onset is the branch in which disease arises without a hyperplastic thymic germinal-centre reaction.
Late-Onset Autoimmunity Against an Involuted Thymus -> Striational Autoantibody Response DIRECT The late-onset immune response characteristically broadens beyond AChR to intracellular muscle antigens.
Show evidence (2 references)
PMID:16186537 SUPPORT Human Clinical
"The two onset types of MG may thus be distinct disorders. The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors."
The original epidemiological statement of the two-disorder hypothesis, including its environmental-trigger corollary.
PMID:26562150 SUPPORT Human Clinical
"Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG."
Genetic support for distinct predisposing mechanisms in the late-onset subgroup.
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Discussions and Knowledge Gaps

2
Are early-onset and late-onset myasthenia gravis mechanistically distinct disorders, or one continuous disease whose features shift with age at onset?
CONTROVERSY OPEN onset_dichotomy_vs_continuum
Attached to
pathophysiology#Age-at-Onset Stratification of Myasthenia Gravis
The genetic and epidemiological evidence points to separation: the MHC associations differ in magnitude and in direction between the subgroups, the early-onset TNIP1 signal is absent in late onset, and late-onset incidence has risen four-fold in a population where early-onset incidence did not move at all. The clinical evidence points the other way: cohort comparisons find extensively overlapping features and read the difference as a shift in proportions along one spectrum rather than a boundary. Note also that the conventional cut-point is itself unstable in the literature — 50 years in most genetic and cohort work, 65 years in others — which is hard to reconcile with a true biological discontinuity. This entry curates the subgroups because the upstream immunopathology and treatment evidence genuinely differ by onset age, without asserting that they are separate diseases.
Show evidence (2 references)
PMID:22476514 REFUTE Human Clinical
"Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset."
Direct argument against a two-disorder reading, from a cohort that compared the subgroups clinically. Recorded as REFUTE against the strong separation claim.
PMID:16186537 SUPPORT Human Clinical
"The two onset types of MG may thus be distinct disorders."
The epidemiological argument for separation, stated by the authors themselves.
If the atrophic late-onset thymus cannot support the germinal-centre reaction that explains early-onset autoimmunization, where and how is the anti-AChR response initiated in late-onset disease?
KNOWLEDGE GAP OPEN lomg_initiating_event
Attached to
pathophysiology#Late-Onset Autoimmunity Against an Involuted Thymus
The thymic model of myasthenia gravis is well evidenced for the hyperplastic, early-onset thymus and is the mechanistic basis for thymectomy. No comparably specified site or trigger has been established for late-onset disease, which is now the subgroup driving the global rise in incidence. The gap matters therapeutically: the thymectomy evidence base does not transfer, and the leading published hypothesis — an environmental provocation — has not been resolved to a specific exposure.
Proposed experiments
Compartment-resolved B-cell receptor repertoire comparison by onset age
lomg_bcr_compartment_repertoire
Compare single-cell B-cell receptor repertoires from thymic, lymph-node, and bone-marrow compartments between early- and late-onset AChR-antibody-positive patients, to locate the compartment in which late-onset anti-AChR clones are generated and maintained.
Supporting outcome
  • Recovery of clonally expanded, somatically hypermutated anti-AChR lineages from an extrathymic compartment in late-onset patients but not early-onset patients would support an extrathymic site of autoimmunization in late-onset disease.
Refuting outcome
  • Recovery of the same intrathymic clonal architecture in both onset groups would refute the claim that the germinal-centre mechanism is unavailable in the involuted thymus.
Prospective association of thymic self-antigen presentation with late-onset seroconversion
lomg_thymic_tolerance_seroconversion
Test whether age-related loss of thymic self-antigen presentation is quantitatively associated with anti-AChR seroconversion in prospectively sampled older adults.
Supporting outcome
  • An inverse association between residual thymic self-antigen presentation and incident seroconversion would support failing central tolerance as the late-onset initiating event.
Refuting outcome
  • No association across the observed range would refute a central-tolerance-failure model and redirect attention to peripheral or environmental triggers.
Show evidence (1 reference)
PMID:16186537 SUPPORT Human Clinical
"The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors."
The leading published proposal for the late-onset trigger is explicitly framed as a hypothesis, which is what makes this an open gap rather than a settled mechanism.
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Pathophysiology

6
Age-at-Onset Stratification of Myasthenia Gravis
Intrathymic autoimmunization drives early-onset disease Late-onset disease arises without a thymic germinal-centre reaction
Downstream
Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation Early onset is the branch in which the thymus itself becomes the autoimmunizing organ. Intrathymic autoimmunization drives early-onset disease
Late-Onset Autoimmunity Against an Involuted Thymus Late onset is the branch in which disease arises without a hyperplastic thymic germinal-centre reaction. Late-onset disease arises without a thymic germinal-centre reaction
Onset-Age-Stratified Immunogenetic Susceptibility Both branches carry their own, largely non-overlapping susceptibility architecture.
Show evidence (2 references)
PMID:40675735 SUPPORT Human Clinical
"The age at disease onset significantly influences the clinical course, pathophysiology, and treatment response in Myasthenia Gravis (MG)."
States the central claim of this entry directly.
PMID:26376969 SUPPORT Human Clinical
"Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis."
Establishes that onset age sits alongside serotype as a first-class subgrouping axis in the standard classification — the justification for curating it separately from the serotype-stratified parent entry.
Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation
In early-onset disease the hyperplastic thymus acquires the full architecture of a tertiary lymphoid organ: high endothelial venules and lymphatic neoangiogenesis, chemokine-driven recruitment of peripheral B cells and T follicular helper cells, and ectopic germinal centres. Because thymic epithelial and myoid cells express the acetylcholine receptor, the autoantigen is presented in situ to the recruited cells, so the thymus can both initiate and sustain the anti-AChR response rather than merely accompany it.
Intrathymic autoimmunization drives early-onset disease
Thymic Epithelial Cell CL:0002293 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Thymic Epithelial Cell, annotated with epithelial cell of thymus (CL:0002293). CL:0002293 is a cell type from the Cell Ontology. Germinal Centre B Cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Germinal Centre B Cell, annotated with germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology. T Follicular Helper Cell CL:0002038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T Follicular Helper Cell (CL:0002038). CL:0002038 is a cell type from the Cell Ontology.
Ectopic Germinal Centre Formation GO:0002467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ectopic Germinal Centre Formation, annotated with germinal center formation (GO:0002467). GO:0002467 is a biological process from the Gene Ontology. ↑ INCREASED Positive Regulation of Immunoglobulin Production GO:0002639 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Positive Regulation of Immunoglobulin Production (GO:0002639). GO:0002639 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Autoantibody-Mediated Neuromuscular Junction Failure Intrathymic germinal centres supply the anti-AChR antibody that damages the endplate. Intrathymic autoimmunization drives early-onset disease
Show evidence (4 references)
PMID:29125185 SUPPORT Human Clinical
"The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development."
Establishes the tertiary-lymphoid-organ conversion of the thymus specifically in early-onset disease.
PMID:29125185 SUPPORT Human Clinical
"As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells."
Supplies the mechanism by which the autoantigen is presented inside the thymus to recruited effector cells.
PMID:27273086 SUPPORT Human Clinical
"The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies."
Correlates germinal-centre burden with antibody level across 1035 patients, supporting the thymus as a source rather than a bystander.
+ 1 more reference
Late-Onset Autoimmunity Against an Involuted Thymus
Late- and very-late-onset disease arises when the thymus is atrophic rather than hyperplastic, so the germinal-centre mechanism that explains early-onset disease is largely unavailable. The late-onset subgroup is instead characterized by high anti-AChR seropositivity, frequent striational (anti-titin, anti-ryanodine-receptor) antibodies, male predominance, and a high burden of age-related comorbidity that constrains treatment. The initiating event in a thymus that no longer supports germinal centres is not established.
Late-onset disease arises without a thymic germinal-centre reaction
Thymic Epithelial Cell CL:0002293 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Thymic Epithelial Cell, annotated with epithelial cell of thymus (CL:0002293). CL:0002293 is a cell type from the Cell Ontology.
Age-Related Thymic Involution Relation: this pathophysiological event involves this biological process This pathophysiological event involves Age-Related Thymic Involution.
Downstream
Striational Autoantibody Response The late-onset immune response characteristically broadens beyond AChR to intracellular muscle antigens. Late-onset disease arises without a thymic germinal-centre reaction
Autoantibody-Mediated Neuromuscular Junction Failure Late-onset disease converges on the same postsynaptic effector lesion by a different upstream route.
Show evidence (5 references)
PMID:40675735 SUPPORT Human Clinical
"In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."
Establishes thymic atrophy, rather than hyperplasia, as the thymic state in late-onset disease.
PMID:22476514 SUPPORT Human Clinical
"Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"
Quantifies the higher anti-AChR seropositivity of the late-onset subgroup within one cohort.
PMID:22476514 SUPPORT Human Clinical
"Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p = 0.0002)."
Quantifies both the more ocular-restricted phenotype and the excess diabetes burden in late-onset disease.
+ 2 more references
Striational Autoantibody Response
The late-onset immune response characteristically broadens beyond the acetylcholine receptor to intracellular striational antigens. Anti-titin is the onset-discriminating member of the panel: it tracks older onset age and, in late-onset patients, generalized disease, while in younger-onset patients it instead flags thymoma. Anti-ryanodine-receptor antibody travels with the panel but is *not* itself onset-discriminating — it has been detected in early-onset patients and controls as well. All of these target intracellular proteins that circulating IgG cannot reach in intact muscle, so they are best read as markers of a broadened autoimmune response rather than as established effectors of weakness.
Show evidence (4 references)
PMID:38505076 SUPPORT Human Clinical
"Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)."
Links anti-titin seropositivity specifically to generalized disease within the late-onset subgroup.
PMID:38505076 SUPPORT Human Clinical
"Anti-titin positivity correlated with thymoma in patients with age of onset bellow 50 years (P=0.028)."
Shows the *same* antibody carries a different meaning either side of the 50-year onset boundary — thymoma marker in early onset, generalization marker in late onset — which is a concrete demonstration that onset age changes interpretation, not just description.
PMID:33458590 SUPPORT Human Clinical
"LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high."
Independent review confirming high anti-titin frequency in the late-onset subgroup.
+ 1 more reference
Onset-Age-Stratified Immunogenetic Susceptibility
Early- and late-onset disease have largely non-overlapping genetic architectures. Early onset carries an exceptionally strong HLA class I signal that maps to HLA-B*08, plus non-HLA risk at TNIP1 and PTPN22. Late onset carries weaker MHC effects — with the strongest associations running in the *opposite* direction to early onset — plus its own loci (TNFRSF11A, ZBTB10), while the early-onset TNIP1 signal is absent altogether.
Show evidence (6 references)
PMID:23055271 SUPPORT Human Clinical
"By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele"
Localizes the dominant early-onset MHC signal to a class I allele.
PMID:23055271 SUPPORT Human Clinical
"The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis."
Gives the mechanistic reading of the early-onset-specific loci.
PMID:26562150 SUPPORT Human Clinical
"In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG."
Demonstrates that the early-onset non-HLA architecture does not transfer to late onset.
+ 3 more references
Autoantibody-Mediated Neuromuscular Junction Failure
The shared effector lesion of all myasthenia gravis: autoantibody binding at the postsynaptic membrane with complement activation and loss of functional acetylcholine receptor, producing fatigable weakness. Included here only as the convergence point of the two onset branches; the full effector mechanism is curated in `Myasthenia_Gravis.yaml` and is not re-derived.
Skeletal Muscle Cell CL:0000188 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal Muscle Cell, annotated with cell of skeletal muscle (CL:0000188). CL:0000188 is a cell type from the Cell Ontology.
Neuromuscular Synaptic Transmission GO:0007274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Neuromuscular Synaptic Transmission (GO:0007274). GO:0007274 is a biological process from the Gene Ontology. ↓ DECREASED Complement Activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Complement Activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:26376969 SUPPORT Human Clinical
"Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic..."
States the shared postsynaptic autoantibody mechanism that both onset branches converge on.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adult-Onset Myasthenia Gravis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23893883 SUPPORT Human Clinical
"Commonly, patients present with focal (ocular or bulbar) weakness."
Supports bulbar presentation in late-onset disease. Marked PARTIAL because the source names "bulbar" rather than dysphagia specifically.
Eye 2
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23893883 SUPPORT Human Clinical
"Commonly, patients present with focal (ocular or bulbar) weakness."
Supports ocular presentation in late-onset disease. Marked PARTIAL because the source says "ocular" rather than naming ptosis specifically.
Diplopia HP:0000651 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diplopia (HP:0000651). HP:0000651 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23893883 SUPPORT Human Clinical
"Commonly, patients present with focal (ocular or bulbar) weakness."
Supports ocular presentation. Marked PARTIAL because the source does not name diplopia specifically.
Musculoskeletal 2
Fatigable Muscle Weakness Fatigable weakness HP:0003473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigable weakness (HP:0003473). HP:0003473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:391490 SUPPORT Other
"characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness"
Orphanet's definition of the adult-onset subtype names fatigable weakness as its defining feature.
Generalized Muscle Weakness HP:0003324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized muscle weakness (HP:0003324). HP:0003324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:391490 SUPPORT Other
"with frequent ocular signs and/or generalized muscle weakness"
Orphanet's definition names generalized weakness as a feature of the adult-onset subtype.
Nervous System 1
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23893883 SUPPORT Human Clinical
"Commonly, patients present with focal (ocular or bulbar) weakness."
Supports bulbar presentation. Marked PARTIAL because the source does not name dysarthria specifically.
Respiratory 1
Myasthenic Crisis Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22476514 SUPPORT Human Clinical
"Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %)."
Establishes crisis risk in both onset subgroups and, notably, shows it does *not* differ by onset age — a place where the subgroups converge rather than diverge.
Other 3
Ocular-Restricted Disease
phenotype_term deliberately left unbound. The concept curated here is a disease *distribution* - weakness confined to the extraocular muscles, without generalization - not the sign of ophthalmoplegia. HP:0000602 (Ophthalmoplegia) was removed because it names the sign and would be satisfied by any generalized patient with eye involvement, inverting the meaning of this row. No HP term denotes the restricted distribution (HP:0007715 Weak extraocular muscles is likewise a sign); needs an NTR to HPO.
Show evidence (1 reference)
PMID:22476514 SUPPORT Human Clinical
"Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021)."
Quantifies the excess of ocular-restricted disease in the late-onset subgroup.
Thymic Follicular Hyperplasia Thymus hyperplasia HP:0010516 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thymus hyperplasia (HP:0010516). HP:0010516 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27273086 SUPPORT Human Clinical
"We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women."
Documents the lesion and its strong female skew in a 1035-patient thymic-pathology series.
PMID:40675735 SUPPORT Human Clinical
"EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."
Assigns the higher thymic-hyperplasia rate specifically to the early-onset subgroup.
Thymoma HP:0100522 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thymoma (HP:0100522). HP:0100522 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:391490 SUPPORT Other
"generalized muscle weakness, and occasionally associated with thymoma."
Orphanet's definition of the adult-onset subtype records occasional thymoma association.
🧬

