The Embryology and Potential Mechanisms that Tie Together The Pentad;

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

MIND HEAD VISION ABDOMEN CHEST EXTREMITIES Genitourinary SYSTEMIC SKIN
Orthostatic Sx: Dizziness* Light-headedness Near-syncope* Syncope Pain: Migraine Non-migraine Occipital TJM Pain Neck Pain Coat-hanger Pain MIND Anxiety* Insomnia* Attention deficit* Cognitive Impairment* Mood disturbances Sensitivity to sound Recognition Dysautonomia is a SYNDROME: A pattern of signs and symptoms that characterize a particular condition. * Denotes more common symptom VISION Blackout vision* Visual hallucinations Sensitivity to textures Sensitivity to light ABDOMEN Nausea* Early Satiety Indigestion Constipation/Diarrhea Pain: Sharp epigastric Crampy generalized CHEST Racing heart Bursts (Palpitations)* “Rushes of Flushes” Recumbent racing heart Chronic racing heart Shortness of breath Dyspnea Hyperventilation sequence Pain: Chest pain Globus Back pain EXTREMITIES Accrual coldness* Raynaud’s syndrome Dyshydrosis: Hyper-hydrosis Anhydrosis Joint hypermobility Joint dislocations Distal leg/foot pooling Pain: Multiple joint pains Genitourinary Urinary frequency* Chronic UTI (sterile) Incontinence Vaginal Bleeding Dysmenorrhea Pain: Endometriosis Dyspareunia SYSTEMIC Generalized Fatigue* Early exhaustion Exercise intolerance* Muscle weakness* Tremulousness/shakiness Temperature dysregulation Feeling hot* Feeling cold* Hyper-allergenic SKIN Cyanosis and Pooling Hives Livido Reticularis Dyshidrotic eczema on palms and soles Easy Bruising Dysautonomia

MIND HEAD VISION ABDOMEN CHEST EXTREMITIES Genitourinary SYSTEMIC SKIN
Orthostatic Sx: Dizziness* Light-headedness Near-syncope* Syncope Pain: Migraine Non-migraine Occipital TJM Pain Neck Pain Coat-hanger Pain MIND Anxiety* Insomnia* Attention deficit* Cognitive Impairment* Mood disturbances Sensitivity to sound Recognition Dysautonomia versus Mast Cell Activation Syndrome * more common symptom Dysautonomia Mast Cell Activation Ehlers Danlos VISION Blackout vision* Visual hallucinations Sensitivity to textures Sensitivity to light ABDOMEN Nausea* Early Satiety Indigestion Constipation/Diarrhea Pain: Sharp epigastric Crampy generalized CHEST Racing heart Bursts (Palpitations)* “Rushes of Flushes” Recumbent racing heart Chronic racing heart Shortness of breath Dyspnea Hyperventilation sequence Pain: Chest pain Globus Back pain EXTREMITIES Accrual coldness* Raynaud’s syndrome Dyshydrosis: Hyper-hydrosis Anhydrosis Joint hypermobility Joint dislocations Distal leg/foot swelling Pain: Multiple joint pains Genitourinary Urinary frequency* Chronic UTI (sterile) Incontinence Vaginal Bleeding Dysmenorrhea Pain: Endometriosis SYSTEMIC Generalized Fatigue* Early exhaustion Exercise intolerance* Muscle weakness* Tremulousness/shakiness Temperature dysregulation Feeling hot* Feeling cold* Hyper-allergenic SKIN Cyanosis and Pooling Hives Livido Reticularis Dyshidrotic eczema on palms and soles Easy Bruising Dysautonomia

From chaos……. Dysautonomia Dysautonomia High Anxiety
Sjogren’s/Lupus/Celiac Antiphospholipid synd Anti-CV receptor Ab Paraneoplastic Ab High Anxiety Chronic Depression From chaos……. Pan-hypopituitarism Adult GH Deficiency Antibody-Mediated PANS/PANDAS Pituitary Insufficiency Sheehan-Like Syndrome Adult GH Deficiency Restless Leg Syndrome Mitochondrial Dysfunction Empty Sella Syndrome Chronic Fatigue Syndrome Dystonic Movements Dysautonomia Autoimmune Disease “Pseudo-Eagle’s Syndrome” Leaky Blood Brain Barrier MCAS-Mediated PANS Craniocervical Instability Cranial Nerve Neuralgias Multiple Chemical Sensitivity Syndrome Mast Cell Activation Syndrome Obstructive Sleep Apnea Ehlers Danlos Hypermobility Syndrome Intracranial Hypertension Fibromyalgia CSF Leak Gastrointestinal Dysmotility CRPS Intracranial Hypotension Endometriosis Vaginal Bleeding Tethered Cord Leaky Gut Menstrual Irregularity PCOS Neurogentic Bladder Gait Disorder Vascular- MALS Neuro- MALS SIBO IBS Dysautonomia

