Podcast
Questions and Answers
Vomiting, dehydration, and severe metabolic acidosis are symptoms of homocystinuria.
Vomiting, dehydration, and severe metabolic acidosis are symptoms of homocystinuria.
False
A defect in cystathionine synthase results in the accumulation of homocysteine in the urine.
A defect in cystathionine synthase results in the accumulation of homocysteine in the urine.
True
Elevated levels of methionine in the blood are associated with glutaric aciduria type I.
Elevated levels of methionine in the blood are associated with glutaric aciduria type I.
False
Glutaric aciduria type I is caused by a deficiency in glutaryl CoA dehydrogenase.
Glutaric aciduria type I is caused by a deficiency in glutaryl CoA dehydrogenase.
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Dystonia and dyskinesia are symptoms of homocystinuria.
Dystonia and dyskinesia are symptoms of homocystinuria.
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Fructose metabolism is not affected by insulin.
Fructose metabolism is not affected by insulin.
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Sucrose is not cleaved in the intestine.
Sucrose is not cleaved in the intestine.
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Hereditary fructose intolerance is caused by a deficiency of fructokinase.
Hereditary fructose intolerance is caused by a deficiency of fructokinase.
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Essential fructosuria is a benign condition.
Essential fructosuria is a benign condition.
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Accumulation of fructose-1-P can lead to hypoglycemia and liver damage.
Accumulation of fructose-1-P can lead to hypoglycemia and liver damage.
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Fructose promotes fatty acid synthesis.
Fructose promotes fatty acid synthesis.
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Fructosuria involves fructose being present in the urine due to its metabolism.
Fructosuria involves fructose being present in the urine due to its metabolism.
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The treatment for hereditary fructose intolerance includes adding fructose to the diet.
The treatment for hereditary fructose intolerance includes adding fructose to the diet.
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Mitochondrial diseases can lead to progressive neuropathy.
Mitochondrial diseases can lead to progressive neuropathy.
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Ragged red fibers in a muscle biopsy are indicative of normal mitochondrial function.
Ragged red fibers in a muscle biopsy are indicative of normal mitochondrial function.
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Leigh syndrome typically causes children to thrive and develop normally.
Leigh syndrome typically causes children to thrive and develop normally.
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Electron transport chain deficiencies can lead to an elevated NADH+/NAD ratio.
Electron transport chain deficiencies can lead to an elevated NADH+/NAD ratio.
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The maternal nucleus is retained during the procedure used to create a three-parent baby.
The maternal nucleus is retained during the procedure used to create a three-parent baby.
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Mitochondrial defects can lead to dysmorphism.
Mitochondrial defects can lead to dysmorphism.
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Fructose-1,6-bisphosphatase deficiency typically presents with mild hypoglycaemia.
Fructose-1,6-bisphosphatase deficiency typically presents with mild hypoglycaemia.
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Gluconeogenesis involves the synthesis of glucose from carbohydrate substrates.
Gluconeogenesis involves the synthesis of glucose from carbohydrate substrates.
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PEP carboxykinase deficiency is considered extremely rare.
PEP carboxykinase deficiency is considered extremely rare.
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Pyruvate carboxylase deficiency is associated with lactic acidosis.
Pyruvate carboxylase deficiency is associated with lactic acidosis.
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Fatty Acid Oxidation disorders are classified as mitochondrial defects.
Fatty Acid Oxidation disorders are classified as mitochondrial defects.
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Lactate acts as a substrate for gluconeogenesis.
Lactate acts as a substrate for gluconeogenesis.
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Severe neonatal presentation of pyruvate carboxylase deficiency includes psychomotor retardation.
Severe neonatal presentation of pyruvate carboxylase deficiency includes psychomotor retardation.
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The diagnosis of fructose-1,6-bisphosphatase deficiency involves increased levels of glucose-6-phosphate.
The diagnosis of fructose-1,6-bisphosphatase deficiency involves increased levels of glucose-6-phosphate.