Genetic Associations

7
HLA-B*08
Gene: HLA-B hgnc:4932 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-B (hgnc:4932). hgnc:4932 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:23055271 SUPPORT Human Clinical
"We observed the strongest association in the HLA class I region at rs7750641"
Locates the strongest early-onset genome-wide signal in the HLA class I region.
PMID:23055271 SUPPORT Human Clinical
"By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41)."
Resolves the signal to HLA-B*08 specifically and gives the effect size quoted in the description.
HLA-DRB1
Gene: HLA-DRB1 hgnc:4948 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DRB1 (hgnc:4948). hgnc:4948 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:28495048 SUPPORT Human Clinical
"HLA-DRB1*03 allele was overrepresented in the global MG. When the early-onset subgroup was considered, this association became even stronger."
Shows the class II risk allele concentrating in the early-onset subgroup.
PMID:28495048 SUPPORT Human Clinical
"Regarding the late-onset subgroup, the frequency of HLA-DRB1*01 allele was higher than in the CP."
Shows a different class II allele associating with the late-onset subgroup in the same cohort.
HLA-DQA1
Gene: HLA-DQA1 hgnc:4942 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQA1 (hgnc:4942). hgnc:4942 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:26562150 SUPPORT Human Clinical
"Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45)."
States the onset-direction reversal directly, with both effect sizes: DQA1*05:01 is protective in late-onset and predisposing in early-onset disease.
PMID:26562150 SUPPORT Human Clinical
"Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs."
Establishes by conditional analysis that DQA1 accounts for the class II peak in late-onset disease, so the reversed allele is the locus driving the class II signal.
TNIP1
Gene: TNIP1 hgnc:16903 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNIP1 (hgnc:16903). hgnc:16903 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:23055271 SUPPORT Human Clinical
"The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling."
Establishes the TNIP1 association and its mechanistic reading in early-onset disease.
PMID:26562150 SUPPORT Human Clinical
"In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG."
Establishes that the TNIP1 signal is early-onset-specific and does not extend to late onset.
PTPN22
Gene: PTPN22 hgnc:9652 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTPN22 (hgnc:9652). hgnc:9652 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:26562150 SUPPORT Human Clinical
"Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases."
Records the shared PTPN22 signal. Marked PARTIAL because in the late-onset study it reached only suggestive, not genome-wide, significance.
TNFRSF11A
Gene: TNFRSF11A hgnc:11908 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNFRSF11A (hgnc:11908). hgnc:11908 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:26562150 SUPPORT Human Clinical
"The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42)"
Confirms the TNFRSF11A association in a dedicated late-onset cohort.
ZBTB10
Gene: ZBTB10 hgnc:30953 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZBTB10 (hgnc:30953). hgnc:30953 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:26562150 SUPPORT Human Clinical
"identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53)"
Reports ZBTB10 as a genome-wide-significant late-onset locus.
🗃️

External Assertions

1
Orphanet adult-onset myasthenia gravis record
Orphanet Structured disease record ORPHA:391490
Orphanet structured record for adult-onset myasthenia gravis, classed as a clinical subtype of myasthenia gravis, with curated cross-references to MONDO, ICD-10, ICD-11, and UMLS.
Show evidence (2 references)
ORPHA:391490 SUPPORT Other
"Adult-onset myasthenia gravis (Clinical subtype, Subtype of disorder)"
Orphanet's own typing of the concept as a clinical subtype is the honest framing for this entry's relationship to the parent myasthenia gravis entry.
ORPHA:391490 SUPPORT Other
"UMLS:C5680024 | Exact"
The Orphanet cross-reference table exactly maps ORPHA:391490 to UMLS C5680024.
💊

Medical Actions

3
Thymectomy
Action: thymectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is thymectomy (NCIT:C29894). NCIT:C29894 is a clinical intervention from the NCI Thesaurus. Ontology label: Thymectomy NCIT:C29894
Surgical removal of the thymus. The randomized evidence base is explicitly adult and age-bounded — MGTX enrolled patients aged 18 to 65 with generalized non-thymomatous AChR-antibody-positive disease — so it speaks to the early-onset end of the adult-onset spectrum. Whether the benefit extends to late-onset disease is not established by randomized data.
Mechanism Target:
INHIBITS Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation — Removes the hyperplastic thymus in which the early-onset anti-AChR response is generated and sustained.
Show evidence (1 reference)
PMID:27273086 SUPPORT Human Clinical
"Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients."
Links the surgical target (the hyperplastic thymus) to the observed early-onset benefit.
Show evidence (5 references)
PMID:27509100 SUPPORT Human Clinical
"Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included"
Defines the age window of the only randomized thymectomy trial — the reason this entry treats the thymectomy evidence as onset-age-bounded rather than general to myasthenia gravis.
PMID:27509100 SUPPORT Human Clinical
"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)"
Demonstrates benefit within that adult, non-thymomatous population.
PMID:40022458 SUPPORT Human Clinical
"Thymectomy is beneficial for treating early-onset acetylcholine receptor antibody-positive myasthenia gravis (MG); however, its effects on late-onset MG (LOMG) remain less well understood."
States the asymmetry directly: established for early onset, unresolved for late onset. Marked PARTIAL because it qualifies rather than supports a general thymectomy recommendation.
+ 2 more references
Corticosteroid and Azathioprine Immunosuppression
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest. azathioprine CHEBI:2948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azathioprine (CHEBI:2948). CHEBI:2948 is a therapeutic agent from Chemical Entities of Biological Interest.
Combination corticosteroid plus azathioprine immunosuppression, reported to improve outcome in generalized non-thymomatous late-onset disease — the subgroup in which the thymectomy evidence is weakest and in which comorbidity constrains treatment choice.
Mechanism Target:
INHIBITS Autoantibody-Mediated Neuromuscular Junction Failure — Broad immunosuppression reduces the autoantibody response driving endplate damage.
Show evidence (1 reference)
PMID:31811563 SUPPORT Human Clinical
"Use of prednisone + azathioprine had significantly positive effect on outcome."
Outcome evidence that immunosuppression modifies the disease in the late-onset subgroup.
Show evidence (2 references)
PMID:31811563 SUPPORT Human Clinical
"Use of prednisone + azathioprine had significantly positive effect on outcome."
Direct outcome evidence for this combination specifically within generalized non-thymomatous late-onset disease.
PMID:26376969 SUPPORT Human Clinical
"Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments."
Places corticosteroids and azathioprine as first-line immunosuppression in the subgroup-based treatment framework.
Pyridostigmine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridostigmine CHEBI:8665 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridostigmine (CHEBI:8665). CHEBI:8665 is a therapeutic agent from Chemical Entities of Biological Interest.
Acetylcholinesterase inhibition as symptomatic therapy, the preferred first symptomatic treatment across myasthenia gravis subgroups including adult-onset disease.
Mechanism Target:
INHIBITS Autoantibody-Mediated Neuromuscular Junction Failure — Prolongs acetylcholine availability at the endplate, partially compensating for the reduced receptor number without modifying the autoimmune process.
Show evidence (1 reference)
PMID:26376969 SUPPORT Human Clinical
"Pyridostigmine is the preferred symptomatic treatment"
Supports the symptomatic role. Marked PARTIAL because the source establishes preference, not the endplate-level mechanism asserted in the description.
Show evidence (2 references)
PMID:26376969 SUPPORT Human Clinical
"Pyridostigmine is the preferred symptomatic treatment"
Establishes pyridostigmine as the preferred symptomatic therapy in the subgroup-based framework.
PMID:26376969 SUPPORT Human Clinical
"Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis."
Supports the entry's premise that treatment is tailored by subgroup rather than uniform.
🔬

Biochemical Markers

3
Anti-Acetylcholine Receptor Antibody
Context: Circulating IgG against the muscle nicotinic acetylcholine receptor. Present in the large majority of adult-onset patients and reported at a higher rate in late- than early-onset disease.
Show evidence (1 reference)
PMID:22476514 SUPPORT Human Clinical
"Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"
Gives the onset-stratified seropositivity rates in a single cohort tested identically.
Anti-Titin Antibody
Context: Antibody against the intracellular sarcomeric protein titin. Strongly associated with older onset age; in late-onset patients it flags generalized disease, whereas in early-onset patients it flags thymoma.
Show evidence (2 references)
PMID:31811563 SUPPORT Human Clinical
"In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive."
Quantifies anti-titin seropositivity at 61% in generalized non-thymomatous late-onset disease.
PMID:38505076 SUPPORT Human Clinical
"Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)."
Establishes the late-onset-specific clinical correlate of anti-titin positivity.
Anti-Ryanodine Receptor Antibody
Context: Striational antibody against the skeletal-muscle ryanodine receptor, part of the broadened autoantibody repertoire reported in older-onset and thymoma-associated disease.
Show evidence (2 references)
PMID:30918333 SUPPORT Human Clinical
"MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies."
Places anti-ryanodine-receptor antibody within the striational panel of late-onset and thymoma-associated disease.
PMID:30918333 REFUTE Human Clinical
"In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies."
Refutes any claim that anti-ryanodine-receptor antibody is itself onset-discriminating: unlike anti-titin and anti-Kv1.4, it was also found in early-onset patients and controls. Recorded so the striational panel is not read as uniformly late-onset-specific.
📈

Progression

1
Onset
Age: After puberty (adult onset)
Onset after puberty is the defining feature of this entry. The boundary is not arbitrary: thymic follicular hyperplasia, the central early-onset lesion, is markedly more prominent in females after puberty than before it.
Show evidence (1 reference)
PMID:38886398 SUPPORT Human Clinical
"These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty."
Provides a thymic-histological rationale for the pubertal boundary between juvenile and adult-onset myasthenia gravis rather than treating it as a purely administrative cut-point.
📊

Prevalence

3
Worldwide (all myasthenia gravis; context for the adult-onset majority)
Annual Incidence 2.0 per 100,000 1–9 per 100,000
Approximately 20 per million person-years, converted to 2.0 per 100,000. Reported for myasthenia gravis overall rather than for adult-onset disease specifically; adult onset accounts for the large majority of cases.
Show evidence (1 reference)
PMID:40675734 SUPPORT Human Clinical
"Recent high-quality studies have found an annual MG incidence of approximately 20 per million person-years, and a prevalence of approximately 25 per 100,000 population."
Gives the contemporary incidence figure. Marked PARTIAL because the quoted rate is for myasthenia gravis as a whole, not for the adult-onset subtype in isolation.
Denmark, 1970-1999 (population-based, anti-AChR seropositive)
Annual Incidence 0.47–2.08 per 100,000 1–9 per 100,000 LOMG
Late-onset annual incidence rose from 4.7 to 20.8 per million (0.47 to 2.08 per 100,000) over three decades while early-onset incidence stayed flat at 3.5 per million. The range crosses a band boundary — it starts in the 1-9 per 1,000,000 band and ends in the 1-9 per 100,000 band; `prevalence_class` records the band it ended in, and that crossing is itself the finding.
Show evidence (1 reference)
PMID:16186537 SUPPORT Human Clinical
"The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6). The two onset types of MG may thus be distinct disorders."
Directly quantifies the divergent incidence trajectories of the two onset subgroups, which is the epidemiological argument that they are not merely two ends of one homogeneous population.
Global (secular trend)
Unknown Unknown LOMG
Qualitative secular trend rather than a rate; recorded for the direction of change only.
Show evidence (2 references)
PMID:40675734 SUPPORT Human Clinical
"MuSK MG is more common in the Mediterranean area, juvenile MG is most common in China, whereas late onset MG with AChR antibodies is a subtype that has increased in incidence and prevalence globally."
Confirms that the late-onset AChR-antibody subgroup is the one driving the global rise.
PMID:40675734 SUPPORT Human Clinical
"MG prevalence has increased in recent years because of more elderly people in the general population, improved case finding, and improved MG treatment with reduced mortality."
Attributes the rise partly to population ageing and partly to ascertainment and survival — an important caveat against reading the trend as purely biological.
{ }

Source YAML

click to show 
name: Adult-Onset Myasthenia Gravis
creation_date: '2026-08-19T09:00:00Z'
description: >-
  Adult-onset myasthenia gravis is acquired autoimmune myasthenia gravis whose symptoms begin after
  puberty. It shares the postsynaptic neuromuscular-junction effector mechanism of myasthenia gravis
  generally — autoantibody binding, complement-mediated damage to the endplate, and fatigable
  weakness — but is defined by an additional axis that the serotype axis does not capture: age at
  onset. Early-onset disease (EOMG, conventionally onset before 50 years) is female-predominant and
  is driven by a hyperplastic thymus that behaves as a tertiary lymphoid organ, with ectopic
  germinal centres, intrathymic acetylcholine-receptor antigen presentation, and a very strong
  HLA-B*08/DRB1*03 class I-anchored susceptibility signal. Late-onset disease (LOMG, onset at or
  after 50 years, with a very-late-onset tier beyond 65 years) is male-predominant, arises against an
  atrophic involuted thymus, carries striational (anti-titin and anti-ryanodine-receptor)
  autoantibodies, and has an HLA architecture that is weaker and in places directionally opposite to
  EOMG. LOMG incidence has risen substantially in ageing populations while EOMG incidence has stayed
  flat, and the thymectomy evidence base is restricted to the adult non-thymomatous population.
category: Autoimmune
synonyms:
- adult-onset acquired myasthenia
- adult-onset autoimmune myasthenia gravis
parents:
- Myasthenia Gravis
- Neuromuscular Disease
- Autoimmune Disease
disease_term:
  preferred_term: adult-onset myasthenia gravis
  term:
    id: MONDO:0018324
    label: adult-onset myasthenia gravis
notes: >-
  Scope relative to `Myasthenia_Gravis.yaml` (MONDO:0009688): the parent entry stratifies myasthenia
  gravis by **serotype** (AChR / MuSK / seronegative). This entry stratifies the same disease by
  **age at onset**, which MONDO models as an explicit post-composition
  (MONDO:0018324 = myasthenia gravis and has-onset HP:0003581 adult onset) and which the literature
  treats as an independent and equally load-bearing subgrouping. Content here is deliberately
  restricted to what is onset-age-specific — thymic pathology by onset age, onset-stratified HLA and
  non-HLA genetics, the striational antibody profile of late onset, the divergent incidence trends,
  and the age-bounded thymectomy evidence. The shared serotype and effector biology is not
  re-derived; see the parent entry.

