graph LR
Downstream_Signaling_Cascade_Activation["Downstream Signaling Cascade Activation"]
H1_H2_Antihistamines["H1/H2 Antihistamines"]
Pruritus["Pruritus"]
Mast_Cell_Surface_Receptor_Engagement["Mast Cell Surface Receptor Engagement"]
Abdominal_pain["Abdominal pain"]
Tachycardia["Tachycardia"]
Oral_Cromolyn["Oral Cromolyn"]
Serum_tryptase_event_related_rise["Serum tryptase, event-related rise"]
Dyspnea["Dyspnea"]
NSAID_exposure["NSAID exposure"]
Multisystem_Mediator_Driven_Symptom_Generation["Multisystem Mediator-Driven Symptom Generation"]
Epinephrine_for_Acute_Anaphylaxis["Epinephrine for Acute Anaphylaxis"]
Ketotifen["Ketotifen"]
Diarrhea["Diarrhea"]
Mast_Cell_Degranulation_and_Mediator_Release["Mast Cell Degranulation and Mediator Release"]
Urticaria["Urticaria"]
Alcohol_consumption["Alcohol consumption"]
Omalizumab["Omalizumab"]
Hypotension["Hypotension"]
Antihistamine_Occupancy_of_H1_Receptors["Antihistamine Occupancy of H1 Receptors"]
Leukotriene_Receptor_Antagonist["Leukotriene Receptor Antagonist"]
Wheezing["Wheezing"]
Angioedema["Angioedema"]
Flushing["Flushing"]
Mast_Cell_Surface_Receptor_Engagement --> Downstream_Signaling_Cascade_Activation
Downstream_Signaling_Cascade_Activation --> Mast_Cell_Degranulation_and_Mediator_Release
Mast_Cell_Degranulation_and_Mediator_Release --> Multisystem_Mediator_Driven_Symptom_Generation
Multisystem_Mediator_Driven_Symptom_Generation --> Flushing
Multisystem_Mediator_Driven_Symptom_Generation --> Urticaria
Multisystem_Mediator_Driven_Symptom_Generation --> Angioedema
Multisystem_Mediator_Driven_Symptom_Generation --> Pruritus
Multisystem_Mediator_Driven_Symptom_Generation --> Abdominal_pain
Multisystem_Mediator_Driven_Symptom_Generation --> Diarrhea
Multisystem_Mediator_Driven_Symptom_Generation --> Hypotension
Multisystem_Mediator_Driven_Symptom_Generation --> Tachycardia
Multisystem_Mediator_Driven_Symptom_Generation --> Dyspnea
Multisystem_Mediator_Driven_Symptom_Generation --> Wheezing
Alcohol_consumption --> Mast_Cell_Surface_Receptor_Engagement
NSAID_exposure --> Mast_Cell_Surface_Receptor_Engagement
H1_H2_Antihistamines --> Antihistamine_Occupancy_of_H1_Receptors
H1_H2_Antihistamines --> Multisystem_Mediator_Driven_Symptom_Generation
Leukotriene_Receptor_Antagonist --> Multisystem_Mediator_Driven_Symptom_Generation
Oral_Cromolyn --> Mast_Cell_Degranulation_and_Mediator_Release
Ketotifen --> Mast_Cell_Degranulation_and_Mediator_Release
Omalizumab --> Mast_Cell_Surface_Receptor_Engagement
Epinephrine_for_Acute_Anaphylaxis --> Multisystem_Mediator_Driven_Symptom_Generation
Epinephrine_for_Acute_Anaphylaxis --> Hypotension
Mast_Cell_Degranulation_and_Mediator_Release -.-> Serum_tryptase_event_related_rise
style Downstream_Signaling_Cascade_Activation fill:#dbeafe
style H1_H2_Antihistamines fill:#fce7f3
style Pruritus fill:#fef3c7
style Mast_Cell_Surface_Receptor_Engagement fill:#dbeafe
style Abdominal_pain fill:#fef3c7
style Tachycardia fill:#fef3c7
style Oral_Cromolyn fill:#fce7f3
style Serum_tryptase_event_related_rise fill:#e0e7ff
style Dyspnea fill:#fef3c7
style NSAID_exposure fill:#dcfce7
style Multisystem_Mediator_Driven_Symptom_Generation fill:#dbeafe
style Epinephrine_for_Acute_Anaphylaxis fill:#fce7f3
style Ketotifen fill:#fce7f3
style Diarrhea fill:#fef3c7
style Mast_Cell_Degranulation_and_Mediator_Release fill:#dbeafe
style Urticaria fill:#fef3c7
style Alcohol_consumption fill:#dcfce7
style Omalizumab fill:#fce7f3