Out of chaos -- > Order

“Pentad Super-Syndrome”
From chaos…..ORDER! “Pentad Super-Syndrome” Dysautonomia Autoimmune Disease Ehlers Danlos Hypermobility Syndrome Genetics Mast Cell Activation Syndrome Triggers Gastrointestinal Dysmotility Dysautonomia

“Pentad Super-Syndrome”
From chaos…..ORDER! High Anxiety Chronic Depression Sjogren’s/Lupus/Celiac Antiphospholipid synd Anti-CV receptor Ab Paraneoplastic Ab Pan-hypopituitarism Adult GH Deficiency Mitochondrial Dysfunction Antibody-Mediated PANS/PANDAS Pituitary Insufficiency Sheehan-Like Syndrome Adult GH Deficiency Restless Leg Syndrome Empty Sella Syndrome Dysautonomia Autoimmune Disease Chronic Fatigue Syndrome Dystonic Movements “Pseudo-Eagle’s Syndrome” Leaky Blood Brain Barrier MCAS-Mediated PANS Craniocervical Instability Cranial Nerve Neuralgias Ehlers Danlos Hypermobility Syndrome Mast Cell Activation Syndrome Genetics Multiple Chemical Sensitivity Syndrome Triggers Obstructive Sleep Apnea Intracranial Hypertension Fibromyalgia Gastrointestinal Dysmotility CSF Leak CRPS Intracranial Hypotension Endometriosis Vaginal Bleeding Tethered Cord Leaky Gut Menstrual Irregularity PCOS Neurogentic Bladder Gait Disorder Vascular- MALS Neuro- MALS SIBO IBS Dysautonomia

How are the 5 syndromes of The Pentad Connected?

4 Major Places were the 5 Syndromes Intertwine
Dysautonomia

4 Major Places where the 5 Syndromes Intertwine
At the Craniocervical-Eagle Space Dysautonomia

At the Craniocervical-Eagle Space At the Brain-Gut Axis Vortex Dysautonomia

At the Craniocervical-Eagle Space At the Brain-Gut Axis Vortex At the Activation of Mast Cells Dysautonomia

At the Craniocervical-Eagle Space At the Brain-Gut Axis Vortex At the Activation of Mast Cells At the Folate-Methylation Pathway Dysautonomia

The Embryology of The Pentad

Multiple Routes to Same Final Common Pathway
Clinical Phases Multiple Routes to Same Final Common Pathway Primary Dysfunction Of Vagus Nerve Primary Hypermobile Ehlers Danlos Primary Gastrointestinal Derangement Primary Mast Cell Derangement Dysautonomia

Multiple Routes to Same Final Common Pathway
Clinical Phases Multiple Routes to Same Final Common Pathway Primary Dysfunction Of Vagus Nerve Dysautonomia

Phase 1 Phase 2 Phase 3 Phase 4
Clinical Phases Clinical Phases …… as observed by a cardiologist…. Phase 1 Pure Vagal Dysfunction Phase 2 Renal Hypovolemia Phase 3 Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of Diuresis Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Urinary Frequency Signs and Sx of Autoimmunity Joint Pains Fibromyalgia Hyper-allergic Responses Specific Autoimmune Diseases Structural Changes Visceroptosis Symptoms of Vagal Dysfunction Palpitations Orthostatic Intolerance Head Symptoms Symptoms of: Mitochondrial Dysfunction Mast Cell Activation Leaky Gut Hypermobility Mood Disorder Weeks from onset Dysautonomia

Natural Course of The Pentad IV III
….. IV III II I ….. Autoimmunity Hypermobility MCAS Dysautonomia Grade or Phase Years Dysautonomia

