The Embryology and Potential Mechanisms that Tie Together
The Embryology and Potential Mechanisms that Tie Together The Pentad; Dysautonomia, Mast Cell Activation Syndrome, Ehlers Danlos, Gastrointestinal Dysmotility, and Autoimmunity Andrew J. Maxwell, M. D. FACC Heart of the Valley Pediatric Cardiology, Pleasanton, CA
Learning Objectives: • Consider a core set of 5 syndromes (The Pentad Super-Syndrome) as the basis for all other sub-syndromes • Consider the Embryology and Natural History of The Pentad • Consider the various theoretical connections tying together these 5 syndromes • Consider the Unstable Craniocervical Region connecting The Pentad • Consider the Brain-Gut Axis Vortex connecting The Pentad • Consider Mast Cell Activation connecting The Pentad • Consider the Methylation/Folate Pathways connecting The Pentad No disclosures
HEAD * Denotes more common symptom CHEST Orthostatic Sx: Dizziness* Light-headedness Near-syncope* Syncope Pain: Migraine Non-migraine Occipital TJM Pain Neck Pain Coat-hanger Pain Racing heart Bursts (Palpitations)* “Rushes of Flushes” Recumbent racing heart Chronic racing heart Shortness of breath Dyspnea Hyperventilation sequence Pain: Chest pain Globus Generalized Fatigue* Back pain Early exhaustion Exercise intolerance* Muscle weakness* Cyanosis and Pooling Tremulousness/shakiness Hives Temperature dysregulation Livido Reticularis Feeling hot* Dyshidrotic eczema Feeling cold* on palms and soles Hyper-allergenic Easy Bruising SYSTEMIC SKIN MIND Anxiety* Insomnia* Attention deficit* Cognitive Impairment* Mood disturbances Sensitivity to sound VISION Dysautonomia is a SYNDROME: A pattern of signs and symptoms that characterize a particular condition. Blackout vision* Visual hallucinations Sensitivity to textures Sensitivity to light EXTREMITIES Accrual coldness* Raynaud’s syndrome Dyshydrosis: Hyper-hydrosis Anhydrosis Joint hypermobility Joint dislocations Distal leg/foot pooling Pain: Multiple joint pains ABDOMEN Nausea* Early Satiety Indigestion Constipation/Diarrhea Pain: Sharp epigastric Crampy generalized Genitourinary Urinary frequency* Chronic UTI (sterile) Incontinence Vaginal Bleeding Dysmenorrhea Pain: Endometriosis Dyspareunia
HEAD • • * more common symptom Dysautonomia Mast Cell Activation Ehlers Danlos CHEST Orthostatic Sx: Dizziness* Light-headedness Near-syncope* Syncope Pain: Migraine Non-migraine Occipital TJM Pain Neck Pain Coat-hanger Pain Racing heart Bursts (Palpitations)* “Rushes of Flushes” Recumbent racing heart Chronic racing heart Shortness of breath Dyspnea Hyperventilation sequence Pain: Chest pain Globus Generalized Fatigue* Back pain Early exhaustion Exercise intolerance* Muscle weakness* Cyanosis and Pooling Tremulousness/shakiness Hives Temperature dysregulation Livido Reticularis Feeling hot* Dyshidrotic eczema Feeling cold* on palms and soles Hyper-allergenic Easy Bruising SYSTEMIC SKIN