Inborn Errors of Metabolism Overview
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Questions and Answers

What causes the buildup of phenylalanine in phenylketonuria (PKU)?

  • Deficiency of phenylalanine hydroxylase (correct)
  • Increased tetrahydrobiopterin levels
  • Faulty dihydropteridine reductase
  • Excess tyrosine production

    • Which enzyme deficiency is associated with Alkaptonuria?

  • Tyrosine aminotransferase
  • Dihydropteridine reductase
  • Phenylalanine hydroxylase
  • Homogentisic acid oxidase (correct)

    • In the metabolism of tyrosine, which compound is produced that leads to energy generation?

  • Melanin
  • Fumarate (correct)
  • Homogentisic acid
  • Phenylalanine

    • What is the end product of the reaction catalyzed by fumarylacetoacetate hydrolase in Tyrosinaemia Type I?

    <p>Acetoacetate and fumarate</p> Signup and view all the answers

    Which cofactor is necessary for the conversion of phenylalanine to tyrosine?

    <p>Tetrahydrobiopterin (BH₄)</p> Signup and view all the answers

    What is the primary consequence of medium-chain fatty acyl-CoA dehydrogenase deficiency (MCADD)?

    <p>Inhibition of FADH2 formation</p> Signup and view all the answers

    Which of the following substrates is NOT utilized in gluconeogenesis?

    <p>Fatty acids</p> Signup and view all the answers

    How does pyruvate carboxylase deficiency primarily present in neonates?

    <p>Seizures and coma with lactic acidosis</p> Signup and view all the answers

    What is the inheritance pattern of mitochondrial diseases?

    <p>Maternal inheritance only</p> Signup and view all the answers

    A patient presents with hepatomegaly, hypoglycaemia, and seizures. Which deficiency is most likely related to these symptoms?

    <p>Fructose-1,6-bisphosphatase deficiency</p> Signup and view all the answers

    What is a common diagnostic feature seen in muscle biopsies associated with respiratory chain deficiencies?

    <p>Presence of ragged red fibers (RRF)</p> Signup and view all the answers

    What symptom is NOT typically associated with Leigh syndrome?

    <p>Muscle strength enhancement</p> Signup and view all the answers

    What role does pyruvate dehydrogenase play in mitochondrial function?

    <p>Catalyzes the conversion of pyruvate to acetyl-CoA</p> Signup and view all the answers

    In the context of mitochondrial diseases, what does an increased plasma lactate level often indicate?

    <p>Impaired oxidative phosphorylation</p> Signup and view all the answers

    What does the procedure used to create a 'three-parent baby' involve?

    <p>Removing the mother's nucleus and inserting it into a donor egg</p> Signup and view all the answers

    What is the major cause of clinical presentations in inborn errors of metabolism?

    <p>Accumulation of toxic substances</p> Signup and view all the answers

    Which of the following diseases is classified under disorders of amino acid metabolism?

    <p>Maple syrup urine disease</p> Signup and view all the answers

    What is the primary goal of emergency treatment for inborn errors of metabolism?

    <p>To achieve metabolic stabilization</p> Signup and view all the answers

    At what age do disorders of carbohydrate or protein metabolism typically present?

    <p>Neonatal period or early infancy</p> Signup and view all the answers

    What effect can diet have on the severity of inborn errors of metabolism?

    <p>It can exacerbate onset and severity.</p> Signup and view all the answers

    Which screening method is typically used for early detection of inborn errors of metabolism in newborns?

    <p>Heel prick test</p> Signup and view all the answers

    What characterizes the onset of fatty acid oxidation disorders?

    <p>Subtle neurological features in early childhood</p> Signup and view all the answers

    In the context of inborn errors of metabolism, what is meant by 'high index of suspicion'?

    <p>Maintain awareness of potential metabolic disorders during assessment.</p> Signup and view all the answers

    How are disorders of lipid metabolism categorized within inborn errors of metabolism?

    <p>They can dramatically affect childhood development.</p> Signup and view all the answers

    What can the clinical presentation of metabolic disorders indicate?

    <p>Varies by disorder and age of presentation.</p> Signup and view all the answers

    What is the primary cause of Hyperphenylalaninaemia in Phenylketonuria (PKU)?

    <p>Deficiency of phenylalanine hydroxylase</p> Signup and view all the answers

    Which of the following is NOT a clinical sign associated with untreated PKU?

    <p>Increased melanin production</p> Signup and view all the answers

    What is a common method for diagnosing Phenylketonuria in newborns?

    <p>Newborn heel-prick test</p> Signup and view all the answers

    In the management of PKU, what dietary modification is typically recommended?

    <p>Diet low in Phenylalanine</p> Signup and view all the answers

    Which of the following statements about disorders that cause intoxication is true?

