Disorders of Fatty Acid Metabolism

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)
  • 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)
  • 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-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)

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 Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (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 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:
  • 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 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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)