MIND Anxiety* Insomnia* Attention deficit* Cognitive Impairment* Mood disturbances Sensitivity to sound Dysautonomia versus Mast Cell Activation Syndrome VISION Blackout vision* Visual hallucinations Sensitivity to textures Sensitivity to light EXTREMITIES Accrual coldness* Raynaud’s syndrome Dyshydrosis: Hyper-hydrosis Anhydrosis Joint hypermobility Joint dislocations Distal leg/foot swelling Pain: Multiple joint pains ABDOMEN Nausea* Early Satiety Indigestion Constipation/Diarrhea Pain: Sharp epigastric Crampy generalized Genitourinary Urinary frequency* Chronic UTI (sterile) Incontinence Vaginal Bleeding Dysmenorrhea Pain: Endometriosis
Adult G Defic H iency Em pt Syn y Sella dro me “Pse udo Synd -Eagle’s rom e” Cranial Nerve Neuralgias Intracranial Hypertension ranial Intrac sion ten Hypo dder a l B c enti rder g o r Neu ait Diso G ty nxie sion A h Hig Depres nic o r h C Sjogren’s/Lupus/Celiac Antiphospholipid synd Anti-CV receptor Ab Paraneoplastic Ab Antibody. Mediated PANS/PANDAS Res tl Syn ess Leg dro me Dys Mov tonic eme nts Dysautonomia Cranio cerv Instab ical ility Obstructive Sleep Apnea Ehlers Danlos Hypermobility Syndrome itary Pitu iency e ffic Insu han-Lik e She drome Syn drial n o h c Mito unction Dysf ered Teth Mast Cell Activation Syndrome o. Neur S MAL lar. Vascu MALS MCASMediated PANS Fibromyalgia Endometriosis Vaginal Bleeding Gastrointestinal Dysmotility Cord e Fatigu c i n o Chr ome Syndr Multiple Chemical Sensitivity Syndrome k CSF Lea hy GH Adult cy en Defici d Bloo y k a r Le arrie B n i a Br Autoimmune Disease Pan rism a ituit pop Leaky G ut SIBO IBS CRPS Menstrual Irregularity PCOS
Out of chaos -- > Order
“Pentad Super-Syndrome” Autoimmune Disease Dysautonomia Genetics Triggers Mast Cell Activation Syndrome Ehlers Danlos Hypermobility Syndrome Gastrointestinal Dysmotility
“Pentad Super-Syndrome” Adult G Defic H iency Em pt Syn y Sella dro me “Pse udo Synd -Eagle’s rom e” Cranial Nerve Neuralgias Intracranial Hypertension ranial Intrac sion ten Hypo dder a l B c enti rder g o r Neu ait Diso G Sjogren’s/Lupus/Celiac Antiphospholipid synd Anti-CV receptor Ab Antibody- Paraneoplastic Ab Res tl Syn ess Leg dro me drial n o h c Mito unction Dysf Mediated PANS/PANDAS Dys Mov tonic eme nts Cranio cerv Instab ical ility Obstructive Sleep Apnea k o. Neur S MAL Dysautonomia itary Pitu iency e ffic Insu han-Lik e She drome Syn Cord lar. Vascu MALS Pan rism a ituit pop hy GH Adult cy en Defici d Bloo y k a r Le arrie B n i a Br e Fatigu c i n o Chr ome Syndr Multiple Chemical Sensitivity Syndrome Genetics Triggers Mast Cell Activation Syndrome Ehlers Danlos Hypermobility Syndrome CSF Lea ered Teth Autoimmune Disease ty nxie sion A h Hig Depres nic o r h C Fibromyalgia Endometriosis Vaginal Bleeding Gastrointestinal Dysmotility Leaky G ut SIBO MCASMediated PANS IBS CRPS Menstrual Irregularity PCOS
How are the 5 syndromes of The Pentad Connected?