    <p>Symptoms can be both acute and chronic.</p> Signup and view all the answers

    Which group of disorders is characterized by intoxication but does not interfere with embryo-fetal development?

    <p>Amino acidopathies</p> Signup and view all the answers

    Which clinical features may indicate chronic intoxication from metabolic disorders?

    <p>Failure to thrive and developmental delay</p> Signup and view all the answers

    What type of disorders falls under Group 3 mentioned in the content?

    <p>Disturbed synthesis or catabolism of complex molecules</p> Signup and view all the answers

    Which enzyme deficiency accounts for approximately 97% of cases of PKU?

    <p>Phenylalanine hydroxylase</p> Signup and view all the answers

    What additional supplementation might be necessary for patients with cofactor-related PKU?

    <p>Neurotransmitter supplements</p> Signup and view all the answers

    What is the primary metabolic defect in Glutaric Aciduria Type I?

    <p>Deficiency in glutaryl CoA dehydrogenase</p> Signup and view all the answers

    Which group of symptoms is most commonly associated with mitochondrial defects in energy metabolism disorders?

    <p>Hypoglycaemia, lactic acidaemia, and hepatomegaly</p> Signup and view all the answers

    What is the consequence of untreated Glutaric Aciduria Type I?

    <p>Brain damage and possibly death</p> Signup and view all the answers

    What type of metabolic disorder is Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD)?

    <p>A disorder of fatty acid oxidation</p> Signup and view all the answers

    Which of the following compounds accumulates in the urine of patients with Glutaric Aciduria Type I?

    <p>3-hydroxy glutaric acid</p> Signup and view all the answers

    Which treatment is commonly recommended for patients with Medium-chain acyl-coenzyme A dehydrogenase deficiency?

    <p>Supplementation with carnitine</p> Signup and view all the answers

    What is a key feature of organic acids in this context?

    <p>They are water soluble and ninhydrin stain negative</p> Signup and view all the answers

    What metabolic process is impaired in Medium-chain acyl-coenzyme A dehydrogenase deficiency?

    <p>Fatty acid oxidation</p> Signup and view all the answers

    Study Notes

    Inborn Errors of Metabolism (IEMs)

    • IEMs are genetic disorders of metabolism, primarily impacting enzymes in metabolic pathways or transport proteins

    • IEMs are individually rare but collectively common.

    • They present at any age, from neonate to adulthood.

    • IEMs often result from:

      • Accumulation of toxic substances interfering with normal function
      • Deficiency of a metabolic pathway product

    Impaired Enzyme Activity

    • A key characteristic is impaired enzyme activity, leading to:
      • Deficiency in product formation
      • Accumulation of substrate from the reaction.
      • Conversion to an alternate(different) product/intermediate

    Substrate Build-Up

    • Accumulation of the substrate can occur when an enzyme is defective.
      • Accumulation of substrate
      • Conversion to an alternate product

    Inborn Errors of Metabolism (IEMs) - Presentation

    • The specifics (types and severity) vary by the IEM and its variants
    • The timing of presentation depends on the level of accumulation of toxic metabolites and the degree of enzyme product deficiency
    • Onset and severity can be affected by diet or intercurrent illness
    • Disorders of carbohydrate or protein metabolism and energy production tend to present in neonatal or early infancy
    • Less severe variants often appear later
    • Disorders of fatty acid oxidation, glycogen storage, and lysosomal storage tend to present in infancy or childhood with subtle neurological or psychiatric features(potentially undiagnosed until adulthood)

    Rationale for Newborn Screening (NBS)

    • NBS enables early detection of IEMs before symptoms manifest
    • Early diagnosis allows for timely intervention, which, in turn, leads to better clinical outcomes and reduces morbidity or premature mortality.
    • The heel prick test is conducted at 3 - 5 days of age.

    Newborn Screening in Ireland

    • NBS in Ireland screens for specific IEMs including: -Galactosemia -Phenylketonuria (PKU) -Maple syrup urine disease (MSUD) -Homocystinuria -Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) -Glutaric aciduria type 1 (GA1)
    • Ireland also screens for cystic fibrosis and congenital hypothyroidism (not IEMs).

    Classification of IEMs

    • Group 1: Intoxication: Progressive accumulation of toxic compound (e.g., PKU, MSUD, organic acidurias)
    • Group 2: Energy Metabolism: Intermediary metabolism disturbance, symptoms relating to energy insufficiency(e.g, mitochondrial/cytoplasmic energy defects)
    • Group 3: Complex Molecules: Cellular organelle involvement, including issues in synthesis/catabolism of complex molecules (e.g., lysosomal storage disorders, peroxisomal disorders, intracellular trafficking disorders)

    Group 1: Disorders Leading to Intoxication

    • They don't interfere with embryo-fetal development but present after a symptom-free interval.
    • Clinical signs may include acute symptoms (vomiting, coma, liver failure) or chronic symptoms (failure to thrive, developmental delay, lens dislocation).
    • Many are treatable through toxin removal.