  The `has_subtypes` entries (EOMG / LOMG / VLOMG) deliberately carry a `preferred_term` with no
  bound `term:`. `SubtypeDescriptor.term` binds to MONDO or NCIT, and neither ontology has a term
  for early-, late-, or very-late-onset myasthenia gravis — MONDO's only onset-qualified myasthenia
  gravis class is MONDO:0018324 itself, which is this entry. Binding an approximate term here would
  assert an identity that does not exist, so the slot is left unbound rather than filled.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018324
      label: adult-onset myasthenia gravis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:391490
    mapping_justification: Orphanet lists MONDO:0018324 as an exact cross-reference for ORPHA:391490.
    consistency:
    - reference: ORPHA:391490
      consistent: CONSISTENT
      notes: "MONDO:0018324 | Exact"
  - term:
      id: MONDO:0009688
      label: myasthenia gravis
    mapping_predicate: skos:broadMatch
    mapping_source: ORPHA:391490
    mapping_justification: >-
      Orphanet classes ORPHA:391490 as a clinical subtype of a disorder, and MONDO asserts
      MONDO:0018324 is_a MONDO:0009688; the general myasthenia gravis concept is therefore broader
      than this entry. Curated as `skos:broadMatch` so it is not mistaken for a mapping that would
      retire MONDO:0009688 from the curation queue — that concept is curated separately in
      `Myasthenia_Gravis.yaml`.
  icd10cm_mappings:
  - term:
      id: ICD10CM:G70.0
      label: Myasthenia gravis
    mapping_predicate: skos:broadMatch
    mapping_source: ORPHA:391490
    mapping_justification: >-
      Orphanet records ICD-10 G70.0 as a *narrower* cross-reference direction for ORPHA:391490 —
      i.e. the ORPHA subtype is narrower than the ICD code — so from this entry's perspective the
      ICD code is the broader concept.
    consistency:
    - reference: ORPHA:391490
      consistent: CONSISTENT
      notes: "ICD-10:G70.0 | Narrower"
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines adult-onset myasthenia gravis as a rare autoimmune disorder of the
    neuromuscular junction with fatigable muscle weakness, frequent ocular signs and/or generalized
    weakness, and occasional thymoma association.
  evidence:
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma."
    explanation: Orphanet's definition for the adult-onset subtype anchors the scope of this entry.
external_assertions:
- name: Orphanet adult-onset myasthenia gravis record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:391490
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=391490
  description: >
    Orphanet structured record for adult-onset myasthenia gravis, classed as a clinical subtype of
    myasthenia gravis, with curated cross-references to MONDO, ICD-10, ICD-11, and UMLS.
  evidence:
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Adult-onset myasthenia gravis (Clinical subtype, Subtype of disorder)"
    explanation: >-
      Orphanet's own typing of the concept as a clinical subtype is the honest framing for this
      entry's relationship to the parent myasthenia gravis entry.
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C5680024 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:391490 to UMLS C5680024.
has_subtypes:
- name: EOMG
  display_name: Early-Onset MG (onset before ~50 years)
  description: >
    Adult-onset disease beginning before approximately 50 years of age. Female-predominant, strongly
    associated with thymic follicular hyperplasia containing ectopic germinal centres, and carrying
    the strongest HLA signal in myasthenia gravis (HLA-B*08 / DRB1*03).
  subtype_term:
    preferred_term: early-onset myasthenia gravis
  evidence:
  - reference: PMID:40675735
    reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."
    explanation: Defines the early-onset subgroup by its immunogenetic profile, sex skew, and thymic pathology.
- name: LOMG
  display_name: Late-Onset MG (onset at or after ~50 years)
  description: >
    Adult-onset disease beginning at or after approximately 50 years of age. Male-predominant,
    typically arising against an atrophic (age-involuted) thymus, frequently anti-AChR and anti-titin
    positive, and with a genetically distinct susceptibility architecture from EOMG.
  subtype_term:
    preferred_term: late-onset myasthenia gravis
  evidence:
  - reference: PMID:33458590
    reference_title: "Myasthenia gravis: MuSK MG, late-onset MG and ocular MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high."
    explanation: Gives the conventional ≥50-year onset boundary together with the male skew and antibody profile that define the subgroup.
  - reference: PMID:40675735
    reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."
    explanation: Contrasts late-onset thymic and genetic biology with the early-onset subgroup.
- name: VLOMG
  display_name: Very Late-Onset MG (onset after ~65 years)
  description: >
    A further tier within late-onset disease, conventionally onset after about 65 years. Incidence in
    this age band has risen continuously, with a clear male predominance. Presentation is typically
    focal (ocular or bulbar), and diagnosis is described as requiring a high index of suspicion.
  subtype_term:
    preferred_term: very late-onset myasthenia gravis
  evidence:
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We define late-onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance."
    explanation: >-
      Documents the ≥65-year boundary used for the very-late-onset tier — and, by differing from the
      ≥50-year boundary used elsewhere, shows that the cut-point itself is a convention rather than a
      measured discontinuity.
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis."
    explanation: Supports focal presentation and diagnostic delay as characteristic of the oldest-onset group.
prevalence:
- population: Worldwide (all myasthenia gravis; context for the adult-onset majority)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.0
  notes: >-
    Approximately 20 per million person-years, converted to 2.0 per 100,000. Reported for myasthenia
    gravis overall rather than for adult-onset disease specifically; adult onset accounts for the
    large majority of cases.
  evidence:
  - reference: PMID:40675734
    reference_title: "Epidemiology of myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent high-quality studies have found an annual MG incidence of approximately 20 per million person-years, and a prevalence of approximately 25 per 100,000 population."
    explanation: >-
      Gives the contemporary incidence figure. Marked PARTIAL because the quoted rate is for
      myasthenia gravis as a whole, not for the adult-onset subtype in isolation.
- subtype: LOMG
  population: Denmark, 1970-1999 (population-based, anti-AChR seropositive)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 0.47
  rate_high: 2.08
  notes: >-
    Late-onset annual incidence rose from 4.7 to 20.8 per million (0.47 to 2.08 per 100,000) over
    three decades while early-onset incidence stayed flat at 3.5 per million. The range crosses a
    band boundary — it starts in the 1-9 per 1,000,000 band and ends in the 1-9 per 100,000 band;
    `prevalence_class` records the band it ended in, and that crossing is itself the finding.
  evidence:
  - reference: PMID:16186537
    reference_title: "Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6). The two onset types of MG may thus be distinct disorders."
    explanation: >-
      Directly quantifies the divergent incidence trajectories of the two onset subgroups, which is
      the epidemiological argument that they are not merely two ends of one homogeneous population.
- subtype: LOMG
  population: Global (secular trend)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: Qualitative secular trend rather than a rate; recorded for the direction of change only.
  evidence:
  - reference: PMID:40675734
    reference_title: "Epidemiology of myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MuSK MG is more common in the Mediterranean area, juvenile MG is most common in China, whereas late onset MG with AChR antibodies is a subtype that has increased in incidence and prevalence globally."
    explanation: Confirms that the late-onset AChR-antibody subgroup is the one driving the global rise.
  - reference: PMID:40675734
    reference_title: "Epidemiology of myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MG prevalence has increased in recent years because of more elderly people in the general population, improved case finding, and improved MG treatment with reduced mortality."
    explanation: >-
      Attributes the rise partly to population ageing and partly to ascertainment and survival —
      an important caveat against reading the trend as purely biological.
progression:
- phase: Onset
  age_range: After puberty (adult onset)
  notes: >-
    Onset after puberty is the defining feature of this entry. The boundary is not arbitrary: thymic
    follicular hyperplasia, the central early-onset lesion, is markedly more prominent in females
    after puberty than before it.
  evidence:
  - reference: PMID:38886398
    reference_title: "Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty."
    explanation: >-
      Provides a thymic-histological rationale for the pubertal boundary between juvenile and
      adult-onset myasthenia gravis rather than treating it as a purely administrative cut-point.
pathophysiology:
- name: Age-at-Onset Stratification of Myasthenia Gravis
  notes: >-
    Age at onset partitions myasthenia gravis into subgroups that differ in immunological profile,
    autoantibody spectrum, thymic pathology, genetic association, and treatment response. This node
    is the organising claim of the entry: onset age is not a descriptive label attached after the
    fact but an axis along which the upstream immunopathology itself differs.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:40675735
    reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at disease onset significantly influences the clinical course, pathophysiology, and treatment response in Myasthenia Gravis (MG)."
    explanation: States the central claim of this entry directly.
  - reference: PMID:26376969
    reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis."
    explanation: >-
      Establishes that onset age sits alongside serotype as a first-class subgrouping axis in the
      standard classification — the justification for curating it separately from the
      serotype-stratified parent entry.
  downstream:
  - target: Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation
    causal_link_type: DIRECT
    description: Early onset is the branch in which the thymus itself becomes the autoimmunizing organ.
    hypothesis_groups:
    - thymic_autoimmunization_eomg
    evidence:
    - reference: PMID:40675735
      reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."
      explanation: Assigns the thymic-hyperplasia branch specifically to the early-onset subgroup.
  - target: Late-Onset Autoimmunity Against an Involuted Thymus
    causal_link_type: DIRECT
    description: Late onset is the branch in which disease arises without a hyperplastic thymic germinal-centre reaction.
    hypothesis_groups:
    - extrathymic_lomg
    evidence:
    - reference: PMID:40675735
      reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."
      explanation: Assigns the atrophic-thymus branch specifically to the late- and very-late-onset subgroups.
  - target: Onset-Age-Stratified Immunogenetic Susceptibility
    causal_link_type: DIRECT
    description: Both branches carry their own, largely non-overlapping susceptibility architecture.
    evidence:
    - reference: PMID:28495048
      reference_title: "HLA and age of onset in myasthenia gravis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study confirms a different genetic background of MG subgroups regarding age of onset."
      explanation: Supports the edge from onset-age stratification to a differing genetic background.
- name: Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation
  description: >
    In early-onset disease the hyperplastic thymus acquires the full architecture of a tertiary
    lymphoid organ: high endothelial venules and lymphatic neoangiogenesis, chemokine-driven
    recruitment of peripheral B cells and T follicular helper cells, and ectopic germinal centres.
    Because thymic epithelial and myoid cells express the acetylcholine receptor, the autoantigen is
    presented in situ to the recruited cells, so the thymus can both initiate and sustain the
    anti-AChR response rather than merely accompany it.
  biological_scale: TISSUE
  subtypes:
  - EOMG
  cell_types:
  - preferred_term: Thymic Epithelial Cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  - preferred_term: Germinal Centre B Cell
    term:
      id: CL:0000844
      label: germinal center B cell
  - preferred_term: T Follicular Helper Cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  biological_processes:
  - preferred_term: Ectopic Germinal Centre Formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: INCREASED
  - preferred_term: Positive Regulation of Immunoglobulin Production
    term:
      id: GO:0002639
      label: positive regulation of immunoglobulin production
    modifier: INCREASED
  evidence:
  - reference: PMID:29125185
    reference_title: "Thymus involvement in early-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development."
    explanation: Establishes the tertiary-lymphoid-organ conversion of the thymus specifically in early-onset disease.
  - reference: PMID:29125185
    reference_title: "Thymus involvement in early-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells."
    explanation: Supplies the mechanism by which the autoantigen is presented inside the thymus to recruited effector cells.
  - reference: PMID:27273086
    reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies."
    explanation: >-
      Correlates germinal-centre burden with antibody level across 1035 patients, supporting the
      thymus as a source rather than a bystander.
  - reference: PMID:27273086
    reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women."
    explanation: Ties the germinal-centre lesion to the female predominance that characterizes the early-onset subgroup.
  downstream:
  - target: Autoantibody-Mediated Neuromuscular Junction Failure
    causal_link_type: DIRECT
    description: Intrathymic germinal centres supply the anti-AChR antibody that damages the endplate.
    hypothesis_groups:
    - thymic_autoimmunization_eomg
    evidence:
    - reference: PMID:27273086
      reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies."
      explanation: Supports the causal direction from thymic germinal-centre reaction to circulating anti-AChR antibody.
- name: Late-Onset Autoimmunity Against an Involuted Thymus
  description: >
    Late- and very-late-onset disease arises when the thymus is atrophic rather than hyperplastic, so
    the germinal-centre mechanism that explains early-onset disease is largely unavailable. The
    late-onset subgroup is instead characterized by high anti-AChR seropositivity, frequent
    striational (anti-titin, anti-ryanodine-receptor) antibodies, male predominance, and a high
    burden of age-related comorbidity that constrains treatment. The initiating event in a thymus
    that no longer supports germinal centres is not established.
  biological_scale: ORGANISM
  subtypes:
  - LOMG
  - VLOMG
  cell_types:
  - preferred_term: Thymic Epithelial Cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  biological_processes:
  - preferred_term: Age-Related Thymic Involution
    description: >-
      Physiological age-related atrophy of the thymus, in which functional thymic tissue is
      progressively replaced by adipose tissue. Deliberately left unbound: GO has no thymic
      involution term, and involution is not reduced thymus development, so the nearest
      candidate (GO:0048538 thymus development, DECREASED) would misstate the biology.
      Needs an NTR to GO.
  evidence:
  - reference: PMID:40675735
    reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, LOMG and VLOMG are characterized by thymic atrophy, differing genetic associations, and milder long-term disease courses with variable treatment responses."
    explanation: Establishes thymic atrophy, rather than hyperplasia, as the thymic state in late-onset disease.
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"
    explanation: Quantifies the higher anti-AChR seropositivity of the late-onset subgroup within one cohort.
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p = 0.0002)."
    explanation: Quantifies both the more ocular-restricted phenotype and the excess diabetes burden in late-onset disease.
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A higher burden of comorbidities, such as diabetes mellitus, may warrant a modified approach to treatment of myasthenia in LOMG."
    explanation: Supports the claim in the description that comorbidity burden constrains late-onset treatment choice.
  - reference: PMID:31811563
    reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive."
    explanation: Gives the male predominance and the combined anti-AChR / anti-titin serological profile of generalized late-onset disease.
  downstream:
  - target: Striational Autoantibody Response
    causal_link_type: DIRECT
    description: The late-onset immune response characteristically broadens beyond AChR to intracellular muscle antigens.
    hypothesis_groups:
    - extrathymic_lomg
    evidence:
    - reference: PMID:31811563
      reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive."
      explanation: Documents the co-occurrence of the striational anti-titin response with late-onset disease at 61%.
  - target: Autoantibody-Mediated Neuromuscular Junction Failure
    causal_link_type: DIRECT
    description: Late-onset disease converges on the same postsynaptic effector lesion by a different upstream route.
    evidence:
    - reference: PMID:22476514
      reference_title: "Characteristics of late-onset myasthenia gravis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"
      explanation: >-
        Confirms that late-onset patients reach the same anti-AChR effector mechanism, at an even
        higher seropositivity rate than early onset.
- name: Striational Autoantibody Response
  description: >
    The late-onset immune response characteristically broadens beyond the acetylcholine receptor to
    intracellular striational antigens. Anti-titin is the onset-discriminating member of the panel:
    it tracks older onset age and, in late-onset patients, generalized disease, while in
    younger-onset patients it instead flags thymoma. Anti-ryanodine-receptor antibody travels with
    the panel but is *not* itself onset-discriminating — it has been detected in early-onset
    patients and controls as well. All of these target intracellular proteins that circulating IgG
    cannot reach in intact muscle, so they are best read as markers of a broadened autoimmune
    response rather than as established effectors of weakness.
  biological_scale: MOLECULAR
  subtypes:
  - LOMG
  - VLOMG
  evidence:
  - reference: PMID:38505076
    reference_title: "Anti-titin antibodies in a cohort of myasthenia gravis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)."
    explanation: Links anti-titin seropositivity specifically to generalized disease within the late-onset subgroup.
  - reference: PMID:38505076
    reference_title: "Anti-titin antibodies in a cohort of myasthenia gravis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-titin positivity correlated with thymoma in patients with age of onset bellow 50 years (P=0.028)."
    explanation: >-
      Shows the *same* antibody carries a different meaning either side of the 50-year onset
      boundary — thymoma marker in early onset, generalization marker in late onset — which is a
      concrete demonstration that onset age changes interpretation, not just description.
  - reference: PMID:33458590
    reference_title: "Myasthenia gravis: MuSK MG, late-onset MG and ocular MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high."
    explanation: Independent review confirming high anti-titin frequency in the late-onset subgroup.
  - reference: PMID:31811563
    reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of anti-titin antibodies had no significant effect on severity and outcome."
    explanation: >-
      Counterweight to over-reading the striational antibodies: in generalized non-thymomatous
      late-onset disease they did not predict severity or outcome, supporting the marker-not-effector
      framing in the description.
- name: Onset-Age-Stratified Immunogenetic Susceptibility
  description: >
    Early- and late-onset disease have largely non-overlapping genetic architectures. Early onset
    carries an exceptionally strong HLA class I signal that maps to HLA-B*08, plus non-HLA risk at
    TNIP1 and PTPN22. Late onset carries weaker MHC effects — with the strongest associations
    running in the *opposite* direction to early onset — plus its own loci (TNFRSF11A, ZBTB10), while
    the early-onset TNIP1 signal is absent altogether.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:23055271
    reference_title: "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele"
    explanation: Localizes the dominant early-onset MHC signal to a class I allele.
  - reference: PMID:23055271
    reference_title: "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis."
    explanation: Gives the mechanistic reading of the early-onset-specific loci.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG."
    explanation: Demonstrates that the early-onset non-HLA architecture does not transfer to late onset.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG"
    explanation: >-
      The directional reversal of MHC association is the strongest single piece of evidence that the
      two onset subgroups are not one susceptibility population sampled at different ages.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG."
    explanation: The authors' own conclusion that onset-age subgrouping reflects distinct predisposing mechanisms.
  - reference: PMID:28495048
    reference_title: "HLA and age of onset in myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study confirms a different genetic background of MG subgroups regarding age of onset."
    explanation: Independent replication of an onset-age-dependent HLA background in a separate population.
- name: Autoantibody-Mediated Neuromuscular Junction Failure
  description: >
    The shared effector lesion of all myasthenia gravis: autoantibody binding at the postsynaptic
    membrane with complement activation and loss of functional acetylcholine receptor, producing
    fatigable weakness. Included here only as the convergence point of the two onset branches; the
    full effector mechanism is curated in `Myasthenia_Gravis.yaml` and is not re-derived.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Neuromuscular Synaptic Transmission
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
    modifier: DECREASED
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  evidence:
  - reference: PMID:26376969
    reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction."
    explanation: States the shared postsynaptic autoantibody mechanism that both onset branches converge on.
mechanistic_hypotheses:
- hypothesis_group_id: thymic_autoimmunization_eomg
  hypothesis_label: Intrathymic autoimmunization drives early-onset disease
  status: CANONICAL
  description: >
    In early-onset disease the hyperplastic thymus is the site of autoimmunization: it converts to a
    tertiary lymphoid organ, presents acetylcholine receptor locally, and generates the anti-AChR
    response. This model predicts — and is supported by — the benefit of thymectomy in the
    early-onset, non-thymomatous, AChR-positive population.
  applies_to_subtypes:
  - EOMG
  evidence:
  - reference: PMID:27273086
    reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients."
    explanation: Explicitly connects the thymic-autoimmunization model to the therapeutic benefit observed in early-onset patients.
- hypothesis_group_id: extrathymic_lomg
  hypothesis_label: Late-onset disease arises without a thymic germinal-centre reaction
  status: ALTERNATIVE
  description: >
    In late- and very-late-onset disease the thymus is atrophic and the germinal-centre mechanism is
    largely unavailable, so autoimmunization is presumed to occur elsewhere. The genetic architecture
    is distinct from — and in the MHC partly directionally opposite to — early-onset disease, and the
    incidence trajectories of the two subgroups have diverged over decades. What the initiating
    event actually is in the involuted thymus remains unidentified; this is recorded as an open
    knowledge gap rather than asserted.
  applies_to_subtypes:
  - LOMG
  - VLOMG
  evidence:
  - reference: PMID:16186537
    reference_title: "Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two onset types of MG may thus be distinct disorders. The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors."