Clinical Phases Clinical Phases …… as observed by a cardiologist…. Phase 1 Pure Vagal Dysfunction Phase 2 Renal Hypovolemia Phase 3 Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of Vagal Dysfunction Palpitations Orthostatic Intolerance Head Symptoms Weeks from onset Dysautonomia

Pure Vagal Dysfunction
Phase 1 Pure Vagal Dysfunction is only the beginning…. Dysautonomia

Phase 1 Symptoms of Poor Orthostatic Perfusion Dizziness Fainting
Clinical Phases 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 Dysautonomia

Pure Vagal Dysfunction
Clinical Phases Phase 1 Pure Vagal Dysfunction Dysautonomia

Phase 1 Vagal Nerve Injury Carotid Body Compression
Clinical Phases Vagal Nerve Injury Major Sites of Injury Phase 1 Pure Vagal Dysfunction Carotid Body Compression Brainstem/pannus Compression Pseudo-Eagle Syndrome Compression Nerve body or Axonal Inflammation Enteric Afferent Inflammation Dysautonomia

Phase 1 Vagal Nerve Injury Direct toxin or inflammation
Clinical Phases Vagal Nerve Injury Direct toxin or inflammation Top down approach Bottom up approach Phase 1 Pure Vagal Dysfunction Vagus neuritis by: EBV, Parvovirus B19, 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. Traumatic injury to hypothalamus, medulla, or vagus nerve. Dysautonomia VanElzakker MB Med Hypotheses Sep;81(3): doi: /j.mehy Epub 2013 Jun 19Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis

Phase 1 Vagal Nerve Injury Craniocervical / Pseudo-Eagle Instability
Clinical Phases Vagal Nerve Injury Craniocervical / Pseudo-Eagle Instability Phase 1 Pure Vagal Dysfunction Dysautonomia

Phase 1 Eagle Space Vagal Nerve Injury
Clinical Phases Vagal Nerve Injury Craniocervical / Pseudo-Eagle Instability Phase 1 Pure Vagal Dysfunction CNs IX, X, and XI Eagle Space Dysautonomia

Upper Airway Resistance Syndrome and Pseudo-Eagle Syndrome
Clinical Phases Upper Airway Resistance Syndrome and Pseudo-Eagle Syndrome Increased CSF Pressure in response to hypoxia/hypercapnia UARS with hypoxia/ hypercapnia Obstructed CSF Drainage though glymphatics and Lymphatics from high jugular venous pressure Nighttime Supine Spikes in ICP Pseudo-Eagle Syndrome with Jugular Compression Dysautonomia

Unifying Theory of the Pentad Super-syndrome
Craniocervical / Pseudo-Eagle Instability Dysautonomia Autoimmune Disease Ehlers Danlos Hypermobility Syndrome Mast Cell Activation Syndrome Gastroparesis Dysautonomia

Clinical Phases Clinical Phases …… as observed by a cardiologist…. Phase 1 Pure Vagal Dysfunction Phase 2 Renal Hypovolemia Phase 3 Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of Diuresis Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Urinary Frequency Weeks from onset

Phase 2 The Aldosterone Paradox Renal Hypovolemia
Clinical Phases The Aldosterone Paradox Phase 2 Renal Hypovolemia Symptoms of Excess Diuresis and Hypovolemia Worsening Orthostatic Intolerance Worsening Head Symptoms Worsening Cardiac Filling Deficit Dyspnea Tachycardia Urinary Frequency Pooling Blood Inappropriate Diuresis Dysautonomia

Clinical Phases Phase 2 Renal Hypovolemia Dysautonomia

Clinical Phases Clinical Phases …… as observed by a cardiologist…. Phase 1 Pure Vagal Dysfunction Phase 2 Renal Hypovolemia Phase 3 Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Symptoms of: Mitochondrial Dysfunction Mast Cell Activation Leaky Gut Hypermobility Mood Disorder Weeks from onset Dysautonomia

Metabolic Dysfunction
Depression Anxiety Sensory Intolerance Mood Swings Cognitive dysfunction Clinical Phases Weakness Exercise Intolerance Tremulousness / Shakiness Phase 3 Metabolic Dysfunction Hypermobile joints Joint dislocations TMJ symptoms Thin skin Ehlers-Danlos III SIBO Leaky Gut MCAS Nausea, Bloating Early Satiety Gut dysmotility Gastroparesis Dysautonomia