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Cytoplasmic defects include disorders related to glycolysis and gluconeogenesis.
Cytoplasmic defects include disorders related to glycolysis and gluconeogenesis.
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Pyruvate dehydrogenase deficiency presents with muscular hypotonia.
Pyruvate dehydrogenase deficiency presents with muscular hypotonia.
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Galactokinase deficiency is an autosomal dominant condition.
Galactokinase deficiency is an autosomal dominant condition.
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Glycogen Storage Disorders affect both liver and muscle tissues.
Glycogen Storage Disorders affect both liver and muscle tissues.
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Classic galactosemia is caused by a deficiency in UDP-hexose-4-epimerase.
Classic galactosemia is caused by a deficiency in UDP-hexose-4-epimerase.
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Lactose is cleaved into glucose and galactose by the enzyme lactase.
Lactose is cleaved into glucose and galactose by the enzyme lactase.
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Elevated galactose in blood and urine is a symptom of galactokinase deficiency.
Elevated galactose in blood and urine is a symptom of galactokinase deficiency.
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Excess galactose is converted to galactitol, which can cause cataracts.
Excess galactose is converted to galactitol, which can cause cataracts.
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Hypoglycemia is a common sign of glycogen storage disorders.
Hypoglycemia is a common sign of glycogen storage disorders.
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Tyrosinemia Type-1 is caused by a deficiency in homogentisic acid oxidase.
Tyrosinemia Type-1 is caused by a deficiency in homogentisic acid oxidase.
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Symptoms of Alkaptonuria include arthritis and a characteristic dark urine that turns black on standing.
Symptoms of Alkaptonuria include arthritis and a characteristic dark urine that turns black on standing.
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Maple syrup urine disease is caused by a deficiency in branched chain α-keto acid dehydrogenase.
Maple syrup urine disease is caused by a deficiency in branched chain α-keto acid dehydrogenase.
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The primary treatment for phenylketonuria includes increasing dietary phenylalanine.
The primary treatment for phenylketonuria includes increasing dietary phenylalanine.
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The incidence of phenylketonuria is higher in the USA than in Ireland.
The incidence of phenylketonuria is higher in the USA than in Ireland.
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Ochronosis is a pigmentation phenotype associated with alkaptonuria.
Ochronosis is a pigmentation phenotype associated with alkaptonuria.
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The accumulation of succinyl acetone is a symptom related to alkaptonuria.
The accumulation of succinyl acetone is a symptom related to alkaptonuria.
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Inborn errors of metabolism can be inherited in both recessive and dominant patterns.
Inborn errors of metabolism can be inherited in both recessive and dominant patterns.
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The primary cause of clinical presentation in IEMs is the accumulation of useful substances.
The primary cause of clinical presentation in IEMs is the accumulation of useful substances.
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Phenylalanine is not typically restricted in the diet of patients with Maple syrup urine disease.
Phenylalanine is not typically restricted in the diet of patients with Maple syrup urine disease.
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Diagnosing inborn errors of metabolism requires extensive knowledge of individual metabolic diseases.
Diagnosing inborn errors of metabolism requires extensive knowledge of individual metabolic diseases.
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Age at clinical presentation for inborn errors of metabolism can vary significantly.
Age at clinical presentation for inborn errors of metabolism can vary significantly.
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Emergency treatment for metabolic disorders must prioritize metabolic stabilization.
Emergency treatment for metabolic disorders must prioritize metabolic stabilization.
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An understanding of biochemical pathways is the most critical factor in diagnosing IEMs.
An understanding of biochemical pathways is the most critical factor in diagnosing IEMs.
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Inborn errors of metabolism are collectively rare but individually common.
Inborn errors of metabolism are collectively rare but individually common.
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IEMs can manifest in individuals at any age, including adulthood.
IEMs can manifest in individuals at any age, including adulthood.
