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Disorders of Fatty Acid Metabolism

Fatty acid oxidation disorders (FAODs) are a group of genetic conditions caused by disruptions in beta-oxidation or the carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transport pathway. These disruptions lead to an inability to metabolize fatty acids Fatty acids Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated. Fatty Acids and Lipids. All FAOD types are autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance. Because of the inability of the body to break down fatty acids Fatty acids Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated. Fatty Acids and Lipids, these fats Fats The glyceryl esters of a fatty acid, or of a mixture of fatty acids. They are generally odorless, colorless, and tasteless if pure, but they may be flavored according to origin. Fats are insoluble in water, soluble in most organic solvents. They occur in animal and vegetable tissue and are generally obtained by boiling or by extraction under pressure. They are important in the diet (dietary fats) as a source of energy. Energy Homeostasis accumulate in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and other internal organs. The clinical presentations of each disorder vary, but they commonly include hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types, encephalopathy Encephalopathy Hyper-IgM Syndrome, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, myopathy Myopathy Dermatomyositis, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction. Screening Screening Preoperative Care of newborns can detect these diseases, and DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure sequencing is usually performed to confirm the diagnosis. Management includes dietary changes or substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes supplementation.

Last updated: 26 Nov, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Disorders of fatty acid oxidation are inborn errors of metabolism that disrupt mitochondrial beta-oxidation or fatty acid transportation via the carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transport pathway.

Types and classification

  • Beta-oxidation disorders:
    • Short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (SCADD)
    • Medium-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (MCADD)
    • Very-long-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (VLCADD)
    • Long-chain 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (LCHADD)
    • Medium-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (MADD)
    • 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (HADD)
  • Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transport disorders:
    • Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transporter deficiency (CTD)
    • Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase type 1 Type 1 Spinal Muscular Atrophy deficiency (CPT1D)
    • Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism-acylcarnitine translocase deficiency (CACTD)
    • Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase type 2 Type 2 Spinal Muscular Atrophy deficiency (CPT2D)
Carnitine transports fatty acids between the cytosol and mitochondrial matrix

Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transports fatty acids Fatty acids Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated. Fatty Acids and Lipids between the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton and mitochondrial matrix. Problems with this process lead to disorders of fatty acid metabolism Fatty acid metabolism Fatty acid metabolism includes the processes of either breaking down fatty acids to generate energy (catabolic) or creating fatty acids for storage or use (anabolic). Besides being a source of energy, fatty acids can also be utilized for cellular membranes or signaling molecules. Synthesis and beta oxidation are almost the reverse of each other, and special reactions are required for variations. Fatty Acid Metabolism.
CoA: coenzyme A

Image: “Acyl-CoA from cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton to the mitochondrial matrix” by Slagt. License: CC0 1.0

Epidemiology

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: approximately 1 in 5000–10,000 live births
  • The most common is MCADD.
  • All autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
  • Affects both boys and girls

Pathophysiology

The exact pathophysiology varies depending on the deficiency, but there are a couple of overall consequences of disrupting the fatty acid oxidation process:

  • Reduced energy supply:
    • Fatty acids Fatty acids Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated. Fatty Acids and Lipids (FAs) are metabolized for energy in multiple tissues, particularly in a fasting state Fasting state Abstaining from food. Energy Homeostasis.
    • An inability to use FAs → body uses glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance stores normally reserved for vital tissues (e.g., brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification) → hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Some tissues (e.g., skeletal muscle, heart) use FAs in the fed state Fed state Energy Homeostasis → loss of this energy source → clinical manifestations
  • Accumulation of fatty acid metabolites:
    • Unable to progress through the beta-oxidation process, FA FA Inhaled Anesthetics metabolites can build up (particularly within mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles)
    • Some metabolites can be toxic → mitochondrial dysfunction → tissue and organ dysfunction

Clinical Presentation

The presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor and severity varies depending on the disorder. However, there are common signs and symptoms:

  • Systemic: 
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Poor appetite
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
  • Neurologic: 
    • Extreme sleepiness
    • Behavior changes
    • Irritable mood Irritable mood Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience. Oppositional Defiant Disorder
    • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
    • Encephalopathy Encephalopathy Hyper-IgM Syndrome
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Peripheral neuropathy Neuropathy Leprosy
  • GI: 
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Hepatic abnormalities are common in infants and children
    • Hepatomegaly
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Muscle:
    • Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy
    • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis may occur in older children and young adults
  • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR):
    • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types may be the initial presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor in the neonatal period
    • Arrhythmia
  • Other:
    • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Retinal degeneration

Diagnosis and Management

Diagnosis

  • Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care (NBS) detects most cases in developed countries.
  • Confirmed with:
    • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products acylcarnitine profile
    • Total and free carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism levels
    • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure testing provides the final diagnosis
  • Supportive laboratory evaluation (may vary based on the disorder): 
    • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance and ketones Ketones Organic compounds containing a carbonyl group =C=O bonded to two hydrocarbon groups. Basics of Carbohydrates (nonketotic hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia)
    • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • Transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis
    • Ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance
    • ↑ CK

Management

Common treatment options include:

  • Emergency management for decompensation: IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids with dextrose Dextrose Intravenous Fluids
  • Dietary modification:
    • Avoid fasting.
    • Snack on low-fat foods.
    • Eat high-carbohydrate diet.
  • Supplementation may be helpful in some disorders:    
    • L-carnitine L-carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Drug-induced Liver Injury 
    • Medium-chain triglyceride oil and triheptanoin are substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes therapies for long-chain fatty acid oxidation disorders

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Long-chain fatty acid oxidation disorders are associated with a higher mortality Mortality All deaths reported in a given population. Measures of Health Status:
    • LCHADD
    • VLCADD
    • CPT2D
    • CACTD
  • Individuals diagnosed through NBS (as opposed to clinically) tend to have better outcomes.