style Hypotension fill:#fef3c7
style Antihistamine_Occupancy_of_H1_Receptors fill:#dbeafe
style Leukotriene_Receptor_Antagonist fill:#fce7f3
style Wheezing fill:#fef3c7
style Angioedema fill:#fef3c7
style Flushing fill:#fef3c7
graph LR
T_Cell_Immunometabolic_Dysfunction["T-Cell Immunometabolic Dysfunction"]
Possible_Neuroimmune_Activation["Possible Neuroimmune Activation"]
Cognitive_Impairment["Cognitive Impairment"]
Proposed_Muscle_Sodium_Calcium_Loading["Proposed Muscle Sodium-Calcium Loading"]
Low_Dose_Naltrexone["Low-Dose Naltrexone"]
Patient_Derived_Skeletal_Myotubes["Patient-Derived Skeletal Myotubes"]
Patient_NK_Cell_TRPM3_Assays["Patient NK-Cell TRPM3 Assays"]
Patient_Serum_Vesicle_Microglia_Assay["Patient Serum Vesicle-Microglia Assay"]
TRPM3_Associated_NK_Cell_Calcium_Dysregulation["TRPM3-Associated NK-Cell Calcium Dysregulation"]
Small_Fiber_Neuropathy["Small-Fiber Neuropathy"]
Erythrocyte_Microfluidic_Deformability_Assay["Erythrocyte Microfluidic Deformability Assay"]
Pyridostigmine["Pyridostigmine"]
Central_Motor_Activation_Abnormality["Central Motor Activation Abnormality"]
Individualized_Energy_Management["Individualized Energy Management"]
Proposed_Peripheral_Vesicle_Microglial_Signaling["Proposed Peripheral Vesicle-Microglial Signaling"]
Post_Exertional_Malaise["Post-Exertional Malaise"]
Orthostatic_Cerebral_Hypoperfusion["Orthostatic Cerebral Hypoperfusion"]
Atg13_Depleted_Mouse["Atg13-Depleted Mouse"]
Reduced_Erythrocyte_Deformability["Reduced Erythrocyte Deformability"]
Orthostatic_Intolerance["Orthostatic Intolerance"]
Fatigue["Fatigue"]
Elevated_Skeletal_Muscle_Tissue_Sodium["Elevated Skeletal Muscle Tissue Sodium"]
Autophagy_Associated_Macrophage_Dysfunction["Autophagy-Associated Macrophage Dysfunction"]
Endothelial_Vasodilator_Dysfunction["Endothelial Vasodilator Dysfunction"]
Impaired_Peripheral_Oxygen_Extraction["Impaired Peripheral Oxygen Extraction"]
Patient_T_Cell_Metabolic_Assays["Patient T-Cell Metabolic Assays"]
Exercise_Intolerance["Exercise Intolerance"]
Natural_Killer_Cell_Dysfunction["Natural Killer Cell Dysfunction"]
Skeletal_Muscle_Bioenergetic_Disturbance["Skeletal Muscle Bioenergetic Disturbance"]
Impaired_Venous_Return["Impaired Venous Return"]
Reduced_Exercise_Cardiac_Output["Reduced Exercise Cardiac Output"]
Myalgia["Myalgia"]
Proposed_Delayed_Immunometabolic_Amplification["Proposed Delayed Immunometabolic Amplification"]
Exertion_Beyond_Individual_Tolerance["Exertion Beyond Individual Tolerance"]
Small_Fiber_Neuropathy --> Impaired_Venous_Return
Small_Fiber_Neuropathy --> Impaired_Peripheral_Oxygen_Extraction
Impaired_Venous_Return --> Reduced_Exercise_Cardiac_Output
Reduced_Exercise_Cardiac_Output --> Exercise_Intolerance
Impaired_Peripheral_Oxygen_Extraction --> Exercise_Intolerance
Impaired_Peripheral_Oxygen_Extraction --> Skeletal_Muscle_Bioenergetic_Disturbance
Endothelial_Vasodilator_Dysfunction --> Skeletal_Muscle_Bioenergetic_Disturbance
Reduced_Erythrocyte_Deformability --> Myalgia
Reduced_Erythrocyte_Deformability --> Fatigue
Skeletal_Muscle_Bioenergetic_Disturbance --> Proposed_Delayed_Immunometabolic_Amplification
Elevated_Skeletal_Muscle_Tissue_Sodium --> Proposed_Muscle_Sodium_Calcium_Loading
Proposed_Muscle_Sodium_Calcium_Loading --> Skeletal_Muscle_Bioenergetic_Disturbance
TRPM3_Associated_NK_Cell_Calcium_Dysregulation --> Natural_Killer_Cell_Dysfunction
Proposed_Delayed_Immunometabolic_Amplification --> Post_Exertional_Malaise
