Understanding about the biochemical aspects of inborn errors of aminoacid metabolism is important in the field of pediatrics, metabolic medicine and medical genetics. This presentation mainly includes the biochemical aspects, the enzyme defect, clinical features, Screening and diagnostic testing modalities with their reference and management. Recent developments in the field of IEM is also added
Phenylketonuria (PKU) is a genetic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase. This enzyme is needed to break down the amino acid phenylalanine. Without treatment, high phenylalanine levels can cause intellectual disabilities and other neurological problems. Treatment involves a lifelong low-phenylalanine diet using phenylalanine-free medical foods and supplements. Tyrosinemia and Wilson's disease are also inherited disorders of amino acid or copper metabolism that can cause liver, neurological and other health issues if left untreated. Medical nutrition therapy and medication are used to manage symptoms and prevent complications.
Dr. N. Gautam presented on inborn errors of amino acid metabolism. These disorders involve defects in the synthesis, transport, or breakdown of amino acids, resulting in toxic metabolite accumulation. The presentation classified the disorders based on the defective enzyme or pathway and discussed specific examples like phenylketonuria, tyrosinemias, maple syrup urine disease, and disorders of branched chain and sulfur amino acid metabolism. Treatment involves dietary modifications and supplements depending on the underlying defect.
The document summarizes urea cycle defects and hyperammonemia. It discusses that defects in any of the six urea cycle enzymes or two transporters can cause toxic buildup of ammonia in the blood. Specific urea cycle disorders are described including ornithine transcarbamylase deficiency and N-acetylglutamate synthase deficiency. Treatment focuses on removing ammonia through hemodialysis or drug therapy, and maintaining a protein-restricted diet to prevent further ammonia production. Long-term management requires monitoring amino acid intake and considering liver transplantation.
Hemoglobinopathies and thalassemia are genetic blood disorders that result in abnormal hemoglobin. Hemoglobinopathies are caused by mutations in the globin chains of hemoglobin molecules, while thalassemias are caused by reduced or absent globin chain production. Sickle cell disease is a hemoglobinopathy caused by a mutation in the beta globin chain that results in sickle-shaped red blood cells. Thalassemias include alpha and beta thalassemia, which are characterized by decreased alpha or beta globin chain production leading to anemia. Management involves blood transfusions, iron chelation therapy, and in some cases stem cell transplantation.
Urea cycle disorders result from defects in the metabolic pathway that converts nitrogen into urea for excretion. Symptoms range from hyperammonemia in newborns to neurological issues in older patients. Diagnosis involves measuring elevated ammonia levels and testing for specific enzyme deficiencies. Treatment focuses on reducing ammonia through dialysis, nitrogen scavengers, and dietary protein restriction, as well as replacing deficient cycle intermediates. Long term management centers on minimizing nitrogen intake and promoting alternative excretion routes to prevent hyperammonemic crises.
An inherited enzyme deficiency leading to the disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally produced by the deficient enzyme.
- Fructose metabolism occurs primarily in the liver, intestine and kidney. Fructose is converted to fructose-1-phosphate by fructokinase and can then enter the glycolysis or gluconeogenesis pathways.
- Defects in fructose metabolism can cause disorders like essential fructosuria (deficiency of fructokinase) or hereditary fructose intolerance (deficiency of aldolase B). Patients with these defects need to restrict dietary fructose intake.
- The polyol pathway converts glucose to fructose via sorbitol and is related to complications of diabetes like cataracts due to sorbitol accumulation inside cells. Inhibitors
This is a powerpoint file of an MBBS practical class taken by Dr. Karthikeyan Pethusamy at All India Institute of Medical Sciences - NewDelhi.
Disclaimer: The views expressed here are of the author only not of the institution.
Phenylketonuria (PKU) is a genetic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase. This enzyme is needed to break down the amino acid phenylalanine. Without treatment, high phenylalanine levels can cause intellectual disabilities and other neurological problems. Treatment involves a lifelong low-phenylalanine diet using phenylalanine-free medical foods and supplements. Tyrosinemia and Wilson's disease are also inherited disorders of amino acid or copper metabolism that can cause liver, neurological and other health issues if left untreated. Medical nutrition therapy and medication are used to manage symptoms and prevent complications.
Dr. N. Gautam presented on inborn errors of amino acid metabolism. These disorders involve defects in the synthesis, transport, or breakdown of amino acids, resulting in toxic metabolite accumulation. The presentation classified the disorders based on the defective enzyme or pathway and discussed specific examples like phenylketonuria, tyrosinemias, maple syrup urine disease, and disorders of branched chain and sulfur amino acid metabolism. Treatment involves dietary modifications and supplements depending on the underlying defect.
The document summarizes urea cycle defects and hyperammonemia. It discusses that defects in any of the six urea cycle enzymes or two transporters can cause toxic buildup of ammonia in the blood. Specific urea cycle disorders are described including ornithine transcarbamylase deficiency and N-acetylglutamate synthase deficiency. Treatment focuses on removing ammonia through hemodialysis or drug therapy, and maintaining a protein-restricted diet to prevent further ammonia production. Long-term management requires monitoring amino acid intake and considering liver transplantation.
Hemoglobinopathies and thalassemia are genetic blood disorders that result in abnormal hemoglobin. Hemoglobinopathies are caused by mutations in the globin chains of hemoglobin molecules, while thalassemias are caused by reduced or absent globin chain production. Sickle cell disease is a hemoglobinopathy caused by a mutation in the beta globin chain that results in sickle-shaped red blood cells. Thalassemias include alpha and beta thalassemia, which are characterized by decreased alpha or beta globin chain production leading to anemia. Management involves blood transfusions, iron chelation therapy, and in some cases stem cell transplantation.
Urea cycle disorders result from defects in the metabolic pathway that converts nitrogen into urea for excretion. Symptoms range from hyperammonemia in newborns to neurological issues in older patients. Diagnosis involves measuring elevated ammonia levels and testing for specific enzyme deficiencies. Treatment focuses on reducing ammonia through dialysis, nitrogen scavengers, and dietary protein restriction, as well as replacing deficient cycle intermediates. Long term management centers on minimizing nitrogen intake and promoting alternative excretion routes to prevent hyperammonemic crises.
An inherited enzyme deficiency leading to the disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally produced by the deficient enzyme.
- Fructose metabolism occurs primarily in the liver, intestine and kidney. Fructose is converted to fructose-1-phosphate by fructokinase and can then enter the glycolysis or gluconeogenesis pathways.
- Defects in fructose metabolism can cause disorders like essential fructosuria (deficiency of fructokinase) or hereditary fructose intolerance (deficiency of aldolase B). Patients with these defects need to restrict dietary fructose intake.
- The polyol pathway converts glucose to fructose via sorbitol and is related to complications of diabetes like cataracts due to sorbitol accumulation inside cells. Inhibitors
This is a powerpoint file of an MBBS practical class taken by Dr. Karthikeyan Pethusamy at All India Institute of Medical Sciences - NewDelhi.
Disclaimer: The views expressed here are of the author only not of the institution.
The adrenal glands are located above the kidneys and are divided into an outer cortex and inner medulla. The cortex secretes steroid hormones like cortisol and aldosterone which are involved in glucose metabolism, mineral balance, and sexual development. The medulla secretes catecholamines which increase heart rate and blood pressure. Diseases can result from hypo- or hyperfunction of the adrenal cortex or medulla. Tests are used to identify the cause and guide treatment options such as surgery or medication.
