Inborn Errors of Metabolism Overview

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.