Orthostatic_Cerebral_Hypoperfusion --> Orthostatic_Intolerance
Orthostatic_Cerebral_Hypoperfusion --> Cognitive_Impairment
Central_Motor_Activation_Abnormality --> Exercise_Intolerance
Proposed_Peripheral_Vesicle_Microglial_Signaling --> Possible_Neuroimmune_Activation
Exertion_Beyond_Individual_Tolerance --> Post_Exertional_Malaise
Individualized_Energy_Management --> Post_Exertional_Malaise
Pyridostigmine --> Reduced_Exercise_Cardiac_Output
Pyridostigmine --> Impaired_Venous_Return
Low_Dose_Naltrexone --> TRPM3_Associated_NK_Cell_Calcium_Dysregulation
Patient_Derived_Skeletal_Myotubes --> Skeletal_Muscle_Bioenergetic_Disturbance
Patient_NK_Cell_TRPM3_Assays --> TRPM3_Associated_NK_Cell_Calcium_Dysregulation
Patient_T_Cell_Metabolic_Assays --> T_Cell_Immunometabolic_Dysfunction
Erythrocyte_Microfluidic_Deformability_Assay --> Reduced_Erythrocyte_Deformability
Patient_Serum_Vesicle_Microglia_Assay --> Proposed_Peripheral_Vesicle_Microglial_Signaling
Atg13_Depleted_Mouse --> Autophagy_Associated_Macrophage_Dysfunction
style T_Cell_Immunometabolic_Dysfunction fill:#dbeafe
style Possible_Neuroimmune_Activation fill:#dbeafe
style Cognitive_Impairment fill:#fef3c7
style Proposed_Muscle_Sodium_Calcium_Loading fill:#dbeafe
style Low_Dose_Naltrexone fill:#fce7f3
style Patient_Derived_Skeletal_Myotubes fill:#ccfbf1
style Patient_NK_Cell_TRPM3_Assays fill:#ccfbf1
style Patient_Serum_Vesicle_Microglia_Assay fill:#ccfbf1
style TRPM3_Associated_NK_Cell_Calcium_Dysregulation fill:#dbeafe
style Small_Fiber_Neuropathy fill:#dbeafe
style Erythrocyte_Microfluidic_Deformability_Assay fill:#ccfbf1
style Pyridostigmine fill:#fce7f3
style Central_Motor_Activation_Abnormality fill:#dbeafe
style Individualized_Energy_Management fill:#fce7f3
style Proposed_Peripheral_Vesicle_Microglial_Signaling fill:#dbeafe
style Post_Exertional_Malaise fill:#fef3c7
style Orthostatic_Cerebral_Hypoperfusion fill:#dbeafe
style Atg13_Depleted_Mouse fill:#ede9fe
style Reduced_Erythrocyte_Deformability fill:#dbeafe
style Orthostatic_Intolerance fill:#fef3c7
style Fatigue fill:#fef3c7
style Elevated_Skeletal_Muscle_Tissue_Sodium fill:#dbeafe
style Autophagy_Associated_Macrophage_Dysfunction fill:#dbeafe
style Endothelial_Vasodilator_Dysfunction fill:#dbeafe
style Impaired_Peripheral_Oxygen_Extraction fill:#dbeafe
style Patient_T_Cell_Metabolic_Assays fill:#ccfbf1
style Exercise_Intolerance fill:#fef3c7
style Natural_Killer_Cell_Dysfunction fill:#dbeafe
style Skeletal_Muscle_Bioenergetic_Disturbance fill:#dbeafe
style Impaired_Venous_Return fill:#dbeafe
style Reduced_Exercise_Cardiac_Output fill:#dbeafe
style Myalgia fill:#fef3c7
style Proposed_Delayed_Immunometabolic_Amplification fill:#dbeafe
style Exertion_Beyond_Individual_Tolerance fill:#dcfce7
name: com_Mast_Cell_Activation_Syndrome__Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome
creation_date: '2026-11-02T16:15:36Z'
curation_status: CANDIDATE
notes: >-
Evidence linking mast cell activation syndrome (MCAS) with myalgic
encephalomyelitis/chronic fatigue syndrome (ME/CFS) is thin. The main study
is an Austrian ME/CFS cohort (687 survey responses and a retrospective
review of 383 patients). In that cohort, up to 25.3% of followed-up patients
met the authors' criteria for clinically relevant mast cell activation,
this proportion rose over the disease course, and orthostatic intolerance,
particularly POTS, was more common in patients with mast cell activation.