4 Major Places were the 5 Syndromes Intertwine
4 Major Places where the 5 Syndromes Intertwine 1) At the Craniocervical-Eagle Space
4 Major Places where the 5 Syndromes Intertwine 1) At the Craniocervical-Eagle Space 2) At the Brain-Gut Axis Vortex
4 Major Places where the 5 Syndromes Intertwine 1) At the Craniocervical-Eagle Space 2) At the Brain-Gut Axis Vortex 3) At the Activation of Mast Cells
4 Major Places where the 5 Syndromes Intertwine 1) At the Craniocervical-Eagle Space 2) At the Brain-Gut Axis Vortex 3) At the Activation of Mast Cells 4) At the Folate-Methylation Pathway
The Embryology of The Pentad
Multiple Routes to Same Final Common Pathway Primary Dysfunction Of Vagus Nerve Primary Mast Cell Derangement Primary Hypermobile Ehlers Danlos Primary Gastrointestinal Derangement
Multiple Routes to Same Final Common Pathway Primary Dysfunction Of Vagus Nerve
Phase 1 Phase 2 Pure Vagal Dysfunction Renal Hypovolemia 1 2 3 4 Metabolic Dysfunction Symptoms of Diuresis Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Urinary Frequency Symptoms of Vagal Dysfunction Palpitations Orthostatic Intolerance Head Symptoms 0 Phase 3 5 6 7 8 Symptoms of: Mitochondrial Dysfunction Mast Cell Activation Leaky Gut Hypermobility Mood Disorder Weeks from onset 16 Phase 4 Autoimmunity & Structural Changes Signs and Sx of Autoimmunity Joint Pains Fibromyalgia Hyper-allergic Responses Specific Autoimmune Diseases Structural Changes Visceroptosis 26
Natural Course of The Pentad IV …. . III Autoimmunity Hypermobility MCAS Dysautonomia …. . II I Grade or Phase 0 1 2 3 4 5 6 7 8 9 10 11 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Years Dysautonomia
Phase 1 Phase 2 Pure Vagal Dysfunction Phase 3 Renal Hypovolemia Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of Vagal Dysfunction Palpitations Orthostatic Intolerance Head Symptoms 0 1 2 3 4 5 6 7 8 Weeks from onset 16 26
Vagal dysfunction… Phase 1 Pure Vagal Dysfunction is only the beginning….
Phase 1 Pure Vagal Dysfunction Symptoms of Poor Orthostatic Perfusion Dizziness Fainting Loss of Vision Migraine headaches Foggy Thinking Attention deficit Coathanger Pain Blood pooling in lower extremities
Phase 1 Pure Vagal Dysfunction
Vagal Nerve Injury Major Sites of Injury Phase 1 Pure Vagal Dysfunction Brainstem/pannus Compression Pseudo-Eagle Syndrome Compression Nerve body or Axonal Inflammation Enteric Afferent Inflammation Carotid Body Compression
Vagal Nerve Injury Phase 1 Direct toxin or inflammation Top down approach Bottom up approach Pure Vagal Dysfunction Vagus neuritis by: • Traumatic injury to hypothalamus, medulla, or vagus nerve. • • EBV, Parvovirus B 19, Coxackie, Lyme, Rickettsial dz Autoimmune Toxic injury by neurotoxin such as quinine or heavy metals Inflammatory cytokines from chronic inflammation, auto-immune disease, leaky gut act on vagal afferents. Van. Elzakker MB Med Hypotheses. 2013 Sep; 81(3): 414 -23. doi: 10. 1016/j. mehy. 2013. 05. 034. Epub 2013 Jun 19 Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis
Vagal Nerve Injury Phase 1 Pure Vagal Dysfunction Craniocervical / Pseudo-Eagle Instability
Vagal Nerve Injury Phase 1 Pure Vagal Dysfunction Craniocervical / Pseudo-Eagle Instability
Vagal Nerve Injury Phase 1 Pure Vagal Dysfunction Craniocervical / Pseudo-Eagle Instability CNs IX, X, and XI Eagle Space
Upper Airway Resistance Syndrome and Pseudo-Eagle Syndrome Increased CSF Pressure in response to hypoxia/hypercapnia UARS with hypoxia/ hypercapnia Pseudo-Eagle Syndrome with Jugular Compression Obstructed CSF Drainage though glymphatics and Lymphatics from high jugular venous pressure Nighttime Supine Spikes in ICP
