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Urea Cycle Disorders

Urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation disorders (UCDs) are caused by genetic defects and result in deficiencies of 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 and transporters of the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation. As a result of the defects, individuals are unable to rid the body of nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle waste. Common symptoms include vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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, and respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis. Most defects 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 and definitive diagnosis is by molecular genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Treatment aims to reduce 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 concentration in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products. In less severe cases, acute episodes can be prevented through dietary restriction of protein. Untreated disease may lead to 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, 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, or death.

Last updated: 27 Sep, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation disorders (UCDs) are a group of syndromes resulting from genetic mutations Genetic Mutations Carcinogenesis, which cause deficiencies in 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 and amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids transporters of the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation, resulting in the accumulation of nitrogenous waste products.

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
    • Globally: 1 per 35,000 live births
    • United States: 1 per 8,200 live births
    • Higher in individuals with partial defects
    • Difficult to quantify: Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency data is difficult to track.
  • Annual 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 113 new cases in the United States and 149 in Europe
  • Symptomatic in the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn period: approximately 26% of cases
  • Only 2 UCDs are currently detected by newborn screening Newborn Screening The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. Severe Combined Immunodeficiency (SCID) in the United States.

Etiology

All UCDs stem from genetic abnormalities, which cause deficiencies in 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 important to the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation:

  • Carbamyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes synthetase I (CPSI) deficiency 
  • N-acetylglutamate synthetase (NAGS) deficiency 
  • Ornithine Ornithine An amino acid produced in the urea cycle by the splitting off of urea from arginine. Urea Cycle transcarbamylase (OTC) deficiency 
  • Arginase Arginase A ureahydrolase that catalyzes the hydrolysis of arginine or canavanine to yield l-ornithine (ornithine) and urea. Urea Cycle deficiency
  • Argininosuccinate Argininosuccinate This amino acid is formed during the urea cycle from citrulline, aspartate and ATP. This reaction is catalyzed by argininosuccinic acid synthetase. Urea Cycle synthetase (ASS) deficiency (classic/type I citrullinemia) 
  • Argininosuccinate lyase Argininosuccinate lyase An enzyme of the urea cycle which splits argininosuccinate to fumarate plus arginine. Urea Cycle (ASL) deficiency (argininosuccinic aciduria)

All UCDs are inherited as 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 traits except OTC deficiency ( X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) recessive trait).

Pathophysiology

Normal physiology of urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation:

  • Produces amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids: arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle, ornithine Ornithine An amino acid produced in the urea cycle by the splitting off of urea from arginine. Urea Cycle, and citrulline Citrulline Urea Cycle
  • Mechanism for nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle clearance via protein breakdown (catabolism)
  • Protein catabolism results in 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 production.
  • 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 is converted to urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle.

Impairment of the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation 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 causes hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis ( 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 accumulation in the blood). Depending on the severity and age at manifestation, 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 may cause neurotoxic effects on the 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.

Urea cycle

Schematic diagram of the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation: The blue square indicates the feeder reaction.

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Clinical Presentation

Neonatal period

  • In the case of severe disorder, symptoms typically appear after the 1st 24 hours of life.
  • Symptoms appear after feeding.
  • Commonly misdiagnosed as Reye syndrome Reye syndrome A form of encephalopathy with fatty infiltration of the liver, characterized by brain edema and vomiting that may rapidly progress to seizures; coma; and death. It is caused by a generalized loss of mitochondrial function leading to disturbances in fatty acid and carnitine metabolism. Varicella-Zoster Virus/Chickenpox or sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
  • Symptoms:
    • Irritability
    • Refusal to feed
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • 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
    • Floppiness
    • Respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis
    • 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

Childhood

  • Mild/moderate cases of UCD present in early childhood. 
  • If the condition remains undiagnosed, hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis may occur leading to 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 and death.
  • Symptoms:
    • 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
    • Excessive crying
    • Agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus
    • Self-injurious behaviors
    • Refusal to eat high-protein foods
    • 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
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium

Adulthood

  • Individuals with mild deficiencies may not be diagnosed during childhood.
  • Symptoms in mild cases may be observed following an episode of viral illness, excessive exercise, drug use (e.g., valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs), or childbirth.
  • Symptoms:
    • Slurred speech Slurred Speech Cerebellar Disorders
    • Disorientation Disorientation St. Louis Encephalitis Virus
    • Confusion
    • Agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
    • 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
    • Stroke-like symptoms
    • Psychiatric issues like bipolar Bipolar Nervous System: Histology disorder and schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia

Diagnosis

  • Screen 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 level if:
  • Further workup to rule out UCD if:
    • 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 concentration in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products ≥ 100–150 μmol/L
    • Normal anion gap Anion gap Metabolic Acidosis
    • Normal plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products 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 concentration
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids concentrations:
    • Arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle:
      • ↑ Fourfold in arginase Arginase A ureahydrolase that catalyzes the hydrolysis of arginine or canavanine to yield l-ornithine (ornithine) and urea. Urea Cycle deficiency
      • ↓ CPSI deficiency
      • ↓ OTC deficiency
      • ↓ NAGS deficiency
    • Glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids:
      • ↑ CPSI deficiency
      • ↑ OTC deficiency
      • ↑ NAGS deficiency
    • Citrulline Citrulline Urea Cycle:
      • ↑ ASS deficiency
      • ↑ ASL deficiency
      • ↓ CPSI deficiency
      • ↓ OTC deficiency
      • ↓ NAGS deficiency
    • Argininosuccinic acid:
      • Absent in ASS deficiency
      • ↑ ASL deficiency
  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat orotic acid:
    • ↑ OTC deficiency
    • ↓ CPSI deficiency
  • Molecular genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:
    • Primary diagnostic method
    • Superior to enzyme activity as definitive testing method
  • Enzyme activity assay
  • Newborn screening Newborn Screening The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. Severe Combined Immunodeficiency (SCID): inconsistently performed in the United States

Management

Treatment should be tailored to the specific disorder:

Acute management

  • Physiologic stabilization:
  • Discontinuation of protein diet for 12–24 hours
  • To reduce 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 concentration in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products:
    • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis
    • Hemofiltration
  • To excrete excess nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle through an alternative pathway Alternative pathway Complement activation initiated by the interaction of microbial antigens with complement C3b. When complement factor B binds to the membrane-bound C3b, complement factor d cleaves it to form alternative C3 convertase (c3bbb) which, stabilized by complement factor p, is able to cleave multiple complement C3 to form alternative C5 convertase (c3bbb3b) leading to cleavage of complement C5 and the assembly of complement membrane attack complex. Innate Immunity: Barriers, Complement, and Cytokines to the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation:
    • IV arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle hydrochloride
    • IV sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia benzoate
    • IV sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia phenylacetate 
  • Stable individuals: enteral nutrition Enteral nutrition Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. Short Bowel Syndrome with calories from 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, 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, and essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids (treats protein catabolic state)
  • Unstable individuals: total parenteral nutrition Total parenteral nutrition The delivery of nutrients for assimilation and utilization by a patient whose sole source of nutrients is via solutions administered intravenously, subcutaneously, or by some other non-alimentary route. The basic components of tpn solutions are protein hydrolysates or free amino acid mixtures, monosaccharides, and electrolytes. Components are selected for their ability to reverse catabolism, promote anabolism, and build structural proteins. IPEX Syndrome
  • Monitor with continuous EEG EEG Seizures to detect subclinical 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.

Continuing therapy after stabilization

  • Initiate enteral feeds with protein-free nutrition:
    • Specialty formula for infants
    • Supplement with mixed amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids
  • Closely monitor daily protein intake: 
    • Sufficient for normal growth based on age
    • Transition to oral medication.
    • Closely follow serum level of essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids.

Untreated hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis

Untreated hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis may cause:

  • Uremic 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 
  • 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

Differential Diagnosis

  • Fatty acid oxidation defects: genetic disorders resulting in failure of fatty acid transport into the 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 or metabolism by the 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. 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 is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables, but the most severe forms present only a few days after birth. Individuals present with low muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction, retinal degeneration, 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 failure, 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, fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, and sudden death in more severe forms. Laboratory findings include hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis, 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, and elevated 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 function tests ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests/ ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests). Diagnosis is usually through newborn screening Newborn Screening The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. Severe Combined Immunodeficiency (SCID).
  • Disorders of pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis metabolism: a group of inherited disorders caused by deficiencies of 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 in the pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis metabolism pathway. Pyruvates Pyruvates Derivatives of pyruvic acid, including its salts and esters. Synthesis of Nonessential Amino Acids are substrates created during protein and carbohydrate metabolism, which function as a cellular energy source. Depending on the severity, symptoms may present early in childhood or infancy and may include 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 and/or 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. Definitive diagnosis is obtained by enzyme analysis of cultured skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis or DNA analysis DNA analysis Biochemical identification of mutational changes in a nucleotide sequence. 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 and biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the “corners” of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract: Anatomy disease: caused by multiple etiologies including biliary atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), acute 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 failure, and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis of 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. Failure of 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 function may result in hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis, which mimicks the lab findings and symptoms of UCD.

References

  1. Ah Mew N., Simpson K.L., Gropman A.L., Lanpher B.C., Chapman K.A., Summar M.L. (2003). Urea Cycle Disorders Overview. In: Adam M.P., Ardinger H.H., Pagon R.A., et al., eds. GeneReviews. Seattle (WA): University of Washington, Seattle. https://pubmed.ncbi.nlm.nih.gov/20301396/
  2. Gardeitchik T., Humphrey M., Nation J., Boneh A. (2012). Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr. 328-32. https://pubmed.ncbi.nlm.nih.gov/22424941/ 
  3. Summar M.L., Dobbelaere D., Brusilow S., Lee B. (2008). Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. https://pubmed.ncbi.nlm.nih.gov/18647279/ 
  4. Marshall L., Summar, M.L., Stefan Koelker, S., Debra Freedenberg, D., et al. (2013). The incidence of urea cycle disorders. Molecular Genetics and Metabolism, Volume 110, Issues 1–2. Pages 179–180. https://www.sciencedirect.com/science/article/pii/S1096719213002333

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