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Essential Fructosuria is caused by a deficiency of aldolase B.
Essential Fructosuria is caused by a deficiency of aldolase B.
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Fructose is absorbed into cells through an insulin-dependent mechanism.
Fructose is absorbed into cells through an insulin-dependent mechanism.
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Removal of fructose from the diet is the treatment for hereditary fructose intolerance.
Removal of fructose from the diet is the treatment for hereditary fructose intolerance.
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Fructose metabolism is slower than glucose metabolism in the liver.
Fructose metabolism is slower than glucose metabolism in the liver.
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Accumulation of fructose-1-P can cause growth abnormalities and liver damage.
Accumulation of fructose-1-P can cause growth abnormalities and liver damage.
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Essential Fructosuria typically causes significant health complications.
Essential Fructosuria typically causes significant health complications.
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Mitochondrial diseases can lead to symptoms such as cardiomyopathies and encephalopathies.
Mitochondrial diseases can lead to symptoms such as cardiomyopathies and encephalopathies.
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Fructose promotes the synthesis of triglycerides in the liver.
Fructose promotes the synthesis of triglycerides in the liver.
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Hereditary fructose intolerance is characterized by an overload of ATP in cells.
Hereditary fructose intolerance is characterized by an overload of ATP in cells.
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Children diagnosed with Leigh syndrome typically survive longer than 5 years without major complications.
Children diagnosed with Leigh syndrome typically survive longer than 5 years without major complications.
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Ragged red fibers in a muscle biopsy indicate a deficiency in mitochondrial function.
Ragged red fibers in a muscle biopsy indicate a deficiency in mitochondrial function.
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The pyruvate dehydrogenase complex is unaffected by deficiencies in the Electron Transport Chain.
The pyruvate dehydrogenase complex is unaffected by deficiencies in the Electron Transport Chain.
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A three-parent baby is created by adding the father’s nucleus to the donor egg.
A three-parent baby is created by adding the father’s nucleus to the donor egg.
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Galactose-1-phosphate uridyltransferase (GALT) deficiency presents symptoms primarily in adults.
Galactose-1-phosphate uridyltransferase (GALT) deficiency presents symptoms primarily in adults.
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The major source of galactose in the diet comes from lactose in milk products.
The major source of galactose in the diet comes from lactose in milk products.
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Galactokinase deficiency results in elevated levels of galactose in both blood and urine.
Galactokinase deficiency results in elevated levels of galactose in both blood and urine.
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Glycogen storage disorders can only affect muscle tissue.
Glycogen storage disorders can only affect muscle tissue.
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Elevated galactitol in the body can lead to the development of cataracts.
Elevated galactitol in the body can lead to the development of cataracts.
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Pyruvate dehydrogenase deficiency results in symptoms such as muscular hypertonia.
Pyruvate dehydrogenase deficiency results in symptoms such as muscular hypertonia.
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Classic Galactosemia is inherited in an autosomal recessive manner.
Classic Galactosemia is inherited in an autosomal recessive manner.
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The treatment for classic galactosemia includes the addition of galactose to the diet.
The treatment for classic galactosemia includes the addition of galactose to the diet.
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Inborn errors of metabolism can present symptoms exclusively in childhood.
Inborn errors of metabolism can present symptoms exclusively in childhood.
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The mode of inheritance for inborn errors of metabolism is exclusively autosomal recessive.
The mode of inheritance for inborn errors of metabolism is exclusively autosomal recessive.
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Mitochondrial disorders are classified under energy metabolism disorders.
Mitochondrial disorders are classified under energy metabolism disorders.
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Clinical diagnosis of inborn errors of metabolism relies heavily on extensive biochemical pathway knowledge.
Clinical diagnosis of inborn errors of metabolism relies heavily on extensive biochemical pathway knowledge.
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Emergency treatment for inborn errors of metabolism does not prioritize immediate metabolic stabilization.
Emergency treatment for inborn errors of metabolism does not prioritize immediate metabolic stabilization.