The Brain – Gut Axis Vortex
Clinical Phases Motor Vagal Nerve Dysfunction Efferent (Motor) Vagal Nerve Dysfunction Afferent (Sensory) Vagal Nerve Dysfunction Phase 3 Metabolic Dysfunction Elevated Gut pH Dysmotility Efferent Vagus Afferent Vagus Histamine & Immune Cytokine Release Celiac Ganglion Histamine TNF-α Microorganism proliferation (SIBO) Histamine Elastase 2 Further Mast Cell Activation Mast Cell Activation Leaky Gut Dysautonomia VanElzakker MB Med Hypotheses Sep;81(3): doi: /j.mehy Epub 2013 Jun 19Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis

Phase 3 Leaky Gut Syndromes (Increased Intestinal Permeability)
Clinical Phases Leaky Gut Syndromes (Increased Intestinal Permeability) Phase 3 Metabolic Dysfunction Dysautonomia

The Brain – Gut Axis Vortex
Clinical Phases Motor Vagal Nerve Dysfunction Efferent (Motor) Vagal Nerve Dysfunction Afferent (Sensory) Vagal Nerve Dysfunction Phase 3 Metabolic Dysfunction Elevated Gut pH Dysmotility Efferent Vagus Afferent Vagus Histamine & Immune Cytokine Release Celiac Ganglion Histamine TNF-α Microorganism proliferation (SIBO) Histamine Elastase 2 Further Mast Cell Activation Mast Cell Activation Leaky Gut Dysautonomia VanElzakker MB Med Hypotheses Sep;81(3): doi: /j.mehy Epub 2013 Jun 19Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis

Brain-Gut Axis Vortex Dysautonomia Autoimmune Disease Histamine & Immune Cytokine Release Afferent (Sensory) Vagal Nerve Dysfunction Mast Cell Activation Elevated Gut pH Dysmotility Microorganism proliferation (SIBO) Efferent (Motor) Vagal Nerve Dysfunction Celiac Ganglion Vagus Histamine Elastase 2 TNF-α Leaky Gut Further Motor Vagal Nerve Dysfunction Ehlers Danlos Hypermobility Syndrome Mast Cell Activation Syndrome Gastroparesis Dysautonomia

Mast Cell Activation Syndrome Mast Cell Major Components
Clinical Phases Mast Cell Activation Syndrome Mast Cell Major Components Phase 3 Metabolic Dysfunction TNF-α Tryptase Elastase 2 Histamine Heparin Dysautonomia

Phase 3 Unifying Theory of the Pentad Super-syndrome
Clinical Phases Unifying Theory of the Pentad Super-syndrome Elastase 2 versus Cadherins and Integrins Phase 3 Metabolic Dysfunction Elastase 2 Cadherin Family Cadherins in Action Dysautonomia

Phase 3 Unifying Theory of the Pentad Super-syndrome
Clinical Phases Unifying Theory of the Pentad Super-syndrome Elastase 2 versus Cadherins and Integrins Phase 3 Metabolic Dysfunction hypermobility Neuropsychiatric symptoms Elastase 2 Breakdown of Blood Brain Barrier n-cadherins Fibrous Connective Tissue Basal keratinocyte ve-cadherins capillary endothelium Dyshidrotic Eczema Deeper skin tissue Capillary Leak Integrins skin epithelium Angioedema Hives Edema Dysautonomia e-cadherins GI epithelium

Phase 1 Phase 2 Phase 3 Phase 4 Pure Vagal Dysfunction Renal
Clinical Phases Phase 1 Pure Vagal Dysfunction Phase 2 Renal Hypovolemia Phase 3 Metabolic Dysfunction Phase 4 Autoimmunity & Structural Changes Signs and Sx of Autoimmunity Joint Pains Fibromyalgia Hyper-allergic Responses Specific Autoimmune Diseases Structural Changes Weeks from onset Dysautonomia

Phase 4 Symptoms of Mitochondrial Dysfunction Mood Disorder
Clinical Phases MALS CSF Leak Chiari CCI Tethered Cord Phase 4 Autoimmunity & Structural Changes Visceroptosis Cerebroptosis Phase 4 Phase 4 Symptoms of Mitochondrial Dysfunction Mood Disorder Hypermobility Mast Cell Activation Leaky Gut Chemical Hypersensitivity Syndrome Hyper-allergic responses Skin reactions Paroxysmal syncope SIBO Phase 4 Phase 4 Dysautonomia Autoimmune disorders Abnormal IgG levels

