Exercise Intolerance Is Not a Diagnosis

A comprehensive list of possible illnesses or disorders that can be associated with exercise intolerance, grouped by category:

Exercise intolerance refers to an abnormal or reduced response to physical activity — often presenting as excessive fatigue, breathlessness, weakness, or muscle pain — that exceeds what would be expected for an individual's age, fitness level, or health status.
It is not a diagnosis in itself, but a clinical sign pointing to a wide range of possible underlying conditions. These can span cardiovascular, respiratory, neuromuscular, metabolic, genetic, infectious, or systemic causes.

Focus: The list below groups these potential causes by underlying pathophysiology or origin (e.g., genetic, viral, bacterial, etc.), and highlights whether the central nervous system (CNS) is involved.

Note: Psychological or functional causes, including Somatic Symptom Disorder (SSD), have been intentionally excluded due to the lack of objective evidence.

Cardiovascular Causes

Heart failure (systolic or diastolic)

Ischemic heart disease / Coronary artery disease

Arrhythmias (e.g., atrial fibrillation, ventricular tachycardia)

Hypertrophic cardiomyopathy

Dilated cardiomyopathy

Restrictive cardiomyopathy

Valvular heart disease (e.g., aortic stenosis, mitral regurgitation)

Congenital heart defects

Pericarditis / Pericardial effusion / Constrictive pericarditis

Pulmonary hypertension

Pulmonary Causes

Chronic obstructive pulmonary disease (COPD)

Asthma (especially exercise-induced)

Interstitial lung disease

Pulmonary fibrosis

Pulmonary embolism (chronic or acute)

Cystic fibrosis

Restrictive lung disease

Obesity hypoventilation syndrome

Pleural effusion

Pulmonary arterial hypertension

Metabolic & Mitochondrial Disorders

Mitochondrial myopathies

McArdle’s disease (Glycogen storage disease type V)

Pompe disease (Glycogen storage disease type II)

Carnitine palmitoyltransferase deficiency (CPT II)

Multiple acyl-CoA dehydrogenase deficiency (MADD)

Pyruvate dehydrogenase deficiency

Lactic acidosis due to mitochondrial dysfunction

Disorders of fatty acid oxidation

Phenylketonuria (PKU) – if untreated

Thyroid disorders (hypothyroidism or hyperthyroidism)

Neuromuscular Disorders

Myasthenia gravis

Muscular dystrophies (e.g., Duchenne, Becker)

Motor neuron diseases (e.g., ALS)

Polymyositis / Dermatomyositis

Multiple sclerosis

Peripheral neuropathy

Charcot-Marie-Tooth disease

Lambert-Eaton myasthenic syndrome

Metabolic myopathies (see above)

Post-viral fatigue syndromes

Genetic and Congenital Conditions

Ehlers-Danlos syndrome

Marfan syndrome

Noonan syndrome

Friedreich’s ataxia

Mitochondrial DNA mutations (various syndromes)

Hematologic Causes

Anemia (iron deficiency, B12/folate deficiency, chronic disease)

Sickle cell disease

Thalassemia

Polycythemia vera

Hemoglobinopathies

Electrolyte & Nutritional Disorders

Hypokalemia

Hypocalcemia

Hypomagnesemia

Vitamin D deficiency (severe)

Malnutrition or caloric deficiency

Endocrine & Systemic Disorders

Diabetes mellitus (especially poorly controlled)

Hypothyroidism / Hyperthyroidism

Adrenal insufficiency (e.g., Addison’s disease)

Cushing’s syndrome

Pheochromocytoma

Acromegaly

Electrolyte imbalances (see above)

Infectious Causes

Lyme disease

HIV/AIDS

Chronic Epstein-Barr virus (EBV)

Post-COVID syndrome / Long COVID

Tuberculosis (especially miliary TB)

Chagas disease (causing cardiomyopathy)

Other / Rare Causes

Medication side effects (e.g., beta-blockers, statins)

Chronic kidney disease

Liver failure

Cancer / Paraneoplastic syndromes

Autoimmune diseases (e.g., lupus, sarcoidosis, vasculitis)

Postural Orthostatic Tachycardia Syndrome (POTS)

Chronic pain syndromes

Sleep apnea

Overtraining syndrome (in athletes)

The correct diagnosis requires a detailed history, physical exam, and targeted testing (e.g., ECG, echocardiogram, pulmonary function tests, metabolic panels, CPET, EMG, etc.).

Neuromuscular Causes of Exercise Intolerance

These disorders often impair motor function, muscle strength, or energy metabolism, leading to early fatigue, weakness, and poor exercise tolerance.