    explanation: The original epidemiological statement of the two-disorder hypothesis, including its environmental-trigger corollary.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG."
    explanation: Genetic support for distinct predisposing mechanisms in the late-onset subgroup.
discussions:
- discussion_id: onset_dichotomy_vs_continuum
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Are early-onset and late-onset myasthenia gravis mechanistically distinct disorders, or one
    continuous disease whose features shift with age at onset?
  attaches_to:
  - pathophysiology#Age-at-Onset Stratification of Myasthenia Gravis
  rationale: >
    The genetic and epidemiological evidence points to separation: the MHC associations differ in
    magnitude and in direction between the subgroups, the early-onset TNIP1 signal is absent in late
    onset, and late-onset incidence has risen four-fold in a population where early-onset incidence
    did not move at all. The clinical evidence points the other way: cohort comparisons find
    extensively overlapping features and read the difference as a shift in proportions along one
    spectrum rather than a boundary. Note also that the conventional cut-point is itself unstable in
    the literature — 50 years in most genetic and cohort work, 65 years in others — which is hard to
    reconcile with a true biological discontinuity. This entry curates the subgroups because the
    upstream immunopathology and treatment evidence genuinely differ by onset age, without asserting
    that they are separate diseases.
  evidence:
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset."
    explanation: >-
      Direct argument against a two-disorder reading, from a cohort that compared the subgroups
      clinically. Recorded as REFUTE against the strong separation claim.
  - reference: PMID:16186537
    reference_title: "Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two onset types of MG may thus be distinct disorders."
    explanation: The epidemiological argument for separation, stated by the authors themselves.
- discussion_id: lomg_initiating_event
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    If the atrophic late-onset thymus cannot support the germinal-centre reaction that explains
    early-onset autoimmunization, where and how is the anti-AChR response initiated in late-onset
    disease?
  attaches_to:
  - pathophysiology#Late-Onset Autoimmunity Against an Involuted Thymus
  rationale: >
    The thymic model of myasthenia gravis is well evidenced for the hyperplastic, early-onset thymus
    and is the mechanistic basis for thymectomy. No comparably specified site or trigger has been
    established for late-onset disease, which is now the subgroup driving the global rise in
    incidence. The gap matters therapeutically: the thymectomy evidence base does not transfer, and
    the leading published hypothesis — an environmental provocation — has not been resolved to a
    specific exposure.
  proposed_experiments:
  - experiment_id: lomg_bcr_compartment_repertoire
    name: Compartment-resolved B-cell receptor repertoire comparison by onset age
    description: >-
      Compare single-cell B-cell receptor repertoires from thymic, lymph-node, and bone-marrow
      compartments between early- and late-onset AChR-antibody-positive patients, to locate the
      compartment in which late-onset anti-AChR clones are generated and maintained.
    supporting_outcome:
    - >-
        Recovery of clonally expanded, somatically hypermutated anti-AChR lineages from an
        extrathymic compartment in late-onset patients but not early-onset patients would support an
        extrathymic site of autoimmunization in late-onset disease.
    refuting_outcome:
    - >-
        Recovery of the same intrathymic clonal architecture in both onset groups would refute the
        claim that the germinal-centre mechanism is unavailable in the involuted thymus.
  - experiment_id: lomg_thymic_tolerance_seroconversion
    name: Prospective association of thymic self-antigen presentation with late-onset seroconversion
    description: >-
      Test whether age-related loss of thymic self-antigen presentation is quantitatively associated
      with anti-AChR seroconversion in prospectively sampled older adults.
    supporting_outcome:
    - >-
        An inverse association between residual thymic self-antigen presentation and incident
        seroconversion would support failing central tolerance as the late-onset initiating event.
    refuting_outcome:
    - >-
        No association across the observed range would refute a central-tolerance-failure model and
        redirect attention to peripheral or environmental triggers.
  evidence:
  - reference: PMID:16186537
    reference_title: "Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors."
    explanation: >-
      The leading published proposal for the late-onset trigger is explicitly framed as a hypothesis,
      which is what makes this an open gap rather than a settled mechanism.
phenotypes:
- category: Neuromuscular
  name: Fatigable Muscle Weakness
  description: Fluctuating weakness of voluntary muscle that worsens with sustained activity and improves with rest.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness"
    explanation: Orphanet's definition of the adult-onset subtype names fatigable weakness as its defining feature.
- category: Ocular
  name: Ptosis
  description: Drooping of the eyelid, a common presenting sign, and a characteristic focal presentation in the oldest-onset group.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Commonly, patients present with focal (ocular or bulbar) weakness."
    explanation: >-
      Supports ocular presentation in late-onset disease. Marked PARTIAL because the source says
      "ocular" rather than naming ptosis specifically.
- category: Ocular
  name: Diplopia
  description: Double vision from fatigable extraocular muscle weakness.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
  evidence:
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Commonly, patients present with focal (ocular or bulbar) weakness."
    explanation: >-
      Supports ocular presentation. Marked PARTIAL because the source does not name diplopia
      specifically.
- category: Ocular
  name: Ocular-Restricted Disease
  subtype: LOMG
  description: >
    Disease confined to the extraocular muscles, reported roughly twice as often in late-onset as in
    early-onset patients.
  phenotype_term:
    preferred_term: Ocular-restricted disease distribution
  notes: >-
    phenotype_term deliberately left unbound. The concept curated here is a disease
    *distribution* - weakness confined to the extraocular muscles, without generalization -
    not the sign of ophthalmoplegia. HP:0000602 (Ophthalmoplegia) was removed because it
    names the sign and would be satisfied by any generalized patient with eye involvement,
    inverting the meaning of this row. No HP term denotes the restricted distribution
    (HP:0007715 Weak extraocular muscles is likewise a sign); needs an NTR to HPO.
  evidence:
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021)."
    explanation: Quantifies the excess of ocular-restricted disease in the late-onset subgroup.
- category: Bulbar
  name: Dysphagia
  description: Fatigable swallowing difficulty from bulbar muscle involvement.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Commonly, patients present with focal (ocular or bulbar) weakness."
    explanation: >-
      Supports bulbar presentation in late-onset disease. Marked PARTIAL because the source names
      "bulbar" rather than dysphagia specifically.
- category: Bulbar
  name: Dysarthria
  description: Slurred or nasal speech from bulbar muscle fatigue.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Commonly, patients present with focal (ocular or bulbar) weakness."
    explanation: >-
      Supports bulbar presentation. Marked PARTIAL because the source does not name dysarthria
      specifically.
- category: Neuromuscular
  name: Generalized Muscle Weakness
  description: Weakness extending beyond the ocular and bulbar muscles to limb and axial muscle groups.
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  evidence:
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "with frequent ocular signs and/or generalized muscle weakness"
    explanation: Orphanet's definition names generalized weakness as a feature of the adult-onset subtype.
- category: Respiratory
  name: Myasthenic Crisis
  description: >
    Respiratory failure from weakness of the respiratory and bulbar muscles, requiring ventilatory
    support. Reported at similar rates in generalized early- and late-onset disease.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %)."
    explanation: >-
      Establishes crisis risk in both onset subgroups and, notably, shows it does *not* differ by
      onset age — a place where the subgroups converge rather than diverge.
- category: Thymic
  name: Thymic Follicular Hyperplasia
  subtype: EOMG
  description: >
    Lymphofollicular hyperplasia of the thymus with germinal centres, the characteristic thymic
    lesion of early-onset disease and predominantly a finding in women.
  phenotype_term:
    preferred_term: Thymus hyperplasia
    term:
      id: HP:0010516
      label: Thymus hyperplasia
  evidence:
  - reference: PMID:27273086
    reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women."
    explanation: Documents the lesion and its strong female skew in a 1035-patient thymic-pathology series.
  - reference: PMID:40675735
    reference_title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EOMG often presents with distinct immunological and genetic profiles, a predominance of female patients, and a higher incidence of thymic hyperplasia."
    explanation: Assigns the higher thymic-hyperplasia rate specifically to the early-onset subgroup.
- category: Thymic
  name: Thymoma
  description: >
    Thymic epithelial tumour occurring in a minority of adult-onset patients. Not itself
    onset-age-defined, but relevant here because it is the exclusion criterion that defines the
    non-thymomatous populations in which the onset-stratified thymectomy evidence was generated.
  phenotype_term:
    preferred_term: Thymoma
    term:
      id: HP:0100522
      label: Thymoma
  evidence:
  - reference: ORPHA:391490
    reference_title: "Adult-onset myasthenia gravis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "generalized muscle weakness, and occasionally associated with thymoma."
    explanation: Orphanet's definition of the adult-onset subtype records occasional thymoma association.
biochemical:
- name: Anti-Acetylcholine Receptor Antibody
  context: >-
    Circulating IgG against the muscle nicotinic acetylcholine receptor. Present in the large
    majority of adult-onset patients and reported at a higher rate in late- than early-onset disease.
  biomarker_term:
    preferred_term: Anti-acetylcholine receptor antibody positivity
    term:
      id: HP:6001064
      label: Anti-acetylcholine receptor antibody positivity
  evidence:
  - reference: PMID:22476514
    reference_title: "Characteristics of late-onset myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003)"
    explanation: Gives the onset-stratified seropositivity rates in a single cohort tested identically.
- name: Anti-Titin Antibody
  subtype: LOMG
  context: >-
    Antibody against the intracellular sarcomeric protein titin. Strongly associated with older onset
    age; in late-onset patients it flags generalized disease, whereas in early-onset patients it
    flags thymoma.
  biomarker_term:
    preferred_term: Anti-titin antibody positivity
    term:
      id: HP:5000038
      label: Anti-titin antibody positivity
  evidence:
  - reference: PMID:31811563
    reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive."
    explanation: Quantifies anti-titin seropositivity at 61% in generalized non-thymomatous late-onset disease.
  - reference: PMID:38505076
    reference_title: "Anti-titin antibodies in a cohort of myasthenia gravis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)."
    explanation: Establishes the late-onset-specific clinical correlate of anti-titin positivity.
- name: Anti-Ryanodine Receptor Antibody
  subtype: LOMG
  context: >-
    Striational antibody against the skeletal-muscle ryanodine receptor, part of the broadened
    autoantibody repertoire reported in older-onset and thymoma-associated disease.
  biomarker_term:
    preferred_term: Anti-ryanodine receptor antibody
    term:
      id: HP:5000047
      label: Anti-ryanodine receptor antibody
  notes: >-
    No onset-stratified frequency is asserted here: the late-onset cohorts cited in this entry
    quantified anti-titin but not anti-ryanodine-receptor seropositivity, so a frequency would be
    unsupported.
  evidence:
  - reference: PMID:30918333
    reference_title: "Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies."
    explanation: Places anti-ryanodine-receptor antibody within the striational panel of late-onset and thymoma-associated disease.
  - reference: PMID:30918333
    reference_title: "Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies."
    explanation: >-
      Refutes any claim that anti-ryanodine-receptor antibody is itself onset-discriminating: unlike
      anti-titin and anti-Kv1.4, it was also found in early-onset patients and controls. Recorded so
      the striational panel is not read as uniformly late-onset-specific.
genetic:
- name: HLA-B*08
  subtype: EOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-B
    term:
      id: hgnc:4932
      label: HLA-B
  features: >-
    The dominant susceptibility signal in early-onset myasthenia gravis, mapping by conditional
    analysis to the HLA class I allele HLA-B*08 with an odds ratio of 6.41. The class I localization
    is what implicates CD8+ T cells in disease initiation.
  evidence:
  - reference: PMID:23055271
    reference_title: "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed the strongest association in the HLA class I region at rs7750641"
    explanation: Locates the strongest early-onset genome-wide signal in the HLA class I region.
  - reference: PMID:23055271
    reference_title: "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41)."
    explanation: Resolves the signal to HLA-B*08 specifically and gives the effect size quoted in the description.
- name: HLA-DRB1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  features: >-
    Class II susceptibility that differs by onset age: HLA-DRB1*03 is over-represented in myasthenia
    gravis overall and more strongly still in the early-onset subgroup, while a different allele is
    enriched in late-onset patients.
  evidence:
  - reference: PMID:28495048
    reference_title: "HLA and age of onset in myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA-DRB1*03 allele was overrepresented in the global MG. When the early-onset subgroup was considered, this association became even stronger."
    explanation: Shows the class II risk allele concentrating in the early-onset subgroup.
  - reference: PMID:28495048
    reference_title: "HLA and age of onset in myasthenia gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding the late-onset subgroup, the frequency of HLA-DRB1*01 allele was higher than in the CP."
    explanation: Shows a different class II allele associating with the late-onset subgroup in the same cohort.
- name: HLA-DQA1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  features: >-
    The class II allele that carries this entry's central immunogenetic claim: the direction of
    HLA association reverses across the age-at-onset axis. DQA1*05:01 is a risk allele in
    early-onset disease (OR 2.82) and a protective allele in late-onset disease (OR 0.54) in the
    same comparison. Conditional analysis identifies DQA1 as the class II peak in late-onset
    disease, so the reversal sits at the locus that dominates the class II signal rather than at
    a bystander allele. This is the genetic evidence that the two onset groups are not one
    disease sampled at different ages.
  evidence:
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45)."
    explanation: >-
      States the onset-direction reversal directly, with both effect sizes: DQA1*05:01 is
      protective in late-onset and predisposing in early-onset disease.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs."
    explanation: >-
      Establishes by conditional analysis that DQA1 accounts for the class II peak in late-onset
      disease, so the reversed allele is the locus driving the class II signal.
- name: TNIP1
  subtype: EOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TNIP1
    term:
      id: hgnc:16903
      label: TNIP1
  features: >-
    A coding variant at position 151 in TNIP1 confers early-onset risk exceeding that of PTPN22,
    implicating ubiquitin-dependent NF-kB regulation. The signal is specific to early onset — it is
    absent in late-onset cohorts.
  evidence:
  - reference: PMID:23055271
    reference_title: "Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling."
    explanation: Establishes the TNIP1 association and its mechanistic reading in early-onset disease.
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG."
    explanation: Establishes that the TNIP1 signal is early-onset-specific and does not extend to late onset.
- name: PTPN22
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: PTPN22
    term:
      id: hgnc:9652
      label: PTPN22
  features: >-
    The R620W autoimmunity variant contributes risk in early-onset disease and shows only suggestive
    significance in late-onset cohorts — one of the few loci shared, at least partly, across the
    onset boundary.
  evidence:
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases."
    explanation: >-
      Records the shared PTPN22 signal. Marked PARTIAL because in the late-onset study it reached
      only suggestive, not genome-wide, significance.
- name: TNFRSF11A
  subtype: LOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TNFRSF11A
    term:
      id: hgnc:11908
      label: TNFRSF11A
  features: A late-onset susceptibility locus confirmed by genome-wide association study.
  evidence:
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42)"
    explanation: Confirms the TNFRSF11A association in a dedicated late-onset cohort.
- name: ZBTB10
  subtype: LOMG
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: ZBTB10
    term:
      id: hgnc:30953
      label: ZBTB10
  features: A novel late-onset susceptibility gene reaching genome-wide significance.
  evidence:
  - reference: PMID:26562150
    reference_title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53)"
    explanation: Reports ZBTB10 as a genome-wide-significant late-onset locus.
treatments:
- name: Thymectomy
  description: >
    Surgical removal of the thymus. The randomized evidence base is explicitly adult and
    age-bounded — MGTX enrolled patients aged 18 to 65 with generalized non-thymomatous
    AChR-antibody-positive disease — so it speaks to the early-onset end of the adult-onset spectrum.
    Whether the benefit extends to late-onset disease is not established by randomized data.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: thymectomy
    term:
      id: NCIT:C29894
      label: Thymectomy
  target_mechanisms:
  - target: Thymic Follicular Hyperplasia and Ectopic Germinal Centre Formation
    treatment_effect: INHIBITS
    description: Removes the hyperplastic thymus in which the early-onset anti-AChR response is generated and sustained.
    evidence:
    - reference: PMID:27273086
      reference_title: "Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients."
      explanation: Links the surgical target (the hyperplastic thymus) to the observed early-onset benefit.
  evidence:
  - reference: PMID:27509100
    reference_title: "Randomized Trial of Thymectomy in Myasthenia Gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included"
    explanation: >-
      Defines the age window of the only randomized thymectomy trial — the reason this entry treats
      the thymectomy evidence as onset-age-bounded rather than general to myasthenia gravis.
  - reference: PMID:27509100
    reference_title: "Randomized Trial of Thymectomy in Myasthenia Gravis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: Demonstrates benefit within that adult, non-thymomatous population.
  - reference: PMID:40022458
    reference_title: "Can Non-Thymomatous Late-Onset Myasthenia Gravis Benefit From Thymectomy? A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymectomy is beneficial for treating early-onset acetylcholine receptor antibody-positive myasthenia gravis (MG); however, its effects on late-onset MG (LOMG) remain less well understood."
    explanation: >-
      States the asymmetry directly: established for early onset, unresolved for late onset. Marked
      PARTIAL because it qualifies rather than supports a general thymectomy recommendation.
  - reference: PMID:40022458
    reference_title: "Can Non-Thymomatous Late-Onset Myasthenia Gravis Benefit From Thymectomy? A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymectomy may be a potentially effective treatment for LOMG, particularly in patients who undergo the procedure soon after diagnosis. A randomized controlled study for LOMG patients is needed."
    explanation: >-
      The meta-analysis' own hedged conclusion, including its explicit statement that randomized
      evidence for late onset does not yet exist.
  - reference: PMID:23893883
    reference_title: "Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most controversial issue in treatment is thymectomy, because not enough data are available."
    explanation: Independent statement that thymectomy remains the unsettled question in late-onset management.
- name: Corticosteroid and Azathioprine Immunosuppression
  description: >
    Combination corticosteroid plus azathioprine immunosuppression, reported to improve outcome in
    generalized non-thymomatous late-onset disease — the subgroup in which the thymectomy evidence is
    weakest and in which comorbidity constrains treatment choice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  target_mechanisms:
  - target: Autoantibody-Mediated Neuromuscular Junction Failure
    treatment_effect: INHIBITS
    description: Broad immunosuppression reduces the autoantibody response driving endplate damage.
    evidence:
    - reference: PMID:31811563
      reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Use of prednisone + azathioprine had significantly positive effect on outcome."
      explanation: Outcome evidence that immunosuppression modifies the disease in the late-onset subgroup.
  evidence:
  - reference: PMID:31811563
    reference_title: "Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Use of prednisone + azathioprine had significantly positive effect on outcome."
    explanation: Direct outcome evidence for this combination specifically within generalized non-thymomatous late-onset disease.
  - reference: PMID:26376969
    reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments."
    explanation: Places corticosteroids and azathioprine as first-line immunosuppression in the subgroup-based treatment framework.
- name: Pyridostigmine
  description: >
    Acetylcholinesterase inhibition as symptomatic therapy, the preferred first symptomatic treatment
    across myasthenia gravis subgroups including adult-onset disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Autoantibody-Mediated Neuromuscular Junction Failure
    treatment_effect: INHIBITS
    description: >-
      Prolongs acetylcholine availability at the endplate, partially compensating for the reduced
      receptor number without modifying the autoimmune process.
    evidence:
    - reference: PMID:26376969
      reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pyridostigmine is the preferred symptomatic treatment"
      explanation: >-
        Supports the symptomatic role. Marked PARTIAL because the source establishes preference,
        not the endplate-level mechanism asserted in the description.
  evidence:
  - reference: PMID:26376969
    reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyridostigmine is the preferred symptomatic treatment"
    explanation: Establishes pyridostigmine as the preferred symptomatic therapy in the subgroup-based framework.
  - reference: PMID:26376969
    reference_title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis."
    explanation: Supports the entry's premise that treatment is tailored by subgroup rather than uniform.
references:
- reference: PMID:26376969
  title: "Myasthenia gravis: subgroup classification and therapeutic strategies."
- reference: PMID:40675735
  title: "Special populations in myasthenia gravis: Early, late, and very late-onset MG."
- reference: PMID:26562150
  title: "Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations."
- reference: PMID:23055271
  title: "Risk for myasthenia gravis maps to a (151) Pro-Ala change in TNIP1 and to human leukocyte antigen-B*08."
- reference: ORPHA:391490
  title: "Adult-onset myasthenia gravis"
📚