Phase 4 Unifying Theory of the Pentad Super-syndrome Autoimmunity &
Elastases versus Cadherins In Hypermobility And Hypermobile EDS Phase 4 Autoimmunity & Structural Changes hypermobility Elastase 2 visceroptosis n-cadherins Fibrous Connective Tissue Craniocervical ligament instability and dural leak

Elastase 2 Dysautonomia Autoimmune Disease Ehlers Danlos Hypermobility Syndrome Mast Cell Activation Syndrome Elastase 2 Gastroparesis Dysautonomia

Folate / Methylation Pathways
Pathophysiology Folate / Methylation Pathways Vagus Nerve Terminal Mast Cell Syndromes Leaky Gut Gut Dysmotility Allergies, flushing Histidine Pantethine (B5) Palpitations Dizziness Orthostatic Intolerance Syncope Migraines Foggy Thinking Acetylcholine (Ach) Acetyl CoA N-methyl- Histamine Cysteine Histamine Imido- Acetaldehyde Choline DAO Betaine Altered Connective Tissue Syndromes Hypermobility, EDS Mitochondrial Dysfunction IKAP Mitochondrial Dysfunction MTHFR Folic Acid (diet) Methylene Folate IKAP Un-metabolized Folic Acid Products (UMFA) Raynaud’s Increased Pain Sensitivity joint Pain Light Sensitivity Sound Sensitivity Other Pains Depression Mood Disorders Anxiety Dysautonomia Migraines Vascular Volume Issues Chronic Dehydration Cortisol Deficiency

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sould Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) NOS Tryptophan (diet) Tyrosine (diet) DAO BH4 (diet) ) NO BH2 MAO-A S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde N-methyl- Histamine Anxiety Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sould Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) Tyrosine (diet) NOS Tryptophan (diet) DAO BH4 (diet) ) NO BH2 MAO-A S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde N-methyl- Histamine Anxiety Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sould Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) Tyrosine (diet) NOS Tryptophan (diet) DAO BH4 (diet) ) BH2 MAO-A NO S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde Anxiety N-methyl- Histamine Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sould Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) NOS Tryptophan (diet) Tyrosine (diet) DAO BH4 (diet) ) NO BH2 MAO-A S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde N-methyl- Histamine Anxiety Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sould Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) Tryptophan (diet) Tyrosine (diet) NOS DAO BH4 (diet) ) NO BH2 MAO-A S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde N-methyl- Histamine Anxiety Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Pathophysiology Folate / Methylation Pathways Pantethine (B5) (diet) Palpitations Dizziness Orthostatic Interolerance Syncope Headache Foggy Thinking Vagus Nerve Terminal Mitochondrial Dysfunction Weakness Exercise Intolerance Shakiness Acetyl CoA Acetylcholine (Ach) Cysteine (diet) Choline (diet) Folic Acid (diet) Vit B6 (diet) ) Kreb’s Cycle MTHFR Ornithine IKAP Methylene Folate Homocysteine Un-metabolized Folic Acid Products (UMFA) Aspartate Betaine (diet) Methyl-Folate (Diet) MTHFR Histidine Increased Pain Sensitivity joint Pain Light Sensitvity Sound Sensitivity Other Pains Mast Cell Sydromes Leaky Gut Gut Dysmotility Allergies DMG (diet) Arginine (diet) Histamine Methionine (diet) NOS Tryptophan (diet) Tyrosine (diet) DAO BH4 (diet) ) NO BH2 MAO-A S-adenosyl-Methionine IKAP Raynaud’s Serotonin Dopamine Imido- Acetaldehyde N-methyl- Histamine Anxiety Norepinephrine Protein Sulfuration MAO-B DNA Methylation MAO-A Dysautonomia IKAP Depression Mood Disorders COMT Altered Connective Tissue

Folate Methylation Pathways Dysautonomia Autoimmune Disease Ehlers Danlos Hypermobility Syndrome Mast Cell Activation Syndrome MTHFR Gastroparesis Dysautonomia

At the Craniocervical-Eagle Space At the Brain-Gut Axis Vortex At the Activation of Mast Cells At the Folate-Methylation Pathway Dysautonomia

Dysautonomia

The Embryology and Potential Mechanisms that Tie Together The Pentad;

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