Autoimmune Disease Dysautonomia Mast Cell Activation Syndrome Ehlers Danlos Hypermobility Syndrome Gastroparesis
Phase 1 Phase 2 Pure Vagal Dysfunction Phase 3 Renal Hypovolemia Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of Diuresis Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Urinary Frequency 0 1 2 3 4 5 6 7 8 Weeks from onset 16 26
The Aldosterone Paradox Phase 2 Symptoms of Excess Diuresis and Hypovolemia Renal Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Pooling Blood Inappropriate Diuresis Worsening Cardiac Filling Deficit Dyspnea Tachycardia Urinary Frequency
Phase 2 Renal Hypovolemia
Phase 1 Phase 2 Pure Vagal Dysfunction Phase 3 Renal Hypovolemia Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of: Mitochondrial Dysfunction Mast Cell Activation Leaky Gut Hypermobility Mood Disorder 0 1 2 3 4 5 6 7 8 Weeks from onset 16 26
Phase 3 Depression Anxiety Sensory Intolerance Mood Swings Cognitive dysfunction Weakness Exercise Intolerance Tremulousness / Shakiness Metabolic Dysfunction Hypermobile joints Joint dislocations TMJ symptoms Thin skin Ehlers-Danlos III SIBO Leaky Gut MCAS Nausea, Bloating Early Satiety Gut dysmotility Gastroparesis
The Brain – Gut Axis Vortex Motor Vagal Nerve Efferent (Motor) Vagal Nerve Dysfunction Phase 3 Metabolic Dysfunction Elevated Gut p. H Dysmotility Afferent (Sensory) Vagal Nerve Dysfunction Efferent Vagus Celiac Afferent Vagus Ganglion Histamine TNF-α Histamine Elastase 2 Microorganism proliferation Histamine & Immune Cytokine Release (SIBO) Mast Cell Activation Leaky Gut Further Mast Cell Activation Van. Elzakker MB Med Hypotheses. 2013 Sep; 81(3): 414 -23. doi: 10. 1016/j. mehy. 2013. 05. 034. Epub 2013 Jun 19 Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis
Leaky Gut Syndromes (Increased Intestinal Permeability) Phase 3 Metabolic Dysfunction
The Brain – Gut Axis Vortex Motor Vagal Nerve Efferent (Motor) Vagal Nerve Dysfunction Phase 3 Metabolic Dysfunction Elevated Gut p. H Dysmotility Afferent (Sensory) Vagal Nerve Dysfunction Efferent Vagus Celiac Afferent Vagus Ganglion Histamine TNF-α Histamine Elastase 2 Microorganism proliferation Histamine & Immune Cytokine Release (SIBO) Mast Cell Activation Leaky Gut Further Mast Cell Activation Van. Elzakker MB Med Hypotheses. 2013 Sep; 81(3): 414 -23. doi: 10. 1016/j. mehy. 2013. 05. 034. Epub 2013 Jun 19 Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis
The Brain – Gut Axis Vortex Motor Vagal Nerve Efferent (Motor) Vagal Nerve Dysfunction Phase 3 Metabolic Dysfunction Elevated Gut p. H Dysmotility Afferent (Sensory) Vagal Nerve Dysfunction Efferent Vagus Celiac Afferent Vagus Ganglion Histamine TNF-α Histamine Elastase 2 Microorganism proliferation Histamine & Immune Cytokine Release (SIBO) Mast Cell Activation Leaky Gut Further Mast Cell Activation Van. Elzakker MB Med Hypotheses. 2013 Sep; 81(3): 414 -23. doi: 10. 1016/j. mehy. 2013. 05. 034. Epub 2013 Jun 19 Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis
Autoimmune Disease Eleva ted Gut p. H Dys motil ity Ehlers Danlos Hypermobility Syndrome Efferen t (Motor ) Vagal Nerve Dysfun ction Dysautonomia Moto r Vagal Nerv e Dysf uncti on Histami ne & Immun e Cytokin e Release Afferent Vagus Efferent Vagus Celiac Ganglion Micro organ ism prolif eratio n (SIBO ) Affere nt (Senso ry) Vagal Nerve Dysfun ction Histamine TNF-α Histamine Elastase 2 Mast Cell Activa tion Lea ky Gut Furthe r Mast Cell Activa tion Gastroparesis Mast Cell Activation Syndrome