References & Deep Research

References

5
PMID:26376969
Myasthenia gravis: subgroup classification and therapeutic strategies.
No top-level findings curated for this source.
PMID:40675735
Special populations in myasthenia gravis: Early, late, and very late-onset MG.
No top-level findings curated for this source.
PMID:26562150
Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.
No top-level findings curated for this source.
PMID:23055271
Risk for myasthenia gravis maps to a (151) Pro-Ala change in TNIP1 and to human leukocyte antigen-B*08.
No top-level findings curated for this source.
ORPHA:391490
Adult-onset myasthenia gravis
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Adult-Onset Myasthenia Gravis: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 53 citations 2026-08-19T09:20:52.693615

Adult-Onset Myasthenia Gravis: Comprehensive Disease-Characteristics Report

Scope. This report concerns acquired adult-onset autoimmune myasthenia gravis (MG), not congenital myasthenic syndromes (CMS), Lambert–Eaton myasthenic syndrome, or transient neonatal MG. Evidence is labeled as human clinical, human genetic/computational, model-organism, or in vitro. Unless otherwise stated, facts are aggregated disease-level knowledge rather than observations from an individual electronic health record.

Executive summary

Adult-onset MG is a chronic, heterogeneous, T-cell-dependent, autoantibody-mediated disorder of the postsynaptic neuromuscular junction (NMJ). Its defining manifestation is fluctuating, fatigable weakness affecting ocular, bulbar, axial, limb, and sometimes respiratory muscles. Approximately 80% of generalized cases have acetylcholine-receptor antibodies (AChR-Ab); MuSK antibodies account for about 5%–8% of AChR-negative cases, while LRP4-associated and seronegative disease are less common. The 2024 JCI review accurately summarizes the spectrum as weakness “ranging from limited ocular muscle involvement to life-threatening respiratory failure.” Published June 2024; DOI/URL. (kaminski2024myastheniagravisthe pages 1-2)

The disease is not ordinarily monogenic. HLA and immune-regulatory loci confer polygenic susceptibility, whereas pathogenic germline variants in CHRNE, RAPSN, DOK7, MUSK, LRP4, AGRN, and related genes cause CMS and should not be misclassified as causal variants for autoimmune adult-onset MG. Treatment has shifted from nonspecific immunosuppression toward antibody-endotype-directed complement C5 inhibition, FcRn blockade, and B-cell depletion. Nevertheless, conventional therapy, thymectomy in selected AChR-positive disease, and IVIG/plasma exchange in crisis remain central. (OpenTargets Search: myasthenia gravis, kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)

1. Disease information

Definition and classification

MG is an acquired autoimmune disorder in which antibodies against postsynaptic proteins reduce the safety factor for neuromuscular transmission. Clinical classification integrates:

  • distribution: ocular versus generalized;
  • onset: early-onset versus late-onset, commonly separated at 50 years, although studies use 40–60-year cutoffs;
  • antibody: AChR, MuSK, LRP4, or seronegative;
  • thymic pathology: thymoma-associated, hyperplastic, or non-thymomatous;
  • special trigger: immune-checkpoint-inhibitor-associated MG. (antonioni2023theincidenceof pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

Identifiers and synonyms

  • MONDO: adult-onset myasthenia gravis MONDO:0018324; parent MG MONDO:0009688.
  • ICD-10-CM: G70.0, myasthenia gravis without acute exacerbation; more specific national extensions distinguish exacerbation/crisis.
  • ICD-11: classified under myasthenia gravis within disorders of the neuromuscular junction.
  • MeSH: Myasthenia Gravis.
  • Orphanet: myasthenia gravis is represented as a rare autoimmune NMJ disease; national subtype coding varies.
  • Common labels: autoimmune MG, acquired MG, adult MG, adult-onset MG, ocular MG, generalized MG (gMG), late-onset MG (LOMG), AChR-MG, MuSK-MG, LRP4-MG, and seronegative MG. “Late-onset” is a subtype rather than a synonym for every adult case.

The reusable ontology mapping is summarized below.