Genetic Myopathies & Dystrophies

Duchenne Muscular Dystrophy (DMD)

Becker Muscular Dystrophy (BMD)

Dysferlinopathy (e.g., Miyoshi Myopathy, LGMD2B)

Limb-Girdle Muscular Dystrophies (various subtypes, including sarcoglycanopathies, calpainopathies)

Facioscapulohumeral Muscular Dystrophy (FSHD)

Emery-Dreifuss Muscular Dystrophy

Myotonic Dystrophy Type 1 and 2

Congenital Myopathies (e.g., Central core disease, Nemaline myopathy)

Centronuclear Myopathy

Distal Myopathies

Inclusion Body Myositis (IBM) – adult-onset, progressive weakness

SMA (Spinal Muscular Atrophy) – particularly Types 2 and 3 with ambulatory issues

Charcot-Marie-Tooth Disease (CMT) – hereditary motor and sensory neuropathies

ACTN3 Deficiency (α-actinin-3 gene polymorphism)

Not a disease per se, but it affects muscle performance and endurance in some individuals (especially elite athletes).

Pompe Disease (GSD Type II) – glycogen storage disorder with cardiac and skeletal muscle involvement

Metabolic Myopathies / Mitochondrial Disorders

Impair energy production at the cellular level; hallmark symptoms include early fatigue, myalgia, cramps, and myoglobinuria with exertion.

McArdle Disease (Glycogen Storage Disease type V)

CPT II Deficiency (Carnitine Palmitoyltransferase II Deficiency)

PFK Deficiency (Tarui Disease)

Phosphorylase b kinase deficiency

Lactate dehydrogenase deficiency

Mitochondrial myopathies

MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes)

MERRF (Myoclonic Epilepsy with Ragged Red Fibers)

Kearns–Sayre Syndrome

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

Fatty acid oxidation disorders (FAODs)

Pyruvate Dehydrogenase Complex Deficiency

Other Neurological Causes

Post-Polio Syndrome – progressive fatigue and weakness decades after acute poliomyelitis

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis (MS)

Peripheral Neuropathies

Myasthenia Gravis

Lambert-Eaton Myasthenic Syndrome (LEMS)

Guillain-Barré Syndrome (residual fatigue)

Cerebral Palsy – especially spastic or dystonic types

Parkinson’s Disease

Spinal cord injury

Master List of Exercise Intolerance Causes

Here’s the complete categorized list:

Cardiac Causes

Heart failure

Cardiomyopathies (HCM, DCM, RCM)

Arrhythmias

Coronary artery disease

Valvular heart disease

Congenital heart defects

Pericardial disease

Pulmonary hypertension

Pulmonary Causes

Asthma (including EIB)

COPD

ILD / Pulmonary fibrosis

Cystic fibrosis

Pulmonary embolism

Obesity hypoventilation

Restrictive lung diseases

Neuromuscular & Genetic Causes

Duchenne & Becker Muscular Dystrophy

Dysferlinopathy

Limb-Girdle Muscular Dystrophies

Facioscapulohumeral Dystrophy (FSHD)

Myotonic Dystrophy

Emery-Dreifuss Dystrophy

Centronuclear, Nemaline, and Congenital Myopathies

Inclusion Body Myositis (IBM)

SMA (Spinal Muscular Atrophy)

Charcot-Marie-Tooth

Post-Polio Syndrome

ACTN3 Deficiency

ALS

Myasthenia Gravis

LEMS

Guillain-Barré (residual)

Parkinson’s Disease

Cerebral Palsy

Metabolic / Mitochondrial

McArdle disease

Pompe disease

CPT II deficiency

Mitochondrial myopathies (MELAS, MERRF, etc.)

PFK deficiency

Pyruvate dehydrogenase deficiency

FAODs

MADD

Hematologic

Anemia

Sickle cell disease

Thalassemia

Polycythemia

Hemoglobinopathies

Endocrine / Metabolic

Hypothyroidism / Hyperthyroidism

Diabetes mellitus

Adrenal insufficiency

Cushing’s syndrome

Pheochromocytoma

Infectious / Inflammatory

HIV/AIDS

Chronic EBV

Lyme disease

Post-COVID syndrome

Tuberculosis

Sarcoidosis

Lupus

Vasculitis

Other

Medications (beta-blockers, statins, etc.)

Chronic kidney or liver disease

Sleep apnea

Electrolyte disturbances

Malnutrition

Categorized causes of exercise intolerance by underlying origin (e.g., genetic, viral, bacterial, fungal) and whether they involve the central nervous system (CNS) or brain.