Comparison of Fatty Acid Oxidation Disorders (FAODs)

Table: Comparison of FAODs
Type Cause Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor
Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism transport deficiency (CTD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in SLC22A5
  • Defective transporter responsible for moving carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism into cells (deficiency of carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism in cells)
  • Difficulty moving FAs into mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • Asymptomatic to lethal
  • Encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis
  • Skeletal muscle weakness
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism-acylcarnitine translocase deficiency (CACTD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in SLC25A20
  • Defective carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism-acylcarnitine translocase
  • Difficulty moving FAs into mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Hepatomegaly
  • Hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis
  • Skeletal muscle weakness
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Ventricular arrhythmia
  • Sudden infant death
Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase IA deficiency (CPT1AD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in CPT1A
  • Defect in carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase 1 enzyme
  • Difficulty moving FAs into mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction/failure
  • Hepatic encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Elevated levels of carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism
Carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase II (CPT2D)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in CPT2
  • Defect in carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism palmitoyltransferase 2 enzyme
  • Difficulty moving FA FA Inhaled Anesthetics into mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
Mild to severe adult form:
  • Exercise intolerance
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome

Neonatal form:
  • Hypotonia Hypotonia Duchenne Muscular Dystrophy
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Arrhythmia
  • Seizure
  • Dysmorphic facies
  • Renal cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change
  • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification malformations
  • Death
Multiple acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (MADD)
  • Mutations in ETFA, ETFB, ETFDH
  • Defect in the electron transport chain Electron transport chain The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC)
  • Cannot accept electrons from several acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Disrupts beta-oxidation
Neonatal onset:
  • Congenital Congenital Chorioretinitis anomalies
  • Dysmorphic features
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Death

Later onset:
  • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Skeletal muscle myopathy Myopathy Dermatomyositis
Very long-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (VLCADD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in ACADVL
  • Inadequate levels of very-long-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzyme
  • Unable to catalyze initial step in beta-oxidation
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Skeletal myopathy Myopathy Dermatomyositis
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Death
Long-chain 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (LCHADD)
  • Mutations in HADHA gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Inadequate levels of long-chain 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzyme
  • Unable to catalyze step in beta-oxidation
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Hypotonia Hypotonia Duchenne Muscular Dystrophy
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Cholestasis
  • Skeletal myopathy Myopathy Dermatomyositis
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Peripheral neuropathy Neuropathy Leprosy
  • Retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Death
Medium-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (MCADD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in ACADM
  • Inadequate levels of medium-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzyme
  • Unable to catalyze step in beta-oxidation
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dysfunction
  • Hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Death
Short-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (SCADD)
  • Mutations in ACADS
  • Deficiency in short-chain acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzyme
  • Unable to catalyze step in beta-oxidation
Asymptomatic
Short-chain 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism deficiency (HADD)
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in HADH
  • Deficiency in 3-hydroxy acyl-CoA dehydrogenase Acyl-CoA dehydrogenase A flavoprotein oxidoreductase that has specificity for medium-chain fatty acids. It forms a complex with electron transferring flavoproteins and conveys reducing equivalents to ubiquinone. Fatty Acid Metabolism enzyme
  • Unable to catalyze step in beta-oxidation
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia (hyperinsulinism)
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
FA FA Inhaled Anesthetics: fatty acid

References

  1. Merritt, J. L., Norris, M., Kanungo, S. (2018). Fatty acid oxidation disorders. Annals of Translational Medicine 6(24):473. https://doi.org/10.21037/atm.2018.10.57 
  2. Merritt, J.L., Vockley, J. (2020). Overview of fatty acid oxidation disorders. UpToDate. Retrieved October 31, 2021, from https://www.uptodate.com/contents/overview-of-fatty-acid-oxidation-disorders
  3. Vockley, J. (2020). Specific fatty acid oxidation disorders. UpToDate. Retrieved October 31, 2021, from https://www.uptodate.com/contents/specific-fatty-acid-oxidation-disorders
  4. Merritt, J.L., MacLeod, E., Jurecka, A. et al. (2020). Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord 21:479–493. https://doi.org/10.1007/s11154-020-09568-3 
  5. Shekhawat, P., Matern, D., Strauss, A. (2005). Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Pediatr Res 57:78–86. https://doi.org/10.1203/01.PDR.0000159631.63843.3E
  6. Demczko, M. (2020). Beta-oxidation cycle disorders. MSD Manual Professional Version. Retrieved October 31, 2021, from https://www.merckmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/beta-oxidation-cycle-disorders#v25253815

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