Domain Core entity/finding Suggested ontology identifiers/terms Evidence/interpretive note
Disease identity Adult-onset autoimmune myasthenia gravis MONDO: MONDO_0018324; parent disease MONDO_0009688 myasthenia gravis; ICD-10: G70.0 Adult-onset MG is an antibody-mediated autoimmune neuromuscular junction disease; age-, antibody-, thymus-, and trigger-based subgroups are clinically meaningful (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)
Classification Autoimmune, acquired, postsynaptic neuromuscular junction disorder MeSH: Myasthenia Gravis; category: autoimmune disease; not congenital myasthenic syndrome Guideline and review distinguish autoimmune MG from congenital myasthenic syndromes; routine knowledge base entry should treat adult-onset MG as acquired disease-level knowledge, not single-patient EHR-derived only (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)
Synonyms Adult-onset MG; late-onset MG subset when onset ≥50 years; generalized MG / ocular MG as phenotypic forms Labels only: adult-onset myasthenia gravis; autoimmune myasthenia gravis Early- vs late-onset and ocular vs generalized are clinically useful sub-stratifications rather than strict synonyms (kaminski2024myastheniagravisthe pages 2-4, antonioni2023theincidenceof pages 1-2)
Core autoantibody endotypes AChR-MG, MuSK-MG, LRP4-MG, seronegative MG AChR antibody positive; MuSK antibody positive; LRP4 antibody positive; seronegative MG About 80% of generalized MG and ~50% of ocular MG have AChR antibodies; MuSK antibodies occur in 5%–8% of AChR-negative patients; LRP4 is less common (kaminski2024myastheniagravisthe pages 1-2, gu2024efficacyandsafety pages 1-2)
Phenotype Fluctuating fatigable weakness HPO: Muscle weakness; Fatigability Hallmark symptom complex used diagnostically and in severity scoring (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 3-4)
Phenotype Ptosis HPO: Ptosis Common ocular presentation; ocular MG defined by ptosis/diplopia-limited disease (kaminski2024myastheniagravisthe pages 1-2, antonioni2023theincidenceof pages 1-2)
Phenotype Diplopia HPO: Diplopia Core ocular manifestation and frequent presenting feature (kaminski2024myastheniagravisthe pages 1-2)
Phenotype Bulbar weakness/dysphagia/dysarthria HPO: Dysphagia; Dysarthria; Bulbar palsy Especially prominent in MuSK-MG and severe generalized disease (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 1-2)
Phenotype Respiratory insufficiency / myasthenic crisis HPO: Respiratory insufficiency; Acute respiratory failure Life-threatening generalized phenotype; crises incorporated into active/refractory disease definitions (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 3-4)
Phenotype Generalized limb/axial weakness HPO: Proximal muscle weakness; Generalized weakness Generalized MG may involve ocular, bulbar, axial, limb, and respiratory muscles (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 2-3)
Burden/QoL Persistent fatigue and reduced quality of life MG-ADL; QMG; MG-QoL15r; EQ-5D-5L Fatigue can persist even in pharmacologic remission and is associated with lower QoL/depressive symptoms (wiendl2023guidelineforthe pages 17-19, wiendl2023guidelineforthe pages 2-3)
Anatomy Primary anatomical site: neuromuscular junction UBERON: neuromuscular junction; synapse; skeletal muscle Disease mechanism centers on the postsynaptic muscle membrane of the NMJ (kaminski2024myastheniagravisthe pages 1-2, kaminski2024myastheniagravisthe pages 2-4)
Anatomy Postsynaptic membrane / motor end plate UBERON labels: motor end plate; postsynaptic membrane AChR loss, fold simplification, and MAC injury are localized here (kaminski2024myastheniagravisthe pages 2-4)
Anatomy Thymus involvement in major subgroups UBERON: thymus Thymic hyperplasia and thymoma are relevant in AChR-MG; MuSK-MG generally lacks prominent thymic involvement; all patients should be imaged for thymoma (wiendl2023guidelineforthe pages 2-3, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Cell types Autoreactive B cells / plasmablasts / plasma cells CL: B cell; plasmablast; plasma cell B-cell activation and autoantibody production are central upstream mechanisms; rituximab responsiveness supports B-cell contribution (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 10-11)
Cell types CD4+ T cells / T follicular helper-like support CL: T cell; CD4-positive, alpha-beta T cell MG is T-cell-dependent and antibody-mediated; tolerance failure and T-cell help sustain pathogenic antibodies (kaminski2024myastheniagravisthe pages 1-2)
Cell types Thymic epithelial cells CL label: thymic epithelial cell Aberrant thymic biology contributes particularly to AChR-MG and thymoma-associated MG (kaminski2024myastheniagravisthe pages 10-11, seldin2015genomewideassociationstudy pages 1-2)
Mechanism Complement-mediated postsynaptic injury in AChR-MG GO: complement activation; membrane attack complex assembly AChR IgG1/IgG3 antibodies activate complement, causing MAC-mediated injury and fold loss; rationale for C5 inhibitors (kaminski2024myastheniagravisthe pages 2-4, wiendl2023guidelineforthe pages 2-3)
Mechanism Antigenic modulation/internalization of AChR GO: receptor-mediated endocytosis; acetylcholine receptor clustering Cross-linking promotes AChR endocytosis/degradation, reducing receptor density (kaminski2024myastheniagravisthe pages 2-4)
Mechanism Functional block of ACh binding GO label: chemical synaptic transmission; acetylcholine receptor activity Some antibodies directly block AChR function at the binding site (kaminski2024myastheniagravisthe pages 2-4)
Mechanism MuSK-LRP4 signaling disruption GO labels: receptor signaling pathway; neuromuscular junction development; acetylcholine receptor clustering MuSK IgG4 antibodies interfere with LRP4-MuSK interaction and impair AChR clustering rather than complement fixation (vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Mechanism FcRn-mediated IgG recycling sustains pathogenic antibodies Target: FCGRT; GO label: IgG receptor activity / immunoglobulin recycling FcRn antagonists reduce circulating IgG including pathogenic autoantibodies (wiendl2023guidelineforthe pages 2-3, OpenTargets Search: myasthenia gravis)
Mechanism Impaired neuromuscular transmission GO: synaptic transmission, cholinergic; muscle contraction Final common downstream pathway explaining fatigable weakness and decremental physiology (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)
Genetics: susceptibility, not monogenic cause HLA region risk differs by onset subgroup HLA-DQA1; HLA-DRB1; HLA-B; HLA-A HLA is the dominant susceptibility region; onset-specific architecture differs between early- and late-onset disease (topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause TNFRSF11A risk locus HGNC: TNFRSF11A Replicated MG susceptibility locus; not a monogenic cause of acquired adult-onset MG (topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause PTPN22 risk variant (adult-onset association evidence) HGNC: PTPN22 Open Targets associates PTPN22 with adult-onset MG; LOMG GWAS found suggestive rs2476601/R620W association (OpenTargets Search: myasthenia gravis, seldin2015genomewideassociationstudy pages 1-2)
Genetics: susceptibility, not monogenic cause CTLA4, TNIP1, CHRNA1, AGRN HGNC: CTLA4; TNIP1; CHRNA1; AGRN These genes shape susceptibility architecture/endotypes; AGRN is biologically notable because it encodes an NMJ organizer, but this is still susceptibility rather than direct Mendelian causation for adult autoimmune MG (topaloudi2022myastheniagravisgenomewide pages 4-8, topaloudi2022myastheniagravisgenomewide pages 8-12)
Genetics: causal distinction Adult-onset autoimmune MG is generally not caused by germline pathogenic variants in AChR-clustering genes Distinguish from congenital myasthenic syndrome genes: CHRNE, RAPSN, DOK7, MUSK, LRP4, AGRN, COLQ, CHAT These genes are causal in congenital myasthenic syndromes, not typical adult-onset autoimmune MG; important differential annotation in knowledge bases (OpenTargets Search: myasthenia gravis, wiendl2023guidelineforthe pages 2-3)
Environment / triggers Infection, especially SARS-CoV-2, may trigger onset/exacerbation in some cases Labels only: viral infection; SARS-CoV-2 infection Epidemiologic and case-based evidence suggests possible triggering, but causality remains uncertain (antonioni2023theincidenceof pages 1-2)
Environment / triggers Immune checkpoint inhibitor-induced MG Label: checkpoint inhibitor-induced myasthenia gravis Recognized distinct severe-onset subgroup in modern oncology practice (kaminski2024myastheniagravisthe pages 1-2)
Environment / triggers Medication-related worsening Labels only: magnesium; selected antibiotics; immune therapies Guideline/trial eligibility language warns that concurrent medications can worsen weakness; some therapies can induce or unmask MG (NCT06298552 chunk 1, huang2023myastheniagravisnovel pages 1-3)
Diagnostics Diagnostic framework History of fluctuating fatigable weakness + autoantibodies and/or electrophysiology and/or pharmacologic testing Guideline-based confirmation pathway; thymic CT/MRI recommended for all patients to evaluate thymoma (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)
Diagnostics Electrodiagnostic confirmation in seronegative disease Repetitive nerve stimulation; single-fiber EMG In patients without positive serology, repetitive stimulation and single-fiber testing confirm diagnosis in ~90% (kaminski2024myastheniagravisthe pages 1-2)
Biomarkers Serologic biomarkers AChR antibody; MuSK antibody; LRP4 antibody; total IgG Core diagnostic and treatment-stratifying biomarkers; total IgG often tracked in FcRn-therapy trials (kaminski2024myastheniagravisthe pages 1-2, NCT06298552 chunk 1)
Omics Predictive metabolomic signature for steroid response Histidine; free fatty acid (13:0); γ-cholestenol; guanosine Discovery study from MGTX biospecimens found an AUC of 0.90 for a responder panel; promising but not routine clinical practice yet (sikorski2023serummetabolomicsof pages 1-2)
Standard symptomatic treatment Pyridostigmine (acetylcholinesterase inhibitor) NCIT label: Pyridostigmine Bromide; target/class: ACHE inhibitor First-line symptomatic treatment for most MG; may be less useful or problematic in MuSK-MG (wiendl2023guidelineforthe pages 3-4, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Standard immunotherapy Corticosteroids NCIT label: Prednisone / glucocorticoid therapy Foundational disease-modifying therapy for mild/moderate to active disease (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 9-10)
Steroid-sparing immunotherapy Azathioprine, MMF, tacrolimus, cyclosporine, methotrexate NCIT labels; classes: antimetabolite, calcineurin inhibitor, antimetabolite antifolate Used as conventional long-term immunotherapies; azathioprine is the most established standard steroid-sparing agent in guidelines (wiendl2023guidelineforthe pages 9-10)
Rescue / crisis therapy IVIG, plasmapheresis, immunoadsorption NCIT labels: Immune Globulin; Plasma Exchange Recommended for impending/manifest myasthenic crisis and severe exacerbation (wiendl2023guidelineforthe pages 3-4)
Surgery Thymectomy for AChR-positive generalized MG and thymoma-associated MG NCIT label: Thymectomy MGTX showed better QMG, lower prednisone exposure, less azathioprine use, and fewer hospitalizations versus prednisone alone in nonthymomatous AChR-positive generalized MG (wolfe2016randomizedtrialof pages 1-3, wiendl2023guidelineforthe pages 2-3)
Targeted biologic Eculizumab / ravulizumab / zilucoplan Target: C5; class: complement inhibitor Best mechanistic fit for AChR-positive complement-mediated MG; guideline recommends in highly active AChR-positive generalized MG (wiendl2023guidelineforthe pages 2-3, zhong2024initiationresponsemaximized pages 1-2)
Targeted biologic Efgartigimod / rozanolixizumab Target: FCGRT/FcRn; class: FcRn modulator/antagonist FcRn blockade lowers pathogenic IgG broadly; major 2023-2024 therapeutic advance with strong trial activity and approvals (wiendl2023guidelineforthe pages 2-3, habib2024efficacyandsafety pages 1-2, NCT06298552 chunk 1)
Targeted biologic Rituximab Target: CD20; class: B-cell depletion therapy Particularly effective in MuSK-MG and considered in seronegative/LRP4-positive/highly active disease (wiendl2023guidelineforthe pages 3-4, vakrakou2023immunotherapiesinmuskpositive pages 1-2)
Recent trial signal Rozanolixizumab in MuSK-positive generalized MG FcRn inhibitor; MuSK-specific subgroup efficacy In MycarinG MuSK subgroup, MG-ADL improved versus placebo without serious TEAEs or deaths in the subgroup analysis (habib2024efficacyandsafety pages 1-2)
Active clinical development Inebilizumab Target: CD19; class: B-cell depletion therapy Phase 3 MINT includes AChR- and MuSK-antibody-positive adults; reflects continued B-cell-targeted development (NCT04524273 chunk 1)
Active clinical development KYV-101 / mivocabtagene autoleucel Target/class: anti-CD19 CAR-T cell therapy Phase 2/3 trial in generalized MG after failure of multiple immunosuppressive/immunomodulatory therapies (NCT06193889 chunk 1)
Active clinical development NMD670 Class: skeletal muscle ClC-1 chloride channel inhibitor / neuromuscular function enhancer Phase 2b symptom-focused therapy in AChR/MuSK-positive MG (NCT06414954 chunk 1)
Prevention / care considerations Vaccination review, avoidance of precipitants, medication reconciliation Labels only: vaccination assessment; trigger avoidance Guideline recommends checking vaccination history before prolonged immunotherapy; tertiary prevention focuses on avoiding crises and treatment complications (wiendl2023guidelineforthe pages 9-10)

Table: This table summarizes knowledge-base-ready entities for adult-onset autoimmune myasthenia gravis, including disease identifiers, phenotypes, anatomy, mechanisms, susceptibility genes versus non-causal CMS genes, and treatment targets/classes. It is designed to support ontology mapping and evidence-linked curation.

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

The proximal cause is loss of immune tolerance followed by production of pathogenic antibodies against NMJ proteins. AChR antibodies are usually complement-fixing IgG1/IgG3; MuSK antibodies are predominantly IgG4 and disrupt protein–protein signaling rather than fixing complement. Thymic germinal-center-like reactions and abnormal thymic epithelial biology are important in many AChR-positive cases. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, kaminski2024myastheniagravisthe pages 2-4, wiendl2023guidelineforthe pages 2-3)

Genetic susceptibility

Human genetic evidence. A 2022 GWAS meta-analysis of 1,401 cases and 3,508 controls confirmed TNFRSF11A rs4369774 (OR 1.40, p=1.09×10⁻¹³), identified HLA-DQA1 rs34481484 (OR 2.11, p=3.72×10⁻⁹), and implicated CTLA4, AGRN, and ISG15. Estimated SNP heritability was 0.37 overall, 0.64 in early-onset and 0.53 in late-onset disease, supporting substantial but non-Mendelian inherited susceptibility. Published August 2022; DOI/URL. (topaloudi2022myastheniagravisgenomewide pages 8-12)

A dedicated LOMG GWAS of 532 AChR-positive cases and 2,128 controls found TNFRSF11A rs4574025 (OR 1.42, p=3.9×10⁻⁷), protective ZBTB10 rs6998967 (OR 0.53, p=8.9×10⁻¹⁰), and suggestive PTPN22 R620W/rs2476601 association (OR 1.62, p=6.5×10⁻⁶). HLA-DQA1*05:01 showed opposite effects in LOMG (OR 0.54) and early-onset MG (OR 2.82), demonstrating that onset-defined subgroups have different immunogenetic architectures. Published November 10, 2015; DOI/URL. (seldin2015genomewideassociationstudy pages 1-2)

Interpretation: these are susceptibility alleles, not clinically deterministic pathogenic variants. Penetrance, carrier frequency, anticipation, germline mosaicism, consanguinity, and Mendelian recurrence-risk concepts are therefore not applicable in the way they are for CMS. Open Targets specifically links PTPN22 to adult-onset MG and identifies therapeutically validated targets including C5, FCGRT, and ACHE; target association should not be equated with germline causation. (OpenTargets Search: myasthenia gravis)

Non-genetic risk and trigger factors

  • Age and sex: early adult AChR-MG has a female predominance of about 3:1 and peaks in the third decade; late-onset disease peaks around the sixth decade and has a male predominance (women:men about 2:3). MuSK-MG also has a female bias and often peaks around the fourth decade. (kaminski2024myastheniagravisthe pages 2-4)
  • Thymoma: a causal immune-tolerance context in a minority of generalized AChR-MG; neoplastic thymic epithelial cells may inadequately express HLA class II and AIRE-dependent self-antigens. Approximately 10% of generalized AChR-positive MG had thymoma in older European series, while one recent Ferrara cohort reported 17%. (antonioni2023theincidenceof pages 1-2, seldin2015genomewideassociationstudy pages 1-2)
  • Infection: respiratory and systemic infections commonly precipitate exacerbation or crisis. SARS-CoV-2-associated onset has been reported, but a population study concluded that causal evidence remains inconclusive. (antonioni2023theincidenceof pages 1-2)
  • Iatrogenic triggers: immune-checkpoint inhibitors can induce rapidly severe MG, sometimes with myositis/myocarditis overlap. Magnesium, aminoglycosides, fluoroquinolones, macrolides, neuromuscular blockers, and selected antiarrhythmics or beta-blockers may worsen transmission; associations vary in strength and do not imply that every exposed patient will deteriorate. (kaminski2024myastheniagravisthe pages 2-4)
  • Pregnancy/postpartum: disease activity may improve, worsen, or remain stable during pregnancy; postpartum exacerbation is recognized. Maternal IgG may cause transient neonatal MG, but this is passive antibody transfer, not inheritance.