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The accumulation of toxic substances is one of the main causes of clinical presentations in inborn errors of metabolism.
The accumulation of toxic substances is one of the main causes of clinical presentations in inborn errors of metabolism.
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Disorders of lipid metabolism include conditions such as hereditary fructose intolerance.
Disorders of lipid metabolism include conditions such as hereditary fructose intolerance.
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High index of suspicion is crucial for diagnosing inborn errors of metabolism.
High index of suspicion is crucial for diagnosing inborn errors of metabolism.
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Disorders of carbohydrate or protein metabolism typically present in late adulthood with mild symptoms.
Disorders of carbohydrate or protein metabolism typically present in late adulthood with mild symptoms.
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The ‘heel-prick’ test is conducted at 3-5 days old to screen for several metabolic disorders.
The ‘heel-prick’ test is conducted at 3-5 days old to screen for several metabolic disorders.
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Group 2 inherited metabolic disorders are primarily characterized by the accumulation of toxic substances.
Group 2 inherited metabolic disorders are primarily characterized by the accumulation of toxic substances.
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Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, leading to high levels of phenylalanine.
Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, leading to high levels of phenylalanine.
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Lysosomal storage disorders typically present violently in the neonatal period with severe chronic symptoms.
Lysosomal storage disorders typically present violently in the neonatal period with severe chronic symptoms.
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Urea cycle disorders can cause clinical signs such as vomiting and coma due to toxic accumulation.
Urea cycle disorders can cause clinical signs such as vomiting and coma due to toxic accumulation.
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All inborn errors of metabolism are inherited in an autosomal dominant pattern.
All inborn errors of metabolism are inherited in an autosomal dominant pattern.
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Amino acidopathies do not interfere with embryo-fetal development and present after a symptom-free interval.
Amino acidopathies do not interfere with embryo-fetal development and present after a symptom-free interval.
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Sucrose is entirely unaffected by the enzymes present in the gastrointestinal tract.
Sucrose is entirely unaffected by the enzymes present in the gastrointestinal tract.
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Fructose intolerance primarily leads to metabolic derangements due to the accumulation of fructose-1-P.
Fructose intolerance primarily leads to metabolic derangements due to the accumulation of fructose-1-P.
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Mitochondrial diseases often result in conditions such as cardiomyopathies and encephalopathies.
Mitochondrial diseases often result in conditions such as cardiomyopathies and encephalopathies.
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Increased levels of lactate are typically observed in the blood and cerebrospinal fluid of individuals with mitochondrial disorders.
Increased levels of lactate are typically observed in the blood and cerebrospinal fluid of individuals with mitochondrial disorders.
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Ragged red fibers in muscle biopsy are a positive indicator of effective mitochondrial function.
Ragged red fibers in muscle biopsy are a positive indicator of effective mitochondrial function.
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Leigh syndrome is known for severe psychomotor development that typically lasts beyond three years of age.
Leigh syndrome is known for severe psychomotor development that typically lasts beyond three years of age.
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Defects in electron transport chain proteins can contribute to elevated NADH+/NAD ratios, inhibiting pyruvate dehydrogenase.
Defects in electron transport chain proteins can contribute to elevated NADH+/NAD ratios, inhibiting pyruvate dehydrogenase.
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Deficiency in fumarylacetoacetate hydrolase characterizes Tyrosinemia Type-1.
Deficiency in fumarylacetoacetate hydrolase characterizes Tyrosinemia Type-1.
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Elevated levels of homogentisic acid in the urine indicate a defect in the enzyme phenylalanine hydroxylase.
Elevated levels of homogentisic acid in the urine indicate a defect in the enzyme phenylalanine hydroxylase.
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Patients with Maple syrup urine disease generally present with a characteristic maple syrup odor in their urine.
Patients with Maple syrup urine disease generally present with a characteristic maple syrup odor in their urine.