    Specific Examples of Amino Acidopathies

    • Phenylketonuria (PKU)
      • Defects in phenylalanine hydroxylase
      • Elevated phenylalanine and phenylketones in urine
      • Potential for brain damage due to accumulation of phenylalanine
      • Managed through phenylalanine-restricted diet & supplemented tyrosine
    • Maple Syrup Urine Disease (MSUD)
      • Deficiency in branched-chain α-ketoacid dehydrogenase complex
      • Accumulation of branched-chain amino acids and their metabolic by-products in the urine(and blood)
      • Symptoms include severe neurological dysfunction(or issues) and even death without dietary management.
    • Homocystinuria
      • Defect in cystathionine synthase
      • Accumulation of homocysteine
      • Increased risk of cardiovascular problems(and possibly more).
    • Tyrosinemia type I
      • Defect in fumarylacetoacetate hydrolase
      • Accumulation of fumarylacetoacetate and other metabolites in urine.
      • Managed through diet restriction & treatment with nitisinone.

    Specific Examples of Other Disorders

    • Organic Acidurias
    • Urea cycle disorders
    • Sugar intolerances
    • Metal intoxication disorders
    • Porphyrias

    Hyperphenylalaninaemia (Phenylketonuria - PKU)

    • Autosomal recessive inheritance pattern.
    • Involves a defect within phenylalanine hydroxylase
    • A lack of phenylalanine hydroxylase prevents the conversion of phenylalanine to tyrosine(leading to toxic buildup)
    • Screening and management should include a low phenylalanine diet + additional tyrosine.

    Homocystinuria

    • Defect in cystathionine synthase
    • Elevated levels of methionine and homocysteine in blood and urine.
    • Increased risk of cardiovascular problems, thromboembolism and/or stroke among others.

    Organic Acidurias

    • Characterised by the accumulation of specific organic acids in blood and urine.
    • Often from defects in specific metabolic enzymes.

    Glutaconic Aciduria type 1 (GA1)

    • Metabolism of lysine, hydroxylysine and tryptophan is affected due to deficiency in glutaryl-CoA dehydrogenase
    • Toxic accumulation within the patient
    • Managed through dietary restrictions of protein and carnitine supplementation.

    Group 2: Disorders of Energy Metabolism

    • Includes various mitochondrial defects that often complicate diagnosis.
    • Common symptoms include hypoglycaemia, lactic acidosis(increased lactate levels), hepatomegaly, hypotonia, myopathy, cardiomyopathy, and sudden infant death syndrome(SIDS).
    • Often includes defects in pyruvate dehydrogenase(PDH) complex, the TCA cycle, electron transport chain (ETC), or ATP synthase.

    Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)

    • Defect impacting medium-chain fatty acid breakdown.
    • Leads to issues with fatty acid oxidation resulting in hypoketotic hypoglycemia, liver dysfunction, and possible SIDS, lethargy, seizures and coma(generally).
    • Individuals with MCADD have an intolerance to fasting.

    Gluconeogenesis

    • Synthesis of glucose from non-carbohydrate sources
    • Substrates in gluconeogenesis include lactate, glycerol, and amino acids
    • Specific enzymes (needed) bypass the irreversible reactions in glycolysis
    • Disorders in gluconeogenesis can lead to hypoglycemia and may involve pyruvate carboxylase deficiency and/or fructose 1,6 bisphosphatase deficiency

    Mitochondrial Diseases

    • Often involve maternal inheritance, affecting multiple tissues
    • Many have symptoms that appear in adulthood(though many factors contribute to the variability in age of onset).
    • Diagnostic criteria include clinical symptoms (encephalopathies, myopathies, cardiomyopathies), biochemical features (lactic acidosis), and specific enzyme studies/biopsies.

    Storage Disorders

    • Genetic diseases with abnormal accumulation of lipids or carbohydrates
    • Typically impact glycogen metabolism.
    • Disorders of liver and muscle include Hypoglycemia, organ failure, and/or a high level of organ damage(depending on specifics).

    Group 3: Disorders Involving Complex Molecules

    • Primarily affect cellular organelles (e.g., Lysosomes, peroxisomes).
    • Include several types of lysosomal storage disorders, mucopolysaccharide storage disorders, and peroxisomal disorders which can lead to permanent progressive problems largely unrelated to food(and/or dietary) intake.

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    Inborn Errors of Metabolism PDF

    Description

    Explore the genetic disorders known as Inborn Errors of Metabolism (IEMs), which primarily affect enzymes and transport proteins. Understand the implications of impaired enzyme activity and substrate accumulation, and learn about their presentations across different age groups. This quiz will guide you through key concepts related to these disorders.

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