Protective factors

No validated genetic protective variant or diet prevents MG. The ZBTB10 signal above is statistically protective but is not an actionable intervention. Smoking, alcohol, exercise, specific diets, or supplements have no established primary-preventive effect. Vaccination, infection control, sleep, graded exercise, and medication review are best viewed as tertiary prevention of exacerbation and treatment complications—not prevention of autoimmune onset. (seldin2015genomewideassociationstudy pages 1-2, wiendl2023guidelineforthe pages 17-19)

Gene–environment interaction

The prevailing model is polygenic immune susceptibility plus a context that disrupts tolerance—thymic pathology, infection, age-related immune remodeling, or checkpoint blockade—followed by autoreactive T/B-cell expansion. Direct, replicated locus-by-exposure interaction estimates remain sparse; most claimed environmental associations are observational or case-based rather than proven G×E effects.

3. Phenotypes

Phenotype and type Characteristics, course, frequency QoL/functional effect Suggested HPO term
Fluctuating fatigable weakness—symptom/sign Universal defining feature; worsens with repeated use and may improve with rest; minute-to-minute and week-to-month fluctuation Limits work, mobility, self-care, and exercise Muscle weakness; Fatigability
Ptosis/diplopia—ocular signs May be unilateral, bilateral, or asymmetric; AChR-Ab present in about 50% of ocular MG Driving, reading, computer use and depth perception impaired Ptosis; Diplopia; Ophthalmoplegia
Generalized limb/axial weakness—sign Variable proximal-predominant weakness; episodic or chronic fluctuating course Falls, impaired transfers, walking and arm elevation Generalized muscle weakness; Proximal muscle weakness; Axial muscle weakness
Bulbar/facial weakness—sign Dysarthria, dysphagia, chewing fatigue and facial weakness; especially prominent in MuSK-MG Aspiration risk, altered diet, communication and social participation Dysphagia; Dysarthria; Facial weakness; Bulbar palsy
Neck weakness—sign Common in MuSK and more severe generalized disease Head drop, pain, impaired posture Neck muscle weakness; Head drop
Respiratory weakness/crisis—sign/complication Severe but minority phenotype; acute or subacute ventilatory failure requiring ICU monitoring and often ventilation Life-threatening; prolonged rehabilitation may follow Respiratory insufficiency; Acute respiratory failure
Persistent non-myasthenic fatigue—symptom Can persist despite control of objective weakness; about one-third of patients in pharmacological remission reportedly have fatigue syndrome Associated with lower QoL and depressive symptoms Fatigue

These manifestations and frequencies are supported by the 2024 JCI review and 2023 guideline. The guideline emphasizes that fatigue may occur independently of neuromuscular fatigability and that only cross-sectional evidence supports its association with depression and reduced QoL. (kaminski2024myastheniagravisthe pages 1-2, wiendl2023guidelineforthe pages 17-19)

Recommended outcome annotations are MG-ADL (0–24), QMG (0–39), MGC, MG-QoL15r (0–30), MGFA class, and post-intervention status. These measure different biological or patient-centered domains and are not interchangeable. (sikorski2023serummetabolomicsof pages 1-2, NCT06298552 chunk 1)

4. Genetic and molecular information

Causal genes and variants

There is no single causal gene, canonical pathogenic variant, chromosomal abnormality, or inheritance pattern for ordinary adult autoimmune MG. Accordingly:

  • ACMG pathogenic/likely pathogenic/VUS classification, somatic-versus-germline status, population allele frequency, carrier frequency, karyotype, FISH, CMA, repeat-expansion, mitochondrial, WES, and WGS testing are not routine MG diagnostics.
  • If onset was congenital/childhood, there is a family history, fixed weakness, dysmorphism, episodic apnea, or antibody/electrophysiologic findings are atypical, evaluate CMS genes such as CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN, DOK7, MUSK, LRP4, AGRN, COLQ, CHAT, GFPT1, and SCN4A. Those variants cause genetic myasthenic syndromes, not acquired autoimmune MG. (OpenTargets Search: myasthenia gravis, wiendl2023guidelineforthe pages 3-4)

Susceptibility and modifier candidates

HLA-DRB1, HLA-DQA1, HLA-B, HLA-A, TNFRSF11A, PTPN22, CTLA4, TNIP1, ZBTB10, AGRN, and ISG15 are susceptibility candidates. No modifier gene has sufficient evidence for routine severity prediction. Genetic architecture differs by age, sex, antibody status, and thymic pathology. (topaloudi2022myastheniagravisgenomewide pages 4-8, topaloudi2022myastheniagravisgenomewide pages 8-12, seldin2015genomewideassociationstudy pages 1-2)

Epigenetics and chromosomal changes

Altered miRNA expression, DNA methylation, and lymphocyte/thymic transcriptional programs have been described, but no epigenetic mark is validated for diagnosis or treatment selection. Large chromosomal abnormalities are not characteristic. Thymoma has tumor genomic alterations, but these belong to the neoplasm and are not defining germline lesions of MG.

5. Environmental information

No toxin, radiation exposure, pollution source, occupation, diet, smoking pattern, alcohol exposure, or exercise behavior has been established as a necessary or sufficient cause. The most actionable environmental information concerns exacerbation:

  1. infection, fever, surgery, sleep deprivation and major physiological stress can increase weakness;
  2. excessive heat may worsen transmission transiently;
  3. medications that impair presynaptic release, postsynaptic responsiveness, or respiratory reserve require review;
  4. immune-checkpoint blockade can induce a distinct, rapidly severe autoimmune phenotype;
  5. evidence linking SARS-CoV-2 infection or vaccination to new-onset MG remains insufficient for causal population-level inference. In Ferrara, incidence was 2.7/100,000/year in 2008–2018 versus 2.1/100,000 during 2019–2022, a non-significant reduction rather than an increase. Published December 30, 2023; DOI/URL. (antonioni2023theincidenceof pages 1-2)

6. Mechanism and pathophysiology

Causal chain

Upstream: polygenic susceptibility/thymic abnormality or acquired trigger → defective central/peripheral tolerance → autoreactive CD4 T-cell help → B-cell, plasmablast and plasma-cell expansion → pathogenic IgG production.

Endotype-specific effector stage:

  • AChR-MG: IgG1/IgG3 binds clustered nicotinic AChR → classical complement activation and C5 cleavage → C5b-9 membrane-attack-complex injury; antibody cross-linking also accelerates receptor endocytosis (“antigenic modulation”), while a subset directly blocks acetylcholine binding. (kaminski2024myastheniagravisthe pages 2-4)
  • MuSK-MG: predominantly functionally monovalent IgG4 blocks LRP4–MuSK interaction → impaired MuSK phosphorylation and rapsyn-dependent AChR clustering. Because IgG4 does not efficiently fix complement, C5 inhibitors are mechanistically inappropriate for this endotype. The 2023 review states that IgG4 antibodies exert pathogenicity “via interfering with the interaction between their targets and binding partners.” Published July 2023; DOI/URL. (vakrakou2023immunotherapiesinmuskpositive pages 1-2)
  • LRP4-MG: antibodies interfere with agrin–LRP4–MuSK signaling; complement contribution is less clearly defined.

Downstream: fewer functional AChRs, damaged junctional folds and reduced sodium-channel density → smaller end-plate potentials → repeated activity lowers the end-plate potential below action-potential threshold → progressive failure of muscle-fiber recruitment → fatigable weakness, dysphagia, diplopia, or ventilatory failure. (kaminski2024myastheniagravisthe pages 2-4)

Relevant ontology suggestions

  • GO biological process: complement activation; membrane attack complex assembly; receptor-mediated endocytosis; regulation of acetylcholine-receptor clustering; cholinergic synaptic transmission; skeletal-muscle contraction; B-cell activation; T-cell activation; immunoglobulin production.
  • GO cellular component: neuromuscular junction; postsynaptic membrane; acetylcholine-gated channel complex; membrane attack complex; immunological synapse.
  • Cell Ontology: B cell, memory B cell, plasmablast, plasma cell, CD4-positive alpha-beta T cell, regulatory T cell, thymic epithelial cell, skeletal-muscle fiber, alpha motor neuron.

Molecular profiling and advanced technologies

  • Metabolomics/lipidomics—human exploratory: an MGTX-serum study found higher phospholipids associated with treatment response. Histidine, free fatty acid 13:0, γ-cholestenol and guanosine predicted a strict corticosteroid-response phenotype with AUC 0.90. The authors stress that the panel “can now undergo validation”; it is not a clinical biomarker. Published October 10, 2023; DOI/URL. (sikorski2023serummetabolomicsof pages 1-2)
  • Single-cell/spatial studies—human research: thymic and peripheral immune-cell studies identify heterogeneous autoreactive B/T-cell states and germinal-center niches. They refine endotyping but have no approved diagnostic use. (kaminski2024myastheniagravisthe pages 10-10, kaminski2024myastheniagravisthe pages 10-11)
  • Proteomics/transcriptomics: candidate cytokine, chemokine, complement and B-cell signatures are reported, but inter-cohort validation is incomplete.
  • Functional platforms—in vitro: cell-based antibody assays and human stem-cell-derived NMJs reproduce native antigen conformation and permit functional/pathogenicity testing and drug screening. (kaminski2024myastheniagravisthe pages 1-2)
  • Spatial transcriptomics, CRISPR screens, routine liquid biopsy: investigational or not established for adult MG.

7. Anatomical structures affected

  • Primary organ/system: peripheral neuromuscular system; voluntary skeletal muscle is functionally denervated at the NMJ despite structurally intact motor axons.
  • Primary site: postsynaptic motor end plate/neuromuscular junction—suggested UBERON term labels: neuromuscular junction, skeletal muscle organ, extraocular muscle, diaphragm, pharyngeal muscle and laryngeal muscle.
  • Secondary organ: thymus—hyperplasia or thymoma in relevant AChR-positive subtypes.
  • Respiratory system: diaphragm and accessory respiratory muscles are secondarily affected during severe disease; lung parenchyma is not the primary target.
  • Subcellular compartments: postsynaptic membrane, junctional folds, AChR complex, MuSK–LRP4 signaling complex, and complement membrane-attack complex.
  • Localization/lateralization: ocular findings are often asymmetric and can alternate; generalized weakness is usually bilateral but not necessarily symmetric. (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)

8. Temporal development and natural history

Onset may be insidious, subacute, or—especially after checkpoint inhibitors—rapid. Early adult AChR disease peaks in young women; late-onset disease increasingly affects older men, with the highest recent Ferrara incidence in people over 70. Ocular disease is often operationally classified as persistent ocular MG if it has not generalized for at least two years. (antonioni2023theincidenceof pages 1-2, kaminski2024myastheniagravisthe pages 2-4)

The course is chronic and fluctuating, with exacerbations, treatment-induced remission, pharmacologic remission, minimal manifestations, or persistent active/refractory disease. A 2024 review estimated relapse in 18%–34% and nonresponse to traditional immunosuppressants in about 10%, although definitions and cohorts vary. (zhong2024initiationresponsemaximized pages 1-2)

The greatest risk of ocular-to-generalized conversion is early in the disease course; early disease control and thymectomy, when indicated, represent important intervention windows. Abrupt withdrawal of immunotherapy can cause recurrence or crisis. Spontaneous permanent remission occurs but cannot be predicted reliably; most patients require prolonged monitoring and many require long-term immunotherapy. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 9-10)

9. Inheritance, epidemiology, and population

Epidemiology

A meta-analysis cited in the Ferrara population study estimated prevalence at 7.7/100,000 and incidence at 0.5/100,000 person-years; recent annual incidence estimates commonly range from 0.3 to 3.0/100,000. A broader 2023 review estimated approximately 700,000 affected worldwide, median prevalence around 10/100,000, and regional incidence ranging from about 0.4/100,000 in Norway to 2.1/100,000 in Italy and Taiwan. Differences reflect age structure, ascertainment, diagnostic access and case definitions. (huang2023myastheniagravisnovel pages 1-3, antonioni2023theincidenceof pages 1-2)

Ferrara’s complete-enumeration study identified 106 incident cases in 2008–2018 (2.7/100,000/year) and 29 in 2019–2022 (2.1/100,000/year), with rising late-onset and declining early-onset disease. (antonioni2023theincidenceof pages 1-2)

Demographics and inheritance

  • Early-onset AChR-MG: women:men approximately 3:1, peak third decade.
  • LOMG: male predominance, peak sixth decade and increasing incidence among those over 70.
  • MuSK-MG: female-biased, often younger/middle adult onset, bulbar-predominant.
  • Thymoma MG: approximately equal sex ratio or slight male bias, peak near fifth decade. (kaminski2024myastheniagravisthe pages 2-4)

Inheritance is multifactorial/polygenic with low absolute familial recurrence, variable expression, and incomplete/age-dependent susceptibility—not autosomal dominant, recessive, X-linked, or mitochondrial. Anticipation, carrier screening, founder-mutation screening, and consanguinity effects are not established. Geographic differences in antibody and thymoma distributions occur, but variant-specific geographic prediction is not clinically mature.