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Alkaptonuria can lead to pigmentation in the eyes called ochronosis.
Alkaptonuria can lead to pigmentation in the eyes called ochronosis.
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The primary treatment for tyrosinemia involves adding a high amount of tyrosine to the diet.
The primary treatment for tyrosinemia involves adding a high amount of tyrosine to the diet.
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The incidence of phenylketonuria is lower in Ireland compared to the USA.
The incidence of phenylketonuria is lower in Ireland compared to the USA.
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A key symptom of alkaptonuria includes liver failure and renal tubular acidosis.
A key symptom of alkaptonuria includes liver failure and renal tubular acidosis.
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The biochemical outcome of Maple syrup urine disease is the accumulation of α-amino acids and their α-keto analogs in both plasma and urine.
The biochemical outcome of Maple syrup urine disease is the accumulation of α-amino acids and their α-keto analogs in both plasma and urine.
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Niemann-Pick disease is caused by a deficiency in sphingomyelinase.
Niemann-Pick disease is caused by a deficiency in sphingomyelinase.
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Hunter's disease is an autosomal dominant disorder.
Hunter's disease is an autosomal dominant disorder.
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Tay-Sachs disease is caused by the accumulation of GM2 gangliosides due to a deficiency of hyaluronidase.
Tay-Sachs disease is caused by the accumulation of GM2 gangliosides due to a deficiency of hyaluronidase.
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Krabbe's disease is characterized by blindness and deafness due to neurodegeneration.
Krabbe's disease is characterized by blindness and deafness due to neurodegeneration.
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Metachromatic leukodystrophy is associated with the improper metabolism of mucopolysaccharides.
Metachromatic leukodystrophy is associated with the improper metabolism of mucopolysaccharides.
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Fabry disease is inherited in an autosomal recessive pattern.
Fabry disease is inherited in an autosomal recessive pattern.
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Hurler's syndrome leads to distinctive facial features and neurological symptoms.
Hurler's syndrome leads to distinctive facial features and neurological symptoms.
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Zellweger syndrome involves defects in peroxisomal biogenesis.
Zellweger syndrome involves defects in peroxisomal biogenesis.
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Gaucher disease is primarily treated with enzyme replacement therapy for glucocerebrosidase.
Gaucher disease is primarily treated with enzyme replacement therapy for glucocerebrosidase.
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Mucopolysaccharidosis disorders primarily involve sphingolipid accumulation.
Mucopolysaccharidosis disorders primarily involve sphingolipid accumulation.
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Niemann-Pick disease is associated with ataxia and seizures leading to death by age 2–3 years.
Niemann-Pick disease is associated with ataxia and seizures leading to death by age 2–3 years.
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Galactocerebrosidase deficiency is linked with Gaucher disease.
Galactocerebrosidase deficiency is linked with Gaucher disease.
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The life expectancy of individuals with Hunter syndrome is dependent on disease severity.
The life expectancy of individuals with Hunter syndrome is dependent on disease severity.
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The enzyme defect in Hurler's disease is α-iduronidase.
The enzyme defect in Hurler's disease is α-iduronidase.