1. Mineralocorticoids such as aldosterone act on minerals like sodium and potassium, regulating their levels in the body.
2. Aldosterone is synthesized in and released from the zona glomerulosa of the adrenal cortex, regulated by factors like angiotensin.
3. It increases sodium reabsorption and potassium excretion, maintaining fluid volume and blood pressure levels. Imbalances can cause issues like hypokalemia or hypertension.
Hemoglobin is composed of four subunits, each containing a heme group and globin protein. It transports oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs. Hemoglobin exists in tense and relaxed states that influence its affinity for oxygen. Abnormalities in hemoglobin synthesis or structure can result in hemoglobinopathies like sickle cell anemia or thalassemias. Sickle cell anemia is caused by a mutation replacing glutamic acid with valine in the beta globin chain, causing red blood cells to sickle and leading to anemia, pain crises and other complications. Thalassemias involve deficiencies in alpha or beta globin chain production causing anemia of varying severity
This document discusses the metabolism of purine nucleotides. It describes how purine bases are recycled through the salvage pathway using phosphoribosyl pyrophosphate (PRPP) and enzymes like adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Primary gout is caused by enzyme defects while secondary gout results from overproduction or decreased excretion of uric acid. Symptoms of gout include arthritis in the big toe joint and treatment involves a low purine diet, allopurinol to inhibit xanthine oxidase, and probenecid or colchicine. Lesch-Ny
Inborn error of metabolism ( Prenatal & Newborn Screening )Dr.Debkumar Ray
This document discusses inborn errors of metabolism (IEM), including definitions, classifications, symptoms, pathophysiology, treatment approaches, and the importance of prenatal and newborn screening. Some key points include:
- IEM are rare genetic disorders caused by defects in metabolic pathways. They are classified into amino acid, carbohydrate, lipid, protein, and pigment metabolism disorders.
- Early detection of IEM is important to prevent permanent mental retardation and other serious consequences through timely intervention. Newborn screening aims to recognize disorders in the first week of life.
- Tandem mass spectrometry allows screening for a wide range of disorders from a single blood sample. Prenatal screening uses maternal serum markers and
This document discusses different types of tyrosinemia, which are errors in the metabolism of the amino acid tyrosine. It describes four main types: Type 1 is the most common and severe, caused by a deficiency of the enzyme fumaryl acetoacetate hydrolase and can lead to liver failure in infants if untreated. Type 2 is less severe and involves a deficiency of hepatic transaminase. Neonatal tyrosinemia occurs in premature infants due to absence of an enzyme. Hereditary tyrosinemia is the rarest and involves deficiency of another enzyme, with symptoms including liver failure and possible complications like hypoglycemia and rickets.
Metabolism of Tryptophan and its disorders.Ashok Katta
Tryptophan is an essential aromatic amino acid that can be metabolized through the kynurenine pathway in the liver or the serotonin pathway. The kynurenine pathway produces metabolites that are used for niacin synthesis, the glucogenic pathway, or the ketogenic pathway. The serotonin pathway produces the neurotransmitter serotonin in the brain and gastrointestinal tract. Disorders of tryptophan metabolism can cause symptoms like depression, skin rashes, and neurological issues due to deficiencies in serotonin and niacin.
Plasma contains proteins that perform important functions like maintaining pH and colloid osmotic pressure. The most abundant protein is albumin, which makes up around 75% of plasma's colloid osmotic pressure. Other major classes of plasma proteins include globulins such as alpha-1 globulins containing thyroxine-binding globulin and alpha-1-antitrypsin; alpha-2 globulins containing ceruloplasmin and haptoglobin; beta-globulins containing transferrin; and gamma-globulins which are antibodies. These proteins transport substances like vitamins, minerals, lipids, and hormones or help in coagulation, immune defense, and acute phase responses.
approach to Inborn Errors of Metabolism in neonatesGokul Das
This document provides an overview of inborn errors of metabolism (IEM), including clinical pointers, initial evaluations, and management. Some key points:
- IEM should be considered in the differential diagnosis of any sick neonate. Clinical pointers include deterioration after normalcy, parental consanguinity, unexplained encephalopathy/seizures, or metabolic acidosis.
- Initial evaluations include blood tests for electrolytes, gases, glucose, ammonia, lactate, liver/kidney function, urine tests. Further tests may include plasma amino acids, acylcarnitines, organic acids if indicated.
- Common presentations are neurologic deterioration with metabolic acidosis, hypoglycemia, or hyper
This document summarizes the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It describes how they are first transaminated to their corresponding keto acids, then undergo oxidative decarboxylation by alpha-keto acid dehydrogenase to form acyl-CoA thioesters. These are further dehydrogenated and enter different pathways, with valine being converted to propionyl-CoA and being glycogenic, leucine producing acetyl-CoA and acetoacetate and being ketogenic, and isoleucine undergoing both glycogenic and ketogenic fates. Defects in these pathways can cause diseases like maple syrup urine disease.
Heme Biosynthesis and Its disorders (Porphyria)Ashok Katta
Hemoglobin is a protein in red blood cells that transports oxygen and carbon dioxide throughout the body. It is made up of four subunits, each containing a heme group with iron at its center. Heme biosynthesis is a multi-step pathway that takes place in the mitochondria and cytoplasm, starting from succinyl-CoA and glycine and resulting in protoporphyrin with iron inserted at the final step to form heme. Regulation of heme biosynthesis occurs through feedback inhibition of the rate-limiting enzyme ALA synthase by heme levels. Deficiencies in the heme biosynthesis pathway can cause various types of porphyrias, a group of rare genetic disorders characterized by neurological and skin abnormalities.
Iron plays an important role in the body, being essential for hematopoiesis, energy production, and enzyme/hormone synthesis. It exists in protein-bound forms like heme and ferritin or insoluble hemosiderin. Iron levels are tightly regulated through dietary intake and absorption in the small intestine. Deficiency can lead to anemia and other issues, while excess free iron is toxic. The document discusses iron transport, absorption, dietary sources, and factors affecting absorption.
This document summarizes tryptophan metabolism. Tryptophan is an essential amino acid that can be metabolized along several pathways to produce important compounds like serotonin, melatonin, niacin, and alanine. It describes the enzymes involved in these pathways and how deficiencies in enzymes or tryptophan can lead to conditions like Hartnup's disease or pellagra. Serotonin functions as a neurotransmitter and its synthesis and metabolism are important for mood, while melatonin regulates sleep-wake cycles and is produced in the pineal gland.
This document discusses hyperammonemia, a condition characterized by excess ammonia in the blood. It describes how ammonia is normally produced and cleared from the body, as well as causes of elevated ammonia levels. Primary hyperammonemia is caused by genetic defects in the urea cycle, while secondary hyperammonemia results from other metabolic disorders or liver dysfunction. Signs and symptoms can range from lethargy to coma and include seizures.
Maple syrup urine disease (MSUD) is caused by a defect in the branched-chain alpha-ketoacid dehydrogenase complex, leading to a buildup of the branched-chain amino acids leucine, isoleucine, and valine. Left untreated, this can cause neurological issues such as developmental delays. Jakob was diagnosed with MSUD as an infant after presenting with irritability and poor feeding. His family found dietary management stressful and he underwent a successful liver transplant at age 4 to provide an alternative source of the defective enzyme, allowing him to discontinue treatment.