10. Diagnostics

Clinical and laboratory workflow

  1. Identify fluctuating, fatigable ocular, bulbar, limb, axial, or respiratory weakness with preserved sensation and usually normal reflexes.
  2. Test serum AChR binding antibodies; where appropriate add blocking/modulating assays or a clustered-AChR cell-based assay.
  3. If AChR-negative, test MuSK-Ab; then consider LRP4-Ab and specialized cell-based assays.
  4. Perform low-frequency repetitive nerve stimulation (RNS) and/or single-fiber EMG (SFEMG), targeting clinically involved muscles. The 2024 review reports that RNS/SFEMG confirms approximately 90% of seronegative clinically suspected cases. (kaminski2024myastheniagravisthe pages 1-2)
  5. Chest CT or MRI for every confirmed patient to evaluate thymoma. (wiendl2023guidelineforthe pages 3-4)
  6. Assess respiratory status during bulbar/generalized deterioration using forced vital capacity, negative inspiratory force, oxygenation and blood gases; normal oxygen saturation does not exclude impending ventilatory failure.
  7. Use MGFA class, MG-ADL, QMG, MGC and MG-QoL15r longitudinally.

The guideline’s exact summary is: “The diagnosis of MG is based on the history and physical findings of fatigable and fluctuating muscle weakness,” confirmed through autoantibodies, electrophysiology and/or pharmacological testing. Published 2023; DOI/URL. (wiendl2023guidelineforthe pages 3-4)

Imaging, biopsy, genetic and omics tests

  • CT/MRI evaluates thymoma but does not diagnose junctional transmission failure.
  • Muscle biopsy is generally unnecessary; if performed, it may be normal or nonspecific and is mainly used to investigate myopathy.
  • WES/WGS/panels are reserved for suspected CMS or alternative genetic neuromuscular disease.
  • CMA, karyotype, FISH, mtDNA and repeat-expansion tests have no routine role.
  • Transcriptomic, proteomic, metabolomic and epigenomic tests remain research tools. (sikorski2023serummetabolomicsof pages 1-2, wiendl2023guidelineforthe pages 3-4)

Differential diagnosis

Important mimics include Lambert–Eaton syndrome (proximal/autonomic symptoms, facilitation, often reduced reflexes), botulism (pupillary/autonomic involvement and descending paralysis), CMS, mitochondrial/chronic progressive external ophthalmoplegia, oculopharyngeal muscular dystrophy, inflammatory or checkpoint-inhibitor myositis, thyroid eye disease, brainstem stroke, multiple sclerosis, motor-neuron disease, cranial neuropathy and functional neurological disorder. MuSK-MG can resemble bulbar-onset motor-neuron disease; ICI-associated MG should prompt simultaneous creatine kinase, troponin, ECG and cardiac evaluation because of myositis/myocarditis overlap.

Screening

There is no population, newborn, carrier, prenatal, or asymptomatic genetic screening program. Targeted evaluation may be appropriate in thymoma, before/after checkpoint blockade when symptoms arise, or in relatives only if the phenotype suggests CMS rather than autoimmune MG.

11. Outcome and prognosis

Modern MG is usually treatable, and most patients achieve substantial control, but complete stable remission is less common than improvement or minimal manifestations. Survival approaches the general population in well-managed patients, although older age, respiratory crisis, aspiration, infection, thymoma, severe bulbar disease, and treatment toxicity increase risk. Contemporary literature does not support a single universal 5- or 10-year survival percentage because cohorts differ markedly.

Morbidity includes fluctuating disability, aspiration, crisis, hospitalization, falls, treatment-associated infection/metabolic disease, anxiety/depression, fatigue and impaired employment. Persistent fatigue can occur in approximately one-third of pharmacologically remitted patients and correlates with poorer QoL. (wiendl2023guidelineforthe pages 17-19)

Poorer prognosis is associated with delayed recognition, severe baseline MGFA class, recurrent crisis, thymoma, older age/comorbidity, MuSK bulbar/respiratory predominance, and insufficient treatment response. AChR antibody concentration alone correlates imperfectly with clinical severity because antibody epitope, subclass and effector mechanism vary. (kaminski2024myastheniagravisthe pages 2-4)

12. Treatment

Staged clinical strategy

  1. Symptomatic: pyridostigmine (ACHE inhibition; NCIt term label: pyridostigmine bromide), adjusted to function and tolerability. MuSK-MG may respond poorly and can worsen with excessive cholinesterase inhibition.
  2. Conventional disease modification: prednisone/prednisolone, usually with steroid-sparing azathioprine; alternatives include mycophenolate, tacrolimus, cyclosporine or methotrexate. Evidence for some alternatives is mixed, and onset of benefit is delayed. (wiendl2023guidelineforthe pages 9-10)
  3. Endotype-directed therapy: C5 inhibitors for complement-mediated AChR-positive gMG; FcRn inhibitors for pathogenic-IgG reduction; rituximab particularly for MuSK-MG.
  4. Crisis/severe exacerbation: ICU-level respiratory/bulbar surveillance, treatment of precipitant, IVIG or plasma exchange/immunoadsorption, with ventilatory and aspiration support. (wiendl2023guidelineforthe pages 3-4)

Thymectomy

Thymoma requires complete oncologic thymectomy where feasible. For non-thymomatous AChR-positive generalized MG, MGTX randomized 126 adults aged 18–65 with disease under five years. At three years, thymectomy plus prednisone versus prednisone alone reduced time-weighted QMG (6.15 vs 8.99), alternate-day prednisone (44 vs 60 mg), azathioprine use (17% vs 48%) and exacerbation hospitalization (9% vs 37%), all p<0.001. The abstract concludes: “Thymectomy improved clinical outcomes over a 3-year period.” Published August 11, 2016; PMID 27509100; DOI/URL. (wolfe2016randomizedtrialof pages 1-3)

Guidelines recommend early thymectomy—ideally within two years and no later than five years after diagnosis—for suitable 18–65-year-old AChR-positive generalized patients. It is not routinely recommended for MuSK-MG. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)

Targeted therapies and 2023–2024 developments

  • C5 complement inhibition: eculizumab, ravulizumab, and zilucoplan prevent terminal complement/MAC injury. Their strongest rationale is AChR-positive gMG. Meningococcal vaccination and infection-risk mitigation are mandatory; breakthrough invasive infection remains possible. Zilucoplan received US approval in October 2023. (gu2024efficacyandsafety pages 1-2, kaminski2024myastheniagravisthe pages 2-4)
  • FcRn blockade: efgartigimod and rozanolixizumab accelerate pathogenic IgG clearance. IV and subcutaneous efgartigimod formulations and rozanolixizumab expanded practical treatment options during 2023–2024. Typical concerns include headache and infection; FcRn blockade lowers total IgG but is not antigen-specific. (zhong2024initiationresponsemaximized pages 1-2, habib2024efficacyandsafety pages 1-2, wiendl2023guidelineforthe pages 2-3)
  • MuSK-MG: rituximab is often used earlier because conventional therapy and IVIG may be less effective. Plasma exchange is frequently effective. Rozanolixizumab is approved for AChR- or MuSK-antibody-positive gMG in the US. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, habib2024efficacyandsafety pages 1-2)

In the 21-patient MuSK subgroup of phase III MycarinG, day-43 MG-ADL changes were −7.28 with 7 mg/kg, −4.16 with 10 mg/kg and +2.28 with placebo; differences from placebo were −9.56 and −6.45. Treatment-emergent adverse events occurred in 80.0%, 62.5% and 37.5%, respectively, but there were no serious events or deaths. The small subgroup warrants cautious interpretation. Published 2024; NCT03971422; DOI/URL. (habib2024efficacyandsafety pages 1-2)

A 2024 network meta-analysis of 21 RCTs, 13 drugs and 1,657 patients ranked batoclimab highest for QMG/MGC, rozanolixizumab highest for MG-ADL, and eculizumab highest for MG-QoL15r; indirect SUCRA rankings should not be interpreted as head-to-head superiority because populations and regimens differed. Published October 2024; DOI/URL. (gu2024efficacyandsafety pages 1-2)

Current experimental applications

  • Inebilizumab/CD19 depletion: phase III MINT, NCT04524273, 238 AChR- or MuSK-positive adults, with MG-ADL at week 26 as primary outcome. (NCT04524273 chunk 1)
  • Efgartigimod in AChR-binding-seronegative gMG: ADAPT SERON, phase III, NCT06298552, 119 participants. (NCT06298552 chunk 1)
  • NMD670: phase IIb SYNAPSE-MG, NCT06414954, estimated 84 participants; a muscle chloride-channel-directed symptomatic approach assessed over 21 days. (NCT06414954 chunk 1)
  • Anti-CD19 CAR-T: KYV-101/mivocabtagene autoleucel, phase II/III KYSA-6, NCT06193889, estimated 66 treatment-refractory participants. This is an experimental immune-reset strategy, not established care. (NCT06193889 chunk 1)
  • Antigen-specific/CAAR-T and RNA/gene approaches: preclinical or early clinical; no approved gene, RNA, stem-cell, or regenerative therapy exists for autoimmune MG. (vakrakou2023immunotherapiesinmuskpositive pages 1-2, keritam2024aclinicalperspective pages 13-13)

Rehabilitation and supportive care

Use individualized aerobic and resistance exercise below the threshold that provokes prolonged weakness; respiratory, swallowing, speech, occupational and physical therapy are indicated by phenotype. Manage aspiration risk, nutrition, sleep, mood, osteoporosis, infection risk and steroid metabolic toxicity. Mechanical ptosis aids, prisms or occlusion may help refractory ocular symptoms. (wiendl2023guidelineforthe pages 17-19)

No validated CPIC/PharmGKB genotype-guided treatment algorithm exists. TPMT/NUDT15 testing may guide azathioprine safety according to general pharmacogenetic practice, but it predicts metabolism/toxicity rather than MG response.

13. Prevention

  • Primary prevention: none established; MG is not preventable through routine genetic screening, diet or vaccination.
  • Secondary prevention: no asymptomatic population screening. Prompt recognition of ptosis, diplopia, bulbar fatigue or respiratory symptoms reduces diagnostic delay.
  • Tertiary prevention: medication reconciliation; infection prevention; completion of indicated vaccines before prolonged immunotherapy; meningococcal vaccination/prophylaxis for C5 blockade; gradual—not abrupt—immunotherapy taper; perioperative planning; crisis education; swallowing and respiratory monitoring. The guideline specifically recommends assessing and completing vaccination history before prolonged immunotherapy. (wiendl2023guidelineforthe pages 9-10)
  • Immunization: non-live vaccines are generally appropriate, but timing should account for B-cell-depleting treatment and other immunosuppression. Vaccination-associated MG reports do not outweigh the recognized risk of infection-triggered exacerbation at the population level.
  • Counseling: ordinary autoimmune MG does not justify carrier or prenatal testing. Counsel women about pregnancy, medication safety, postpartum exacerbation and transient neonatal MG risk.

14. Natural disease in other species

Naturally occurring acquired autoimmune MG occurs most importantly in dogs (Canis lupus familiaris; NCBI Taxon 9615) and more rarely cats (Felis catus; Taxon 9685). Dogs develop AChR-antibody-associated focal or generalized weakness; megaesophagus with regurgitation and aspiration pneumonia is particularly important and differs from typical human presentation. Thymoma-associated MG occurs in dogs and cats. Some canine breed predispositions are reported, but breed effects vary geographically and are not equivalent to a single orthologous causal mutation.

The same postsynaptic AChR/complement biology and response to anticholinesterase or immunomodulatory treatment make canine disease comparatively informative. However, prominent canine megaesophagus, breed structure, species-specific immune responses and differences in treatment constrain direct extrapolation. Autoimmune MG is not infectious or zoonotic and has no cross-species transmission risk.

15. Model organisms and experimental systems

  • Active experimental autoimmune MG (EAMG): mice, rats and rabbits immunized with purified AChR or AChR peptides develop AChR antibodies, complement-mediated endplate injury, decrement and weakness. This is useful for tolerance, complement and therapeutic studies but compresses the chronic, heterogeneous human disease into an induced response.
  • Passive-transfer EAMG: transfer of patient or monoclonal AChR/MuSK antibodies into rodents isolates antibody effector mechanisms and permits causal testing. It does not reproduce thymic initiation, long-term T/B-cell evolution or the full human antibody repertoire.
  • MuSK models: active immunization or passive IgG transfer reproduces impaired AChR clustering and bulbar/generalized weakness; species and IgG-subclass biology can alter complement and Fc effects.
  • Genetic models: knockout/knock-in disruption of Musk, Lrp4, Agrn, Rapsn, or Dok7 elucidates NMJ development but models CMS/developmental failure more directly than acquired autoimmunity.
  • In vitro human systems: clustered-AChR cell assays, myotubes, motor-neuron–muscle co-cultures, iPSC-derived NMJs and microfluidic/organoid-like platforms permit patient-IgG testing and therapeutic screening. The 2024 JCI review notes both “robust animal models since the 1970s” and newer human stem-cell-derived NMJ platforms. (kaminski2024myastheniagravisthe pages 1-2)

Relevant resources include MGI, IMPC, IMSR/MMRRC/EMMA for mouse strains, RGD for rats, Cellosaurus for cell lines, and GEO/SRA/Single Cell Portal for omics datasets.

Evidence limitations and expert interpretation

  1. Adult-onset MG is an umbrella of biologically distinct endotypes; aggregate prevalence, response and prognosis estimates should not be applied indiscriminately to AChR-, MuSK-, LRP4-, thymoma-, ICI-associated or seronegative disease.
  2. Recent network meta-analyses offer useful indirect comparisons but are vulnerable to heterogeneous enrollment, background therapy, outcome timing and antibody subtype. (gu2024efficacyandsafety pages 1-2, zhong2024initiationresponsemaximized pages 1-2)
  3. Antibody positivity supports diagnosis but does not alone establish current activity; titer–severity correlation is imperfect. Conversely, negative conventional serology does not exclude MG. (kaminski2024myastheniagravisthe pages 2-4, kaminski2024myastheniagravisthe pages 1-2)
  4. Genetics and omics presently support mechanistic stratification and target discovery, not routine prediction of individual onset, prognosis, or drug choice. The promising metabolomic AUC of 0.90 requires external validation. (topaloudi2022myastheniagravisgenomewide pages 8-12, sikorski2023serummetabolomicsof pages 1-2)
  5. The authoritative 2023 guideline considers rapid achievement of complete disease control a central goal while emphasizing antibody status, thymic pathology, age, activity and patient-reported outcomes. Precision biologics should complement—not replace—careful diagnosis, crisis prevention, conventional immunotherapy and rehabilitation. (wiendl2023guidelineforthe pages 3-4, wiendl2023guidelineforthe pages 2-3)

References

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Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 16
On topic 7
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.3390/jcm13010236 (5 mentions) - The Incidence of Myasthenia Gravis in the Province of Ferrara, Italy, in the Period of 2008–2022: An Update on a 40-Year Observation and the Influence of the COVID-19 Pandemic
  • shared terms: clinical

Weighed against this report's own most characteristic terms: disease, clinical, genetic, treatment, gene, achr, autoimmune, guideline, generalized, risk, musk, respiratory, weakness, thymic, causal, antibody, patient, effect, complement, muscle.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.