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Study Notes
Fructose Metabolism
- Sucrose is broken down into glucose and fructose in the intestines
- Fructose entry into cells is independent of insulin
- Fructose is phosphorylated by fructokinase to fructose-1-P
- Fructose-1-P is cleaved by aldolase B
- Products are DHAP and glyceraldehyde
- DHAP enters glycolysis or gluconeogenesis
- Glyceraldehyde can be converted to glyceraldehyde-3-phosphate, glycerol-3-phosphate, triglycerides and phosphoglycerides
- Fructose metabolism bypasses phosphofructokinase (rate limiting step in glycolysis)
- Increased fructose metabolism causes an accumulation of Acetyl CoA which promotes increased fatty acid synthesis
- High fructose consumption can lead to obesity
Fructosuria & Hereditary Fructose Intolerance
-
Essential Fructosuria:
- Genetic deficiency of fructokinase
- Results in fructose being found in urine
- Benign condition, often detected due to positive test for reducing sugars in urine
-
Hereditary Fructose Intolerance:
- Genetic deficiency of aldolase B
- Accumulation of fructose-1-P in cells
- Reduced ATP production
- Reduced glucose release from glycogen
- Symptoms: hypoglycemia, vomiting, jaundice, liver damage, kidney damage, growth abnormalities, coma
- Treatment: removal of fructose from the diet
Disorders Involving Complex Molecules
- Permanent and progressive symptoms independent of food intake
- Treatment often limited to enzyme replacement or bone marrow transplant
Homocystinuria
- Defect in cystathionine synthase
- Accumulation of homocysteine in urine
- Elevated methionine and metabolites in the blood
- Symptoms: cardiovascular disease, deep vein thrombosis, thromboembolism, stroke, mental retardation, osteoporosis, lens dislocation
Organic Aciduria
- Organic acids are carboxylic acids with various functional groups (keto, hydroxyl)
- Often water soluble, acidic, and do not stain with ninhydrin (no nitrogen group)
- Derived from protein, fat, and carbohydrate metabolism
- Some organic acids can cause dysmorphism
- Examples:
- Glutaric aciduria type 1 (GA1)
- Defect in the metabolism of lysine, hydroxylysine, and tryptophan
- Deficiency in glutaryl CoA dehydrogenase
- Accumulation of harmful organic acids
- Symptoms: dystonia, dyskinesia
- Glutaric aciduria type 1 (GA1)
Mitochondrial Diseases
- Deficiencies in enzymes or enzyme complexes involved in oxidative phosphorylation
- Include deficiencies in:
- Pyruvate dehydrogenase complex
- TCA cycle enzymes
- Electron transport chain (ETC)
- ATP synthase
- Diagnostic criteria:
- Clinical symptoms: encephalopathies, myopathies, cardiomyopathies
- Biochemical features: lactic acidosis, often elevated in blood and CSF
- Electron transport chain deficiency: enzyme activity of specific ETC complexes often decreased
- Morphological features:
- Ragged red fibers (RRF) in muscle biopsy
- DNA analysis
- Blockage of the ETC due to oxygen deficiency, genetic defects, or inhibitors increases the NADH+/NAD ratio which inhibits PDH and TCA cycle enzymes
Case Study: 'Three-Parent Baby'
- Two siblings with mtDNA defect leading to Leigh Syndrome
- Leigh syndrome:
- Failure to thrive
- Progressive neuropathy
- Muscle weakness
- Psychomotor regression
- Caused by defects in ETC proteins and pyruvate dehydrogenase
- 'Three-parent baby' procedure used maternal nucleus from egg and inserted into a donor egg with removed nucleus
- Donor egg fertilized with father's sperm
- Procedure allows for transfer of some mtDNA
Pyruvate Dehydrogenase Deficiency (PDH)
- Presentation:
- Progressive encephalopathy
- Brain malformation
- Psychomotor retardation
- Muscular hypotonia
- Epilepsy
- Diagnosis:
- Increased plasma lactate and pyruvate
- Enzyme analysis in fibroblasts and muscle
Storage Disorders
- Genetic diseases characterized by abnormal accumulation of lipids or carbohydrates
- Glycogen Storage Disorders (GSDs): due to a defect in the genes coding for enzymes involved in glycogen metabolism
- GSDs affect liver and muscle
- Disease presentation and severity depend on the role played by the enzyme and its tissue specificity