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors like lactate, glycerol, and certain amino acids. It occurs primarily in the liver but also in the kidneys and intestine. Gluconeogenesis is a crucial process that maintains blood glucose levels during periods of fasting or low carbohydrate intake. It involves the reversal of several steps in glycolysis along with some bypass reactions. Key regulatory enzymes include pyruvate carboxylase and phosphoenolpyruvate carboxykinase which control the conversion of pyruvate to phosphoenolpyruvate, and glucose-6-phosphatase which converts glucose-6-phosphate to glucose in the final step. Gl
Beta oxidation defects are inborn errors of metabolism that result in the failure of fatty acid oxidation. There are several types depending on the length of the fatty acid involved: very long chain, long chain, medium chain, or short chain. The main pathways affected are carnitine transport, beta oxidation, and ketogenesis. Presentations range from hypoglycemia in infants to muscle weakness or exercise intolerance in older children and adults. Diagnosis involves testing for intermediary metabolites, acylcarnitines, and enzyme activities. Treatment focuses on avoiding fasting and providing rapid glucose treatment during acute illnesses.
Metabolism of Brached Chain Amino Acid (Valine, Isoleucine, Leucine)Ashok Katta
Branched chain amino acids include leucine, isoleucine, and valine. They are broken down by the branched chain alpha-ketoacid dehydrogenase complex in mitochondria. A defect in this enzyme can cause branched chain ketoaciduria, where patients accumulate branched chain amino acids and their keto acids in their urine, which smells like maple syrup or burnt sugar. This rare genetic disorder impairs other amino acid transport and protein synthesis, and can lead to seizures, vomiting, ketoacidosis, coma, and death if not treated with a low-branched chain amino acid diet and thiamine supplementation.
This document provides an overview of disorders of carbohydrate metabolism. It begins with an introduction to carbohydrates and what happens when carbohydrate metabolism is defective. It then discusses several specific disorders including pyruvate kinase deficiency, pyruvate dehydrogenase deficiency, essential pentosuria, glycogen storage diseases, disorders of fructose metabolism like hereditary fructose intolerance, and disorders of galactose metabolism like galactosemia. It also provides brief summaries of type 1 and type 2 diabetes mellitus.
1. Inborn errors of metabolism are hereditary biochemical diseases caused by single gene defects that result in errors in the metabolism of proteins, carbohydrates, or fats.
2. Symptoms vary depending on the specific disorder but can include developmental delay, organomegaly, neurological abnormalities, and in some cases distinctive odors.
3. Treatment depends on the underlying cause but may include dietary modifications, supplements to replace missing enzymes or cofactors, or gene therapy in some cases. Early diagnosis through newborn screening can help prevent complications.
The adrenal glands are located above the kidneys and are divided into an outer cortex and inner medulla. The cortex secretes steroid hormones like cortisol and aldosterone which are involved in glucose metabolism, mineral balance, and sexual development. The medulla secretes catecholamines which increase heart rate and blood pressure. Diseases can result from hypo- or hyperfunction of the adrenal cortex or medulla. Tests are used to identify the cause and guide treatment options such as surgery or medication.
1. Mineralocorticoids such as aldosterone act on minerals like sodium and potassium, regulating their levels in the body.
2. Aldosterone is synthesized in and released from the zona glomerulosa of the adrenal cortex, regulated by factors like angiotensin.
3. It increases sodium reabsorption and potassium excretion, maintaining fluid volume and blood pressure levels. Imbalances can cause issues like hypokalemia or hypertension.
Hemoglobin is composed of four subunits, each containing a heme group and globin protein. It transports oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs. Hemoglobin exists in tense and relaxed states that influence its affinity for oxygen. Abnormalities in hemoglobin synthesis or structure can result in hemoglobinopathies like sickle cell anemia or thalassemias. Sickle cell anemia is caused by a mutation replacing glutamic acid with valine in the beta globin chain, causing red blood cells to sickle and leading to anemia, pain crises and other complications. Thalassemias involve deficiencies in alpha or beta globin chain production causing anemia of varying severity
This document discusses the metabolism of purine nucleotides. It describes how purine bases are recycled through the salvage pathway using phosphoribosyl pyrophosphate (PRPP) and enzymes like adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Primary gout is caused by enzyme defects while secondary gout results from overproduction or decreased excretion of uric acid. Symptoms of gout include arthritis in the big toe joint and treatment involves a low purine diet, allopurinol to inhibit xanthine oxidase, and probenecid or colchicine. Lesch-Ny
Inborn error of metabolism ( Prenatal & Newborn Screening )Dr.Debkumar Ray
This document discusses inborn errors of metabolism (IEM), including definitions, classifications, symptoms, pathophysiology, treatment approaches, and the importance of prenatal and newborn screening. Some key points include:
- IEM are rare genetic disorders caused by defects in metabolic pathways. They are classified into amino acid, carbohydrate, lipid, protein, and pigment metabolism disorders.
- Early detection of IEM is important to prevent permanent mental retardation and other serious consequences through timely intervention. Newborn screening aims to recognize disorders in the first week of life.
- Tandem mass spectrometry allows screening for a wide range of disorders from a single blood sample. Prenatal screening uses maternal serum markers and
This document discusses different types of tyrosinemia, which are errors in the metabolism of the amino acid tyrosine. It describes four main types: Type 1 is the most common and severe, caused by a deficiency of the enzyme fumaryl acetoacetate hydrolase and can lead to liver failure in infants if untreated. Type 2 is less severe and involves a deficiency of hepatic transaminase. Neonatal tyrosinemia occurs in premature infants due to absence of an enzyme. Hereditary tyrosinemia is the rarest and involves deficiency of another enzyme, with symptoms including liver failure and possible complications like hypoglycemia and rickets.
Metabolism of Tryptophan and its disorders.Ashok Katta
Tryptophan is an essential aromatic amino acid that can be metabolized through the kynurenine pathway in the liver or the serotonin pathway. The kynurenine pathway produces metabolites that are used for niacin synthesis, the glucogenic pathway, or the ketogenic pathway. The serotonin pathway produces the neurotransmitter serotonin in the brain and gastrointestinal tract. Disorders of tryptophan metabolism can cause symptoms like depression, skin rashes, and neurological issues due to deficiencies in serotonin and niacin.
Plasma contains proteins that perform important functions like maintaining pH and colloid osmotic pressure. The most abundant protein is albumin, which makes up around 75% of plasma's colloid osmotic pressure. Other major classes of plasma proteins include globulins such as alpha-1 globulins containing thyroxine-binding globulin and alpha-1-antitrypsin; alpha-2 globulins containing ceruloplasmin and haptoglobin; beta-globulins containing transferrin; and gamma-globulins which are antibodies. These proteins transport substances like vitamins, minerals, lipids, and hormones or help in coagulation, immune defense, and acute phase responses.
approach to Inborn Errors of Metabolism in neonatesGokul Das
This document provides an overview of inborn errors of metabolism (IEM), including clinical pointers, initial evaluations, and management. Some key points:
- IEM should be considered in the differential diagnosis of any sick neonate. Clinical pointers include deterioration after normalcy, parental consanguinity, unexplained encephalopathy/seizures, or metabolic acidosis.
- Initial evaluations include blood tests for electrolytes, gases, glucose, ammonia, lactate, liver/kidney function, urine tests. Further tests may include plasma amino acids, acylcarnitines, organic acids if indicated.