Phase 3 Metabolic Dysfunction Tryptase TNF-α Elastase 2 Histamine Heparin
Phase 3 Metabolic Dysfunction Elastase 2 Cadherin Family Cadherins in Action
Phase 3 Metabolic Dysfunction Neuropsychiatric symptoms hypermobility Elastase 2 Breakdown of Blood Brain Barrier n-cadherins Fibrous Connective Tissue Basal keratinocyte Capillary Leak Angioedema Hives Edema ve-cadherins capillary endothelium Deeper skin tissue Integrins skin epithelium e-cadherins GI epithelium Dyshidrotic Eczema
Phase 1 Phase 2 Pure Vagal Dysfunction Phase 3 Renal Hypovolemia Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Signs and Sx of Autoimmunity Joint Pains Fibromyalgia Hyper-allergic Responses Specific Autoimmune Diseases Structural Changes 0 1 2 3 4 5 6 7 8 Weeks from onset 16 26
CSF Leak Symptoms of Mitochondrial Dysfunction Mood Disorder Hypermobility Mast Cell Activation Leaky Gut SIBO se 4 Pha ase 4 Visceroptosis Pha e 4 Cerebroptosis Autoimmunity & Structural Changes Autoimmune disorders Abnormal Ig. G levels Tethered Cord CCI Phase 4 MALS Chiari Chemical Hypersensitivity Syndrome Hyper-allergic responses Skin reactions Paroxysmal syncope Phas e 4
Phase 4 Autoimmunity & Structural Changes hypermobility Elastase 2 visceroptosis n-cadherins Fibrous Connective Tissue Craniocervical ligament instability and dural leak
Autoimmune Disease Dysautonomia Elastase 2 Mast Cell Activation Syndrome Ehlers Danlos Hypermobility Syndrome Gastroparesis
Vagus Nerve Terminal Folate / Methylation Pathways Pantethine (B 5) Palpitations Dizziness Orthostatic Intolerance Syncope Migraines Foggy Thinking Acetylcholine (Ach) Acetyl Co. A Cysteine Choline Mast Cell Syndromes Histidine N-methyl. Histamine Leaky Gut Dysmotility Allergies, flushing Histamine Imido. Acetaldehyde DAO Betaine Altered Connective Tissue Syndromes Hypermobility, EDS Mitochondrial Dysfunction IKAP Mitochondrial Dysfunction MTHFR Folic Acid (diet) Methylene Folate Un-metabolized Folic Acid Products (UMFA) IKAP Raynaud’s Increased Pain Sensitivity Depression Mood Disorders joint Pain Light Sensitivity Sound Sensitivity Other Pains Anxiety Migraines Vascular Volume Issues Chronic Dehydration Cortisol Deficiency
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sould Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Folate / Methylation Pathways Pantethine (B 5) (diet) Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Vagus Nerve Terminal Acetyl Co. A Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Acetylcholine (Ach) Cysteine (diet) Choline Folic Acid (diet) Vit B 6 Kreb’s Cycle MTHFR (diet) ) Ornithine IKAP Methylene Folate Betaine Methyl-Folate (diet) (Diet) (diet) Histamine Methionine MAO-A NOS (diet) DAO NO Raynaud’s S-adenosyl. Methionine IKAP N-methyl. Histamine DNA Methylation joint Pain Light Sensitvity Sound Sensitivity Other Pains Arginine Increased Pain Sensitivity DMG Leaky Gut Dysmotility Allergies Imido. Acetaldehyde MTHFR Histidine Mast Cell Sydromes Un-metabolized Folic Acid Products (UMFA) Homocysteine Aspartate Protein Sulfuration Altered Connective Tissue (diet) BH 4 (diet) ) Serotonin MAO-A IKAP Depression Mood Disorders Tyrosine Tryptophan BH 2 Dopamine Anxiety MAO-B COMT Norepinephrine
Autoimmune Disease Dysautonomia MTHFR Ehlers Danlos Hypermobility Syndrome Gastroparesis Mast Cell Activation Syndrome
4 Major Places where the 5 Syndromes Intertwine 1) At the Craniocervical-Eagle Space 2) At the Brain-Gut Axis Vortex 3) At the Activation of Mast Cells 4) At the Folate-Methylation Pathway
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