- Signs:
- Hypoglycemia
- Muscle pain, cramps, weakness
Galactose Metabolism
- Galactose is phosphorylated to galactose-1-P by galactokinase
- UDP-galactose is formed by transfer of UDP from UDP-glucose by galactose-1-phosphate uridyl transferase (GALT)
- UDP-galactose can be converted to UDP-glucose by UDP-hexose-4-epimerase
- UDP-glucose is converted to glucose-1-P by galactose-1-phosphate uridyl transferase
- Major dietary source of galactose is lactose from milk products
- Lactose breakdown by lactase yields glucose and galactose
Galactokinase Deficiency
- Autosomal recessive inheritance
- Elevated galactose in blood and urine
- Excess galactose converted to galactitol
- Elevated galactitol can cause cataracts
- Treatment: dietary restriction
Classic Galactosemia
- Autosomal recessive inheritance
- Galactose-1-phosphate uridyltransferase (GALT) deficiency
- Symptoms:
- Most present as neonates
- Galactosemia, galactosuria, vomiting, diarrhea, jaundice, failure to thrive
- Galactose-1-P and galactitol accumulate in nerves, lens, liver, and kidneys
- Symptoms include liver damage, mental retardation, cataracts, verbal dyspraxia, and motor abnormalities
- Treatment:
- Rapid detection and removal of galactose from the diet
- Galactitol is a sugar alcohol formed by reduction of galactose
Inborn Errors of Metabolism (IEMs)
- IEMs are genetic disorders affecting metabolism due to defects in single genes, primarily affecting enzymes in metabolic pathways or transport proteins.
- IEMs can lead to:
- Accumulation of toxic substances interfering with normal function
- Deficiency of products in a metabolic pathway
- The clinical presentation of IEMs varies, occurring at any age, even in adulthood.
- Diagnosis often relies on understanding broad clinical manifestations rather than specific biochemical pathways.
- High index of suspicion is crucial for IEM diagnosis.
- Emergency treatment requires prompt intervention aimed at metabolic stabilization.
Phenylketonuria (PKU)
- Autosomal recessive inheritance with an incidence of 1 in 4,500 (Ireland) – 1 in 11,000 (USA).
- ~97% of cases result from a defect in the PAH enzyme, while ~3% involve a defective synthesis of the cofactor tetrahydrobiopterin.
- PKU presents with:
- Mental retardation by 4-6 months of age
- Reduced melanin production leading to pale skin, fair hair, and blue eyes
- Frequent generalized eczema
- Diagnosis involves:
- Newborn screening (heel-prick/Guthrie) test
- Biochemical amino acid analysis
- Management includes:
- Dietary restriction of phenylalanine and supplementation with tyrosine
- Cofactor-related forms require dihydrobiopterin reductase deficiency treatment and neurotransmitter supplementation.
Tyrosinemia type 1
- Deficiency of fumarylacetoacetate hydrolase.
- Accumulation of fumaryl acetoacetate and its metabolites in urine, particularly succinyl acetone.
- Symptoms include:
- Characteristic cabbage-like odor
- Liver failure
- Renal tubular acidosis
- Treatment involves dietary restriction of phenylalanine and tyrosine.
Alkaptonuria
- One of the first recognized IEMs.
- Accumulation of homogentisic acid due to deficiency of homogentisic acid oxidase.
- Clinical presentation includes:
- Ochronosis (pigmentation of ears and eyes)
- Dark urine that turns black on standing (homogentisic aciduria)
- Arthritis associated with joint calcification.
Maple Syrup Urine Disease (MSUD)
- Defect in the metabolism of leucine, isoleucine, and valine.
- Deficiency of branched-chain α-keto acid dehydrogenase.
- Biochemistry:
- Elevated α-amino acids and their α-keto analogs in plasma and urine.
- This pathway is more active in galactosemic patients.
Fructose Metabolism
- Sucrose is ingested and cleaved into free fructose in the intestines.
- Free fructose is found in fruit, honey, and high fructose corn syrup.
- Western diets contain approximately 10% calories from fructose.
- Fructose is metabolized much faster than glucose.
- Fructose bypasses phosphofructokinase, a rate-limiting step in glycolysis.
- Accumulated acetyl CoA promotes fatty acid synthesis.