- Common presentations are neurologic deterioration with metabolic acidosis, hypoglycemia, or hyper
This document summarizes the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It describes how they are first transaminated to their corresponding keto acids, then undergo oxidative decarboxylation by alpha-keto acid dehydrogenase to form acyl-CoA thioesters. These are further dehydrogenated and enter different pathways, with valine being converted to propionyl-CoA and being glycogenic, leucine producing acetyl-CoA and acetoacetate and being ketogenic, and isoleucine undergoing both glycogenic and ketogenic fates. Defects in these pathways can cause diseases like maple syrup urine disease.
Heme Biosynthesis and Its disorders (Porphyria)Ashok Katta
Hemoglobin is a protein in red blood cells that transports oxygen and carbon dioxide throughout the body. It is made up of four subunits, each containing a heme group with iron at its center. Heme biosynthesis is a multi-step pathway that takes place in the mitochondria and cytoplasm, starting from succinyl-CoA and glycine and resulting in protoporphyrin with iron inserted at the final step to form heme. Regulation of heme biosynthesis occurs through feedback inhibition of the rate-limiting enzyme ALA synthase by heme levels. Deficiencies in the heme biosynthesis pathway can cause various types of porphyrias, a group of rare genetic disorders characterized by neurological and skin abnormalities.
Iron plays an important role in the body, being essential for hematopoiesis, energy production, and enzyme/hormone synthesis. It exists in protein-bound forms like heme and ferritin or insoluble hemosiderin. Iron levels are tightly regulated through dietary intake and absorption in the small intestine. Deficiency can lead to anemia and other issues, while excess free iron is toxic. The document discusses iron transport, absorption, dietary sources, and factors affecting absorption.
This document summarizes tryptophan metabolism. Tryptophan is an essential amino acid that can be metabolized along several pathways to produce important compounds like serotonin, melatonin, niacin, and alanine. It describes the enzymes involved in these pathways and how deficiencies in enzymes or tryptophan can lead to conditions like Hartnup's disease or pellagra. Serotonin functions as a neurotransmitter and its synthesis and metabolism are important for mood, while melatonin regulates sleep-wake cycles and is produced in the pineal gland.
This document discusses hyperammonemia, a condition characterized by excess ammonia in the blood. It describes how ammonia is normally produced and cleared from the body, as well as causes of elevated ammonia levels. Primary hyperammonemia is caused by genetic defects in the urea cycle, while secondary hyperammonemia results from other metabolic disorders or liver dysfunction. Signs and symptoms can range from lethargy to coma and include seizures.
Maple syrup urine disease (MSUD) is caused by a defect in the branched-chain alpha-ketoacid dehydrogenase complex, leading to a buildup of the branched-chain amino acids leucine, isoleucine, and valine. Left untreated, this can cause neurological issues such as developmental delays. Jakob was diagnosed with MSUD as an infant after presenting with irritability and poor feeding. His family found dietary management stressful and he underwent a successful liver transplant at age 4 to provide an alternative source of the defective enzyme, allowing him to discontinue treatment.
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors like lactate, glycerol, and certain amino acids. It occurs primarily in the liver but also in the kidneys and intestine. Gluconeogenesis is a crucial process that maintains blood glucose levels during periods of fasting or low carbohydrate intake. It involves the reversal of several steps in glycolysis along with some bypass reactions. Key regulatory enzymes include pyruvate carboxylase and phosphoenolpyruvate carboxykinase which control the conversion of pyruvate to phosphoenolpyruvate, and glucose-6-phosphatase which converts glucose-6-phosphate to glucose in the final step. Gl
Beta oxidation defects are inborn errors of metabolism that result in the failure of fatty acid oxidation. There are several types depending on the length of the fatty acid involved: very long chain, long chain, medium chain, or short chain. The main pathways affected are carnitine transport, beta oxidation, and ketogenesis. Presentations range from hypoglycemia in infants to muscle weakness or exercise intolerance in older children and adults. Diagnosis involves testing for intermediary metabolites, acylcarnitines, and enzyme activities. Treatment focuses on avoiding fasting and providing rapid glucose treatment during acute illnesses.
Metabolism of Brached Chain Amino Acid (Valine, Isoleucine, Leucine)Ashok Katta
Branched chain amino acids include leucine, isoleucine, and valine. They are broken down by the branched chain alpha-ketoacid dehydrogenase complex in mitochondria. A defect in this enzyme can cause branched chain ketoaciduria, where patients accumulate branched chain amino acids and their keto acids in their urine, which smells like maple syrup or burnt sugar. This rare genetic disorder impairs other amino acid transport and protein synthesis, and can lead to seizures, vomiting, ketoacidosis, coma, and death if not treated with a low-branched chain amino acid diet and thiamine supplementation.
This document provides an overview of disorders of carbohydrate metabolism. It begins with an introduction to carbohydrates and what happens when carbohydrate metabolism is defective. It then discusses several specific disorders including pyruvate kinase deficiency, pyruvate dehydrogenase deficiency, essential pentosuria, glycogen storage diseases, disorders of fructose metabolism like hereditary fructose intolerance, and disorders of galactose metabolism like galactosemia. It also provides brief summaries of type 1 and type 2 diabetes mellitus.
1. Inborn errors of metabolism are hereditary biochemical diseases caused by single gene defects that result in errors in the metabolism of proteins, carbohydrates, or fats.
2. Symptoms vary depending on the specific disorder but can include developmental delay, organomegaly, neurological abnormalities, and in some cases distinctive odors.
3. Treatment depends on the underlying cause but may include dietary modifications, supplements to replace missing enzymes or cofactors, or gene therapy in some cases. Early diagnosis through newborn screening can help prevent complications.
1. Newborn screening involves testing infants shortly after birth for treatable conditions that are not clinically apparent. This allows for early intervention to prevent irreversible damage.
2. Conditions screened for include metabolic disorders, endocrinopathies, hemoglobinopathies, cystic fibrosis, and others. Screening methods include blood tests, hearing tests, and pulse oximetry.
3. Positive results are reported immediately to doctors so treatment can begin, preventing disability or death from conditions like PKU, congenital hypothyroidism, and sickle cell disease.
Screening for any disorder in individuals is a strategy used for identifying a disease before the onset of signs or symptoms, thus enabling earlier detection and management with the aim to reduce morbidity and mortality.
This document discusses various inborn errors of metabolism including phenylketonuria, alkaptonuria, homocystinuria, galactosemia, glycogen storage diseases, mucopolysaccharidoses, Gaucher disease, Niemann-Pick disease, cystic fibrosis, and Wilson's disease. It describes the genetic defects, clinical features, diagnostic tests, and morphological findings for each condition. These hereditary biochemical disorders result from mutations that compromise the function of enzymes or other proteins involved in metabolic pathways.
Protocol based approach to metabolic liver disease seema alamSanjeev Kumar
This document outlines a protocol-based approach to identifying metabolic liver disease (MLD) as the cause of unexplained liver conditions in children. Key points include:
- MLD accounts for a significant percentage of pediatric liver disease cases that were previously classified as cryptogenic or of unknown etiology.
- The most common presentation of MLD is organomegaly.
- Following a series of diagnostic protocols tailored to different clinical presentations can help detect many treatable or palliative MLD cases that may otherwise go undiagnosed.
- Applying these protocols at a large pediatric liver disease center in India reduced the percentage of cases classified as cryptogenic or indeterminate from over 25% to under
An inborn error of metabolism is a genetic disorder that disrupts normal metabolic functions. Early detection through newborn screening is important to provide genetic counseling, begin treatment to prevent irreversible health issues, and avoid exacerbating factors. Symptoms can include those affecting the neurological, cardiac, skin or eye systems. Diagnosis involves tests of electrolytes, blood gases, amino acids and organic acids, while treatments depend on the specific metabolic disorder.