The authors' criteria for clinically relevant mast cell activation are not
stated in the abstract and may be broader than consensus MCAS criteria.
Small laboratory studies report altered mast cell progenitor phenotypes in
peripheral blood of ME/CFS patients, and a five-patient case series reports
benefit from high-dose oral cromolyn in ME/CFS with MCAS (PMID:41728426).
No controlled prevalence study using consensus MCAS criteria in ME/CFS was
found. The overlap may run through POTS, which is common in both
conditions (see the ME/CFS-POTS and MCAS-POTS comorbidity entries).
Directionality is UNKNOWN. No ICEES KG signal is possible, because neither
MCAS nor ME/CFS is a node in the ICEES KG 8-20-2024 snapshot.
disease_a:
slug: Mast_Cell_Activation_Syndrome
preferred_term: mast cell activation syndrome
term:
id: MONDO:0100004
label: mast cell activation syndrome
disease_b:
slug: Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome
preferred_term: myalgic encephalomyelitis/chronic fatigue syndrome
term:
id: MONDO:0005404
label: myalgic encephalomeyelitis/chronic fatigue syndrome
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: in a subgroup of ME/CFS, mast cell activation adds
mediator-driven symptoms and worsens orthostatic intolerance, and these
patients may respond to mast cell-directed treatment. The supporting data
come from one observational cohort and small laboratory studies. Whether
mast cell activation is a cause, a consequence or a marker of a distinct
ME/CFS subgroup is unknown.
evidence:
- reference: PMID:41300853
reference_title: The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001)."
explanation: >-
Self-reported treatment response in an observational cohort, consistent
with mast cell activation contributing to symptoms in this subgroup. It
was not a controlled trial.
- reference: PMID:27362406
reference_title: Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "There was a significant increase in CD117⁺CD34⁺FCεRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls."
explanation: >-
A small study (18 patients, 13 controls) finding more mast cell
progenitors in patient blood. This shows altered mast cell biology in
ME/CFS but not mast cell activation or MCAS.
pathophysiology:
- name: Mast cell activation contributing to ME/CFS symptoms
description: >-
Proposed mechanism: mast cell mediator release adds to symptom burden
and orthostatic intolerance in a subgroup of ME/CFS patients.
biological_processes:
- preferred_term: mast cell degranulation
term:
id: GO:0043303
label: mast cell degranulation
modifier: INCREASED
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0100004
signal_disorder_b_id: MONDO:0005404
population: >-
Austrian ME/CFS patients: 687 online questionnaire responses (CCCFS data
set) and a retrospective review of 383 patients.
mapping_notes: >-
The prevalence is of clinically relevant mast cell activation by the
authors' criteria, which may be broader than consensus MCAS criteria, and
is the upper value over follow-up. No control group.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 25.3
notes: >-
Upper value of the proportion of followed-up ME/CFS patients meeting
criteria for clinically relevant mast cell activation.
evidence:
- reference: PMID:41300853
reference_title: The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA."
explanation: >-
Estimates how often clinically relevant mast cell activation occurs
in an ME/CFS cohort.
- reference: PMID:41300853
reference_title: The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement."
explanation: >-
Links mast cell activation in ME/CFS to orthostatic intolerance and
POTS, which suggests the overlap may run through POTS.
- source: ICEES
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: MONDO:0100004
signal_disorder_b_id: MONDO:0005404
population: ICEES KG snapshot 8-20-2024 (RENCI/UNC).
mapping_notes: >-
No ICEES signal exists for this pair. Searched: downloaded the snapshot
with `just icees-refresh` and grepped its 226-node list; neither MCAS
(MONDO:0100004) nor ME/CFS (MONDO:0005404) is a node.
directionality: UNKNOWN