Fructosuria and Hereditary Fructose Intolerance
- Essential Fructosuria:
- Genetic deficiency of fructokinase.
- Fructose is found in urine.
- Benign condition, often discovered due to positive tests for reducing sugars in urine.
- Hereditary Fructose Intolerance:
- Genetic deficiency of aldolase B.
- Accumulation of fructose-1-P in the cell.
- Reduced ATP production and glucose release from glycogen.
- Hypoglycemia, vomiting, jaundice, liver damage, kidney damage, growth abnormalities, and coma if untreated.
- Treatment: Removal of fructose from the diet.
Disorders involving Complex Molecules
- Symptoms are permanent, progressive, independent of intercurrent events, and unrelated to food intake.
- Treatment is limited to enzyme replacement or bone marrow transplant.
Mitochondrial Diseases
- Include deficiencies in pyruvate dehydrogenase (PDH) complex, TCA cycle, electron transport chain (ETC), and ATP synthase.
- Diagnostic criteria:
- Clinical symptoms: Encephalopathies, myopathies, cardiomyopathies.
- Biochemical features: Lactic acidosis, often elevated in blood and CSF.
- Electron transport chain deficiency:
- Reduced enzyme activity of specific RC complex.
- Morphological features in muscle biopsy: ragged red fibers (RRF).
- DNA analysis.
- Blockage of ETC due to oxygen deficiency, genetic defects, or inhibitors causes a rise in NADH+/NAD ratio, inhibiting PDH and TCA.
Leigh Syndrome
- A mitochondrial disorder with severe symptoms, including failure to thrive, progressive neuropathy, muscle weakness, and psychomotor regression.
- Caused by defects in ETC proteins and some pyruvate dehydrogenase.
- Children usually die within 2-3 years of respiratory failure.,
Pyruvate dehydrogenase deficiency (PDH)
- Presentation:
- Progressive encephalopathy
- Brain malformation
- Psychomotor retardation
- Muscular hypotonia
- Epilepsy
- Diagnosis:
- Increased plasma lactate and pyruvate
- Enzyme analysis in fibroblasts and muscle.
Storage Disorders
- Genetic diseases characterized by abnormal accumulation of lipids or carbohydrates.
- Glycogen Storage Disorders (GSDs):
- Abnormal synthesis or degradation of glycogen.
- Due to a defect in genes coding for enzymes involved in glycogen metabolism.
- GSDs affect liver and muscle.
- Disease presentation and severity depend on the role played by the enzyme and its tissue specificity.
- Signs:
- Hypoglycemia
- Muscle pain, cramps, or weakness.
Galactose Metabolism
- Galactose is phosphorylated to Galactose-1-P by galactokinase.
- Formation of UDP-galactose, transferring UDP from UDP-Glucose by Galactose-1-phosphate uridyl transferase (GALT). (Glucose-1-P is formed).
- UDP Galactose can be converted to UDP-Glucose by UDP-hexose-4-epimerase.
- UDP-Glucose is converted to Glucose-1-P by Gal-1-P uridyl transferase.
Galactokinase Deficiency
- Autosomal recessive inheritance.
- Elevated galactose in blood and urine.
- Excess galactose is converted to galactitol.
- Elevated galactitol can cause cataracts.
- Treatment involves dietary restriction.
Classic Galactosemia
- Autosomal recessive inheritance.
- Deficiency in Gal-1-P uridyl transferase (GALT).
- Symptoms:
- Most present as neonates:
- Galactosemia
- Galactosuria
- Vomiting
- Diarrhoea
- Jaundice
- Failure to thrive
- Gal-1-P and galactitol accumulate in nerves, lenses, liver, and kidneys, leading to liver damage, mental retardation, cataracts, verbal dyspraxia, and motor abnormalities.
- Most present as neonates:
- Therapy: Rapid detection and removal of galactose from the diet.
- Galactitol is a sugar alcohol formed by the reduction of galactose.
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