This document discusses inborn errors of amino acid metabolism. It begins by defining inborn errors of metabolism as inherited metabolic disorders caused by enzymatic defects present from birth. It then discusses several specific inborn errors of amino acid metabolism, including phenylketonuria (PKU), alkaptonuria, tyrosinemia, and albinism. For each, it provides a brief overview of causes, symptoms, diagnosis, and treatment. The document concludes by discussing additional inborn errors of amino acid metabolism such as urea cycle defects, homocystinuria, maple syrup urine disease, hyperprolinemia, nonketotic hyperglycinemia, hyperoxaluria, and glycinuria.
This document presents two case reports of patients diagnosed with Niemann-Pick disease. The first case report describes a 19-month old child from Rajasthan who developed distension of the abdomen and loss of motor skills. Examination revealed enlarged liver and spleen, reduced hemoglobin, diminished reflexes and hypotonia. Further testing confirmed Niemann-Pick type A disease. The second case report describes an Afghan girl who was growing normally until age 1 but then developed hepatomegaly and developmental delays. Testing revealed she had Niemann-Pick disease type C. The document then provides background information on Niemann-Pick disease, describing it as a rare inherited lysosomal storage disorder caused by defects in sphingomy
Case of Neonatal Hyperparathyroidism.pdfmehmood ahmad
This case report describes a male infant who presented at 26 days of age with lethargy, hypotonia, dehydration and reluctance to feed due to neonatal severe hyperparathyroidism. Investigations showed elevated serum calcium and parathyroid hormone levels with reduced bone density. The infant was treated medically but eventually required total parathyroidectomy. Neonatal severe hyperparathyroidism is a rare genetic disorder caused by calcium sensing receptor mutations that usually presents in the first 6 months of life and can be life threatening if not properly treated with medical management or surgery.
This document discusses inborn errors of metabolism (IEMs). IEMs are genetic disorders caused by deficiencies in metabolic pathways. The document outlines categories of IEMs, clinical signs that suggest an IEM, diagnostic testing approaches, differential diagnoses, emergency management including treatment of hyperammonemia, long-term management through diet modification and cofactor supplementation, and the importance of genetic counseling.
This document discusses inborn errors of metabolism (IEM), a group of genetically determined diseases caused by deficiencies in single enzymes. Nearly all IEM result in the accumulation of compounds in metabolic pathways. Many present at birth or in early childhood with issues like jaundice, vomiting, or developmental delays. Specific conditions discussed include phenylketonuria, galactosemia, glycogen storage diseases, mucopolysaccharidoses, and several lipid storage diseases. The causes, signs, diagnosis, and management of some common IEM are explained.
New Born Screening Notes 072109 Dr Galidovarun10anshu
1. The document discusses newborn screening, which primarily detects inborn errors of metabolism and genetic disorders that can be treated if detected early.
2. The mandatory newborn screening tests in the Philippines screen for 5 conditions: congenital adrenal hyperplasia, congenital hypothyroidism, phenylketonuria, galactosemia, and G6PD deficiency.
3. Each condition is described in 1-2 sentences, including what it is, how it is tested for in newborns, and its potential consequences if untreated. The document provides brief but comprehensive overviews of the key genetic disorders included in newborn screening.
MLD presenting with ALF Talk by Dr SK YachhaSanjeev Kumar
Metabolic disorders are a common cause of acute liver failure (ALF) in infants and children. Several key metabolic disorders that can cause ALF include neonatal hemochromatosis, type 1 tyrosinemia, mitochondrial cytopathies such as fatty acid oxidation defects and respiratory chain disorders, galactosemia, and urea cycle defects. Timely diagnosis and specific treatment of the underlying metabolic etiology are important for improving outcomes in pediatric ALF.
INBORN ERRORS OF METABOLISM, PKU, PHENYLKETONURIA, BY: MR. DINABANDHU BARAD, MSC TUTOR, SUM NURSING COLLEGE, SIKSHA O ANUSANDHAN DEEMED TO BE UNIVERSITY, BHUBANESWAR, ODISHA
ACUTE LIVER FAILURE - APPROACH AND MANAGEMENTNishant Yadav
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1. Inborn Errors of
Aminoacid Metabolism
Dr Sarath Krishnan M P
Junior Resident/Biochemistry
AIIMS Rishikesh
11-10-2021
1
2. ✘ Case of inborn errors of amino acid metabolism
✘ Introduction
✘ Classification
✘ Inborn errors
✘ Screening method
✘ Diagnosis and advanced methods
✘ Treatment
✘ COVID 19 and IEM
✘ Approach to cases of inborn errors of amino acid metabolism
✘ Summary
2
3. 3
CASE :
A one-year-old male child was born to consanguineous parents by NVD.
Birth weight: 3.5kgs.
O/E: Alert and no proper eye to eye contact, Microcephaly, Mild spasticity in
lower limbs, No facial asymmetry, Plantar reflux is raised.
Radiological data presents with cerebral atrophy, bilateral diffuse white
matter changes in MRI scan
Provisional diagnosis to be Metachromatic Leukodystrophy (MLD)/
Aminoaciduria/ Leigh syndrome.
4. 4
Advised for Urine and serum aminoacid test, thyroid hormone stimulating test,
creatinine phosphokinase(CPK), nerve conduction study(NCS), serum lactate
pyruvate tests.
He had kept on physiotherapy and on anti-epileptic medications.
Later when the child visited for the outpatient department with conditions of
global developmental delay, right focal seizures
O/E: Hypopigmented scalp hair, increased tone, deep tendon reflux (DTR)
scoring
He had screened for plasma aminoacid analysis and the method used was
reverse phase HPLC.
Elevated levels of phenylalanine levels 300μmol/L (31-75μmol/L), urine
metabolic screening reports are positive for ferric chloride test.
5. Aminoacids………..
✘ Monomer units of proteins
✘ Contains an amine group, a carboxylic acid group and a side chain specific
to each amino acid
✘ Total 300 known amino acids
✘ 22 standard amino acid
✘ Remaining non-proteinogenic or non-standard amino acids
5
7. Inborn errors of aminoacid metabolism
✘ Heterogenous group of disorders
✘ Abnormalities in synthesis, transport and turnover of the aminoacids
✘ Results in aminoacid accumulation and enters into alternate pathway which
results in toxic metabolite formation
7
9. Classification
✘ Two different ways
○ Based on the defect
Defective / Deficient enzymes
Defective transport and storage
○ Based on product / substrate accumulated
Organic acidemias
Aminoacidopathies
9
18. Laboratory diagnosis
✘ Blood and urinary phenyl alanine levels
✘ Normal levels are
○ Adults: 58±15μM/L
○ Teenagers: 60±13μM/L
○ Childhood: 62±18μM/L
○ Newborn: upto 120μM/L
✘ In untreated cases of PKU blood levels are as high as 2mM/L
18
19. Screening tests
✘ Ferric chloride screening test
✘ Guthrie card test
✘ Tandem mass spectroscopy – Recent Advance
*Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A Williams,1,2,* Cyril DS
Mamotte,2 and John R Burnett1,3,*
19
21. Confirmatory diagnosis
✘ Southern blotting
✘ Restriction enzyme digestion
✘ Sequencing and multiplex ligation probe amplification.
*Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A Williams,1,2,* Cyril DS
Mamotte,2 and John R Burnett1,3,*
21
22. Treatment
✘ Infant has to fed a diet where there is complete lack of phenylalanine for
the first 7-10days
✘ Pregnant PKU She is able to prevent her child from PKU symptoms if
she follows a diet low in protein
✘ Phenyl alanine ammonia lyase is combined with low phenyl alanine diet
22
23. Recent Advances!!!!!
✘ Next generation sequencing (NGS) – Confirmatory
✘ Treatment with a BH4 chaperone
✘ Large neutral amino acid (LNAA) therapy
✘ Gene therapy
*Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies Khalid M. Sumaily and
Ahmed H. Mujamammi
23
24. Tyrosinemia
✘ Group of inherited disorders characterized by increased levels of tyrosine
and their catabolic metabolite in blood and their excretion in urine
✘ Classified into three types
24
25. 25
Type Alternate names Enzyme defect
I Hepato-renal tyrosinemia/ Tyrosinosis Fumaryl acetoacetate
hydrolase deficiency
II Richnar-Hanhart syndrome/ Oregon type
tyrosinemia/ Oculocutaneous type
tyrosinosis
Tyrosine
aminotransferase
deficiency
III Neonatal tyrosinemia 4αOH Phenylpyruvate
oxidase deficiency
Classification
26. Type I Tyrosinemia
✘ K/a Hepato-renal tyrosinemia- deficiency of Fumaryl acetoacetate
hydrolase
✘ AR inheritance
26
*Inhibit porphobilinogen synthase
*Forms Schiff base and increase risk of HCC
27. ✘ Stages-Progress in 3 stages
○ Stage I: Hepatic necrosis and Hypermethioninemia
○ Stage II: Nodular cirrhosis and chronic hepatic insufficiency without
hypermethioninemia
○ Stage III: Also k/a Baber syndrome where renal tubular damage and
hypophosphatemic rickets
✘ Clinical features
○ MR
○ Self mutilation
○ Hepatic failure
○ Cardiomyopathy
27
28. Screening
✘ Tandem mass spectrometry - Measurement of Succinyl acetone
✘ TYR 1
*Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy Chris Stinton,1 Julia
Geppert,1 Karoline Freeman,1 Aileen Clarke,1 Samantha Johnson,2 Hannah Fraser,1 Paul Sutcliffe,1 and Sian Taylor-
Phillipscorresponding author1
28
29. ✘ Diagnosis
○ High levels of tyrosine in blood
○ α-Keto gamma methyl butyric acid is present-Cabbage like odour
○ Increased excretion of δ-ALA
○ Prenatal diagnosis: Increased succinyl acetone in amniotic fluid/
Measurement of Fumaryl acetoacetate in cultured amniotic cells
○ Molecular genetic testing for FAH gene mutations – Confirmatory
*Tyrosinemia Type 1 NORD gratefully acknowledges Kshitiz Singh, PhD, Research Fellow, The Children's Hospital of
Philadelphia
29
31. Type II Tyrosinemia
✘ Also K/a Richnar-Hanhart syndrome/ Oregon type tyrosinemia/
Oculocutaneous type tyrosinosis– Tyrosine aminotransferase deficiency
✘ AR inheritance
✘ Diagnosis:
○ Presence of skin/ eye lesions along with elevated blood tyrosine levels
✘ Treatment:
○ Dietary restriction of phenylalanine and tyrosine
31
32. Type III Tyrosinemia
✘ Also K/a Neonatal tyrosinemia- Deficiency of 4α-OH Phenylpyruvate
oxidase
✘ AR inheritance
✘ Milder form disease without liver failure
✘ Children with this disorder have mild MR and/or convulsions
✘ HAWKINSINURIA
32
34. Alkaptonuria
✘ First condition in which mendelian recessive inheritance was proposed
✘ Deficiency of Homogentisate oxidase
34
Homogentisic acid
Homogentisate
oxidase
Maleyl acetoacetate
Benzo quinone acetic
acid
*Binds to collagen fibres
*Darkening of urine
*Calcification of coronary artery and cartilage
35. ✘ Screening tests:
○ Benedict's test
○ FeCl3 test
○ Ammoniacal AgNO3
✘ Diagnostic tests:
○ Estimation of Homogentisate
✘ Treatment:
○ Long term ascorbic acid supplementation
○ NTBC/ NITISINONE
*Measurements of Homogentisic Acid Levels in Alkaptonuria Patients Using an Optimized and Validated Gas Chromatography
Method / Mass Spectrometry September 2014Jordan Journal of Biological Sciences 7(3)
35
36. Recent Advances!!!!!
✘ Enzyme replacement or Gene therapy
✘ Mouse model of AKU is available already
*Alkaptonuria: Current Perspectives. Andrea Zatkova,1 Lakshminarayan Ranganath,2 Ludevit Kadasi1,3. 1Department of Human
Genetics, Biomedical Research Center, Slovak Academy of Sciences, Institute of Clinical and Translational Research, Bratislava,
Slovakia
36
37. Albinism
✘ Spectrum of clinical syndromes characterized by hypomelanosis
✘ Inherited defect in the pigment cells of eye and skin
✘ Gene loci on Chr 11
37
38. ✘ Albinism can be classified in two ways
○ Based on distribution of hypopigmented tissues
■ Oculocutaneous
■ Ocular
○ Based on tyrosinase activity
■ Tyrosinase positive
■ Tyrosinase negative
✘ Clinical features
○ Leads to white hair and skin
○ Lead to skin cancer
○ Photophobia (intolerance to light) and nystagmus ( rapid involuntary
oscillation of the eyeballs)
38
39. ✘ Diagnosis:
○ Detected at birth due to irregular pigmentation
○ Genetic analysis: CVS testing
Amniocentesis
○ Hair from scalp for Tyrosinase activity
○ Radioactive biochemical assay – Recent advance
✘ Treatment
○ NO CURE
○ Only symptomatic management
*Albinism: modern molecular diagnosis SUSAN M CARDEN RAYMOND E BOISSY
PAMELA J SCHOETTKER WILLIAM V GOOD William V Good, MD.