Below is a categorized breakdown of the causes of exercise intolerance grouped by:

Genetic / Hereditary

Viral

Bacterial

Fungal

Brain / CNS Involvement

1. Genetic / Hereditary Causes

Inherited conditions, usually presenting in childhood or early adulthood (some later), often affecting muscles, nerves, mitochondria, or metabolic enzymes.

Neuromuscular Disorders

Duchenne Muscular Dystrophy

Becker Muscular Dystrophy

Dysferlinopathy

Limb-Girdle Muscular Dystrophies (various subtypes)

Facioscapulohumeral Muscular Dystrophy (FSHD)

Emery-Dreifuss Muscular Dystrophy

Congenital Myopathies (Central Core, Nemaline, etc.)

Centronuclear Myopathy

Inclusion Body Myositis (genetic forms)

Charcot-Marie-Tooth Disease

Spinal Muscular Atrophy (SMA)

Myotonic Dystrophy Type 1/2

ACTN3 Deficiency (polymorphism, not pathogenic per se)

Metabolic / Mitochondrial

McArdle Disease (GSD V)

Pompe Disease (GSD II)

CPT II Deficiency

Phosphofructokinase Deficiency (Tarui Disease)

Pyruvate Dehydrogenase Deficiency

Fatty Acid Oxidation Disorders (FAODs)

Mitochondrial Myopathies (e.g., MELAS, MERRF, KSS)

Other Genetic

Marfan Syndrome

Ehlers-Danlos Syndrome

Friedreich’s Ataxia

Noonan Syndrome

Phenylketonuria (if untreated)

2. Viral Causes

Can cause acute or chronic inflammation, fatigue, myocarditis, or CNS damage.

Chronic Fatigue Syndrome (often post-viral; ME/CFS)

Epstein-Barr Virus (EBV)

Cytomegalovirus (CMV)

HIV/AIDS

Hepatitis B/C (chronic fatigue)

COVID-19 (including Long COVID)

Influenza (severe)

Enteroviruses (e.g., Coxsackievirus → myocarditis)

Poliovirus (→ Post-Polio Syndrome)

HTLV-1 (rare, associated with myelopathy)

3. Bacterial Causes

Typically trigger systemic inflammation, myocarditis, or post-infectious syndromes.

Lyme Disease (Borrelia burgdorferi – chronic fatigue, neuroborreliosis)

Tuberculosis (chronic infection, fatigue, hypoxia)

Syphilis (can cause neurosyphilis → CNS involvement)

Chagas Disease (via Trypanosoma cruzi, but transmitted by a vector-borne bacterium-like parasite; chronic cardiomyopathy)

Mycoplasma pneumoniae (may trigger post-infectious fatigue)

Rheumatic fever (post-streptococcal → heart damage)

Sepsis/Post-sepsis syndrome (can lead to long-term fatigue and weakness)

4. Fungal Causes

Rare but relevant in immunocompromised individuals or endemic areas.

Histoplasmosis (can cause chronic pulmonary issues → exertional dyspnea)

Cryptococcosis (may involve brain → fatigue, encephalopathy)

Coccidioidomycosis (Valley Fever) (respiratory symptoms, fatigue)

Aspergillosis (invasive in immunocompromised → lung involvement)

Pneumocystis jirovecii pneumonia (PJP) – particularly in AIDS patients → exertional dyspnea

5. Brain / CNS Involvement

Conditions affecting the central nervous system (brain/spinal cord) that impair motor control, energy levels, or autonomic function.

Neurodegenerative / Demyelinating

Multiple Sclerosis (MS)

Parkinson’s Disease

Amyotrophic Lateral Sclerosis (ALS)

Post-Polio Syndrome (CNS motor neuron damage)

Friedreich’s Ataxia

Cerebral Palsy

Mitochondrial Disorders with CNS Involvement

MELAS

MERRF

Leigh Syndrome

Structural / Genetic Brain Disorders

Noonan Syndrome (may involve cognitive and motor delay)

Phenylketonuria (if untreated → cognitive deficits)

Infections with CNS Involvement

Poliovirus

HIV/AIDS (HIV encephalopathy)

HTLV-1

Neurosyphilis

Lyme disease (neuroborreliosis)

Cryptococcus (fungal meningitis)

Progressive multifocal leukoencephalopathy (PML) – JC virus in immunocompromised patients

Summary Table

Disclaimer: By accessing and reading this blog, you acknowledge that the information provided is for general informational purposes only and does not constitute medical advice, diagnosis, or treatment. The content is intended to address commonly asked questions and is derived from reputable scientific literature. Always consult a qualified healthcare professional for medical concerns or conditions.

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