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 transport pathway. These disruptions lead to an inability to metabolize fatty acids. All FAOD types are autosomal recessive. Because of the inability of the body to break down fatty acids, these fats 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 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). Overview of Cardiomyopathies, encephalopathy, 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, 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 dysfunction. Screening of newborns can detect these diseases, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure sequencing is usually performed to confirm the diagnosis. Management includes dietary changes or substrate supplementation.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Disorders of fatty acid oxidation are inborn errors of metabolism that disrupt mitochondrial beta-oxidation or fatty acid transportation via the carnitine transport pathway.

Types and classification

  • Beta-oxidation disorders:
    • Short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (SCADD)
    • Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
    • Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD)
    • Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHADD)
    • Medium-chain acyl-CoA dehydrogenase deficiency (MADD)
    • 3-hydroxy acyl-CoA dehydrogenase deficiency (HADD)
  • Carnitine transport disorders:
    • Carnitine transporter deficiency (CTD)
    • Carnitine palmitoyltransferase type 1 deficiency (CPT1D)
    • Carnitine-acylcarnitine translocase deficiency (CACTD)
    • Carnitine palmitoyltransferase type 2 deficiency (CPT2D)
Carnitine transports fatty acids between the cytosol and mitochondrial matrix

Carnitine transports fatty acids 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 Cytoskeletonand mitochondrial matrix. Problems with this process lead to disorders of 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 Cytoskeletonto the mitochondrial matrix” by Slagt. License: CC0 1.0

Epidemiology

  • Incidence: approximately 1 in 5000–10,000 live births
  • The most common is MCADD.
  • All autosomal recessive
  • 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 (FAs) are metabolized for energy in multiple tissues, particularly in a fasting state.
    • An inability to use FAs → body uses glucose stores normally reserved for vital tissues (e.g., brain) → 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 → loss of this energy source → clinical manifestations
  • Accumulation of fatty acid metabolites:
    • Unable to progress through the beta-oxidation process, FA metabolites can build up (particularly within mitochondria)
    • Some metabolites can be toxic → mitochondrial dysfunction → tissue and organ dysfunction

Clinical Presentation

The presentation 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
    • Intellectual disability
    • Encephalopathy
    • Seizures
    • Peripheral neuropathy
  • GI: 
    • Nausea and vomiting
    • 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 dysfunction
  • Muscle:
    • Myalgia
    • 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:
    • Cardiomyopathy may be the initial presentation in the neonatal period
    • Arrhythmia
  • Other:
    • Hypoglycemia
    • Retinal degeneration

Diagnosis and Management

Diagnosis

  • Newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening (NBS) detects most cases in developed countries.
  • Confirmed with:
    • Plasma acylcarnitine profile
    • Total and free carnitine levels
    • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure testing provides the final diagnosis
  • Supportive laboratory evaluation (may vary based on the disorder): 
    • ↓ Glucose and ketones (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
    • ↑ Ammonia
    • ↑ 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
  • Dietary modification:
    • Avoid fasting.
    • Snack on low-fat foods.
    • Eat high-carbohydrate diet.
  • Supplementation may be helpful in some disorders:    
    • L-carnitine 
    • Medium-chain triglyceride oil and triheptanoin are substrate therapies for long-chain fatty acid oxidation disorders

Prognosis

  • Long-chain fatty acid oxidation disorders are associated with a higher mortality:
    • 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
Carnitine 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 into cells (deficiency of carnitine in cells)
  • Difficulty moving FAs into mitochondria
  • Asymptomatic to lethal
  • Encephalopathy
  • Liver dysfunction
  • Hyperammonemia
  • Skeletal muscle weakness
  • Hypoglycemia
  • Cardiomyopathy
Carnitine-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-acylcarnitine translocase
  • Difficulty moving FAs into mitochondria
  • Seizures
  • Hypoglycemia
  • Hepatomegaly
  • Hyperammonemia
  • Skeletal muscle weakness
  • Cardiomyopathy
  • Ventricular arrhythmia
  • Sudden infant death
Carnitine 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 palmitoyltransferase 1 enzyme
  • Difficulty moving FAs into mitochondria
  • Hypoglycemia
  • Liver dysfunction/failure
  • Hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy
  • Elevated levels of carnitine
Carnitine 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 palmitoyltransferase 2 enzyme
  • Difficulty moving FA into mitochondria
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

Neonatal form:
  • Hypotonia
  • Cardiomyopathy
  • Arrhythmia
  • Seizure
  • Dysmorphic facies
  • Renal cysts
  • Brain malformations
  • Death
Multiple acyl-CoA dehydrogenase 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 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 anomalies
  • Dysmorphic features
  • Cardiomyopathy
  • Death

Later onset:
  • Vomiting
  • Dehydration
  • 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 dysfunction
  • Skeletal muscle myopathy
Very long-chain acyl-CoA dehydrogenase 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 enzyme
  • Unable to catalyze initial step in beta-oxidation
  • Hypoglycemia
  • Lethargy
  • Liver dysfunction
  • Cardiomyopathy
  • Skeletal myopathy
  • 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 deficiency (LCHADD)
  • Mutations in HADHA gene
  • Inadequate levels of long-chain 3-hydroxy acyl-CoA dehydrogenase enzyme
  • Unable to catalyze step in beta-oxidation
  • Lethargy
  • Hypoglycemia
  • Hypotonia
  • Liver dysfunction
  • Cholestasis
  • Skeletal myopathy
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Peripheral neuropathy
  • Retinopathy
  • Cardiomyopathy
  • 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 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 enzyme
  • Unable to catalyze step in beta-oxidation
  • Hypoglycemia
  • Liver dysfunction
  • Hyperammonemia
  • Lethargy
  • Seizures
  • Death
Short-chain acyl-CoA dehydrogenase deficiency (SCADD)
  • Mutations in ACADS
  • Deficiency in short-chain acyl-CoA dehydrogenase enzyme
  • Unable to catalyze step in beta-oxidation
Asymptomatic
Short-chain 3-hydroxy acyl-CoA dehydrogenase 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 enzyme
  • Unable to catalyze step in beta-oxidation
  • Hypoglycemia (hyperinsulinism)
  • Seizures
  • Intellectual disability
FA: 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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