39
42. Isovaleric acidemia
✘ Classical type of organic acidemia-Prevents normal metabolism of leucine
✘ Deficiency of Isovaleric acid CoA dehydrogenase
✘ AR inheritance
42
Leucine αKeto isocaproic acid Isovaleryl CoA
βMethyl crotonyl CoA
Hydroxy isovalerate
Isovaleryl glycine
43. ✘ Severe and life threatening present in early days of life with distinctive
odour of sweaty foot
✘ Diagnosis
○ Mass spectrometry of urine
○ Increased excretion of Isovaleryl carnitine and Isovaleryl glycine
✘ Treatment
○ Glycine administration in acute episodes
43
44. Methyl butyryl CoA dehydrogenase deficiency
✘ Also K/a Acyl CoA dehydrogenase deficiency/ Methyl butyryl glycinuria
✘ Usually asymptomatic
✘ Certain kids develop developmental delay/ epilepsy
✘ Diagnosi: Plasma and urinary carnitine and glycine conjugates of 2-methyl
butyryl CoA levels are raised
44
45. Propionic acidemia
✘ Also K/a propionic aciduria/ Propionyl CoA carboxylase deficiency/ Ketotic
glycinemia
Defective PCCA/ PCCB genes
Propionyl CoA carboxylase deficiency
Decreased breakdown of Propionyl CoA to methyl malonyl CoA
Altered metabolism of Valine, Isoleucine, Threonine and methionine
Accumulation of Propionyl CoA, Propionic acid, Ketone bodies, Ammonia
45
46. ✘ Clinical symptoms –present at an early stage with progressive
encephalopathy
○ Poor feeding with developmental delay
○ Vomiting / Dehydration/ Acidosis
○ Hypotonia/ Seizures/ Lethargy
✘ Diagnosis:
○ Urine screened for organic acid – Gas chromatography and mass
spectroscopy
✘ Treatment
○ Low protein diet
○ Carnitine replacement
○ Antibiotics for intestinal washout of propiogenic flora(10days/month)
○ Liver transplant is gaining role in the management
46
48. Methyl malonyl CoA mutase deficiency
✘ Also k/a Methyl malonic acidemia
✘ AR inheritance
48
Deficiency of enzyme leads to increased Methyl malonyl CoA
Inhibition of metabolism of Depletion of ATP, CoA
Propionyl CoA
Propionic acidemia Disruption in biosynthesis of
Myelin, Urea, Glucose
49. ✘ Clinical features:
○ Vomiting/ Acidosis
○ Hyperammonaemia/ Hyper glycinemia
○ Hypoglycaemia
○ Hepatomegaly/ Renal failure
○ Thrombocytopenia and Neutropenia at later stages
○ Hypotonia followed by spasticity
○ Dermatitis
○ Osteoporosis
✘ Outcome of these patients is poor and many of them die by the age of 1
year
49
50. ✘ Lab findings
○ Metabolic acidosis
○ Anaemia
○ Elevated ammonia levels in blood
○ Elevated ketone levels in urine
○ Neutropenia and thrombocytopenia
○ Elevated glycine, methylmalonic acid and propionic acid levels in the
blood and urine
50
51. ✘ Treatment
○ Protein restricted diet and carnitine supplementation
○ Bicarbonate, lipids, glucose and insulin may be indicated during
metabolic crisis episodes
○ Liver transplant or combined liver/ kidney transplant may increase
metabolic control
51
53. ✘ Types:
○ Classical : Little/ No enzyme activity <2%
○ Intermediate: More enzyme activity 3-8%
■ Can tolerate greater amount of leucine
○ Intermittent: Even more enzyme activity 8-15%
○ Thiamine-responsive: Thiamine to increase enzyme activity
✘ Symptoms:
○ Occur in newborns within the first 4-7 days of birth
○ Vomiting/ Dehydration/ Metabolic acidosis
○ Burned sugar smell to urine
○ Could lead to death if not treated, but is manageable
53
54. ✘ Diagnosis:
○ Increased serum levels of leucine, isoleucine and valine along with
their respective ketoacids
○ Tandem mass spectrometry
✘ Treatment:
○ Replacing dietary protein by mixture of amino acids that contain low or
no leucine, isoleucine, and valine
54
58. Hypermethioninemia
✘ Enzymes defective are
○ Methionine adenosyl transferase I/III deficiency
○ Glycine N-methyl transferase deficiency
○ S-Adenosyl homocysteine hydrolase deficiency
✘ AR/ AD
✘ Clinical features:
○ Remains asymptomatic/ unnoticed
○ Cabbage like odour of breath, sweat and urine
58
59. ✘ Investigations
○ MAT I/III deficiency:
■ Methionine levels are elevated 30times than normal
■ Concentrations of SAH, Total homocysteine and Cystathionine
are elevated
○ GNMT deficiency:
■ Normal concentration of Sarcosine with elevated level of
methionine and SAM
○ SAHH deficiency:
■ Elevated level of dimethyl glycine
59
61. Classification
61
Types Defects
Homocystinuria I Cystathionine β synthase
Homocystinuria II Synthesis of N5-MTHF
Homocystinuria III Deficiency of methyl B12
Homocystinuria IV Defective intestinal
absorption of Vit B12
63. ✘ Screening test: Methionine breath test
✘ Diagnosis
○ Plasma and urine levels of Homocysteine and Methionine levels are
raised
○ Silver nitroprusside test
○ Methionine loading test
✘ Treatment
○ Reduce the elevated levels of homocysteine thus preventing its
dreadful complication thrombosis
○ Vit B6 and B12
○ Betaine supplementation
○ PROTEIN RESTRICTED DIET
*Validity and reliability of the 13C-methionine breath test for the detection of moderate hyperhomocystinemia in Mexican adults
Jorge Maldonado-Hernández
63
65. Cystathioninuria
✘ Deficiency of Cystathionine γ lyase/ Cystathioninase
✘ No apparent pathology except increased accumulation of cystathionine in
kidney, brain, liver and CSF
✘ Plasma cysteine levels remain normal with mild hyperhomocystinemia
65
68. Glycine encephalopathy
✘ Also k/a non-Ketotic hyperglycinemia
✘ AR
✘ 2nd most common disorder of aminoacid metabolism
✘ Defect lies in glycine cleavage system
✘ Characterised by neurological symptoms and abnormal high levels of
glycine in bodily fluids and tissues especially CSF
68
69. ✘ Classical
○ In first 3 days 2/3rd of infants present with
■ Muscular hypotonia
■ Apnoea and coma
○ Infants who survive the first apnoea attack by 6 months develop
■ Spastic quadriparesis
■ Intractable seizures
■ Severe global retardation
■ CONGENITAL MALFORMATIONS
○ Long term complications are
■ Feeding difficulties, GERD with esophagitis, Gall stones
■ Hip dislocation, Scoliosis, Osteoporosis
69
70. ✘ Mild
○ Less severe mental retardation and less frequent episodes of seizures
○ NO CONGENITAL MALFORMATIONS
○ Characteristic findings: Severe speech retardation and behavioural
problem
✘ Transient
○ Classical clinical and biochemical changes in early infancy but comes
back to normal by 8 weeks of age
○ Outcome being good with slight or no neurological sequelae
70
71. ✘ Diagnosis:
○ Increased concentration of glycine in serum and CSF with an
increased CSF-plasma ratio are pathognomonic features
✘ Treatment
○ Sodium benzoate
○ Dextromethorphan
○ Ketamine
○ Strychnine
○ Diazepam
71
Receptor antagonists
74. Hyperlysinemia
✘ Also k/a Lysine α-keto glutarate reductase deficiency/ α-aminoadipic
semialdehyde synthase deficiency
✘ AR
✘ Clinical features
○ Impaired sexual development
○ Lax ligaments and muscles
○ Mild anaemia
○ Subluxation of lens
○ Comatose due to increase ammonia level in blood
✘ Diagnosis
○ Increased serum lysine, arginine, ammonia are noted
74
77. Histidinemia
✘ Also k/a Histinuria/ Histidase deficiency/ Histidine ammonia lyase
deficiency
✘ AR
✘ Clinical features: Asymptomatic usually, in some MR and developmental
delay
✘ Diagnosis: Increased histidine in blood, urine, CSF with decreased levels of
urocanic acid
✘ Treatment: Specific treatment not necessary
77
78. Urocanic aciduria
✘ Urocanate hydrolase/ Urocanase deficiency
✘ AR
✘ Increased urocanic acid accumulation and its excretion
✘ Histidine levels are normal to slightly elevated
✘ MR and Aggressive behaviour
78
79. Carnosinemia
✘ Also k/a Carnosinase/ Aminoacyl histidine dipeptidase deficiency
✘ AR
✘ Carnosine: Dipeptide formed in muscles and neurons
✘ Lack of enzyme: Accumulated in urine/ CSF/ Blood and Neurons causing
Demyelination and degeneration of axons
79
82. Hyperprolinemia
✘ AR-rare
✘ Two types based on the enzyme involved
○ Type I- Proline oxidase
○ Type II- Pyrroline 5 Carboxylase
✘ Mostly asymptomatic but rarely present as seizures, MR, Neurological
problems
✘ No specific treatment
82
85. Carbomyl phosphate synthetase I deficiency
✘ AR- Excess accumulation of NH3 in blood
✘ Clinical features: Symptoms are evident in the first few days of life
○ Early: CPS I enzyme is totally absent
Cerebral damage and hyperammonaemia coma
○ Delay: Partial deficiency
Hyperammonaemia coma stimulating Reye syndrome
Intermittent seizures
Vomiting and Mild abdominal pain
85
86. Ornithine transcarbamoylase deficiency
✘ Most common urea cycle disorder
✘ X-linked recessive disorder
✘ NH3 increase rapidly causing Ataxia, Lethargy and death
✘ GENETICS: OTC deficiency caused by mutations of OTC gene
86
87. ✘ Clinical features: Depending upon the age of onset of OTC deficiency
○ Classical/ Severe/ Early onset
○ Milder/ Late onset
✘ Affected neonates present with
○ Acrodermatitis enteropathica
○ Metabolic encephalopathy
87
88. Secondary orotic aciduria
✘ Orotic aciduria (AKA hereditary orotic aciduria) – Enzyme deficiency
resulting in a decreased ability to synthesize pyrimidines
✘ Elevated urinary orotic acid levels can also arise secondary to blockage of
the urea cycle, particularly in ornithine transcarbamoylase deficiency (OTC
deficiency)
88
89. Citrullinemia
✘ AR
✘ Argininosuccinate synthetase deficiency
✘ Types:
○ Type I: Changes in the kinetic properties of ASS
○ Type II: Low ASS found in liver but not in the kidney
○ Type III: No enzyme activity for ASS
✘ Clinical features:
○ Enuresis
○ Delayed menarche
○ Insomnia
○ Delusions and Hallucinations
89
90. Arginino succinic aciduria
✘ Arginino succinate lyase deficiency
✘ Clinical features:
○ Evident in the first few days of life because of high ammonia or later in
life presenting with sparse/ brittle hair, developmental delay and
tremors
○ Episodic unconsciousness with hepatomegaly
✘ Diagnosis
○ Low arginine along with hyperammonaemia
90
91. Argininemia
✘ Arginase deficiency
✘ AR
✘ Clinical features
○ Evident by the age of 3
○ Stiffness of legs is early presenting feature
○ Slower normal growth with developmental delay
○ Tremors, Seizures
○ MR
○ Rapid increase in NH3 may lead to episodes of irritability, refusal to
eat and vomiting
91
92. Treatment for urea cycle disorders
✘ Low protein diet
✘ IV Sodium benzoate
✘ IV Sodium phenylacetate
✘ Arginine replacement therapy
✘ Dialysis
92
93. N-Acetyl glutamate synthase deficiency
✘ AR
✘ N-Acetyl glutamate – Natural activator of CPS-I synthesized from acetyl
CoA and Glutamic acid
✘ Gene for NAG synthase located on Chr 17
✘ Severe neonatal disorder with fatal consequences if not detected
immediately upon birth
✘ Treatment : Injection of N-carbamoyl-L-glutamate an analogue of NAG
93
95. Cystinuria
✘ AR – Mutation in SLC3A1 and SLC7A9
✘ Cause defective transport protein synthesis in the kidney
✘ Results in lack of proper reabsorption of aminoacids Lysine, Arginine,
Ornithine, Cysteine
✘ Cysteine level increases – will cause Kidney stones
95
96. ✘ Clinical features
○ Symptoms are secondary to the stones formed
✘ Investigations
○ Urine analysis for cysteine crystals
○ Genetic analysis
96
97. Cystinosis
✘ AR
✘ Excessive accumulation of cystine within the cell leading to crystal
formation
✘ Mutation of CTNS gen on Chr 17 which encodes cystinosin the lysosome
cystine transporter that becomes defective
✘ Types
○ Nephropathic
○ Intermediary
○ Non nephropathic/ Ocular
97
98. ✘ Nephropathic
Present as renal
Fanconi syndrome
Loss of important
minerals, salts
Impairs growth and
hypophosphatemic
rickets
Complete kidney failure
by age 10
✘ Intermediary
Less severe
Late presentation
Clinical features similar
to nephropathic
✘ Ocular
Growth impairment and
kidney failure not seen
Only symptom is
photophobia
98
100. Lysinuric protein intolerance
✘ Also k/a Dibasic aminoaciduria type2/ Cationic aminoaciduria/ Familial
protein intolerance
✘ AR – Mutation of SLC7A7 gene
✘ Defective transport of Lysine, Ornithine, Arginine from kidneys and
intestine
Restriction of urea cycle due to decreased Ornithine and arginine
Hyperammonaemia leading to coma and death
100
101. ✘ Diagnosis
○ Increased urinary concentration of Lysine, Arginine, Ornithine with
corresponding decrease in plasma
○ Increased orotic acid concentration after protein rich meals
○ High levels of glutamine, glycine, ferritin and LDH
✘ Treatment
○ Oral supplementation of Citrulline
101
102. Hartnup disease
✘ Also k/a pellagra like dermatosis
✘ Defective absorption of non polar aminoacids from intestine and kidney
✘ Mainly Tryptophan
✘ AR – Mutation in SLC6A19 gene
✘ Defective SLC6A19(Na+ dependent and Cl- independent neutral AA
transporter)
Decreased absorption of Tryptophan
Decreased Melatonin/ Serotonin/ Niacin
102
103. ✘ Clinical features
○ Affected individuals remain asymptomatic and present with pellagra
like symptoms only on exposure to triggering factors like sunlight and
stress
○ Short stature with failure to thrive
○ Unsteady gait with episodes
○ Intermittent ataxia
○ Nystagmus
○ Psychiatric problems
103
104. ✘ Diagnosis
○ Excessive amount of amino acids such as tryptophan, lysine, glycine
are excreted but not proline, arginine, hydroxy proline thus
differentiating from generalised aminoacidurias
✘ Treatment
○ High protein diet
○ Daily supplementation with nicotinic acid
○ Avoid sunlight and other aggrevating factors
104
105. COVID-19 and IEM
✘ Study suggestive of metabolic decompensation in IEM
105
106. Approach to a case of inborn errors of aminoacid
metabolism
107. IEM – Index Of Suspicion
✘ Rapid deterioration in an otherwise well infant
✘ Septic appearing infant
✘ Failure to thrive
✘ Regression in milestones
✘ Recurrent emesis/ Feeding difficulty, alterations in respirations, abnormal
urine/ body smell, changing MS/ Lethargy, jaundice, intractable hiccups
✘ Can masquerade like pyloric stenosis
✘ Dietary aversion – Proteins, Carbohydrates
107
112. To Conclude!!!!!
✘ Inborn errors of metabolism are rare genetic (inherited) disorders in which
the body cannot properly turn food into energy.
✘ The disorders are usually caused by defects in specific proteins (enzymes)
that help break down (metabolize) parts of food.
✘ Researches are taking place for adequate management for IEM
✘ Enzyme replacement/ Gene therapy
✘ Prenatal diagnosis / Screening
112
113. References
✘ Nelson Textbook of Pediatrics - 21st Edition
✘ Harrison principles of internal medicine - 20th edition
✘ Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A
Williams,1,2, Cyril DS Mamotte,2 and John R Burnett1,3
✘ Phenylketonuria: A new look at an old topic, advances in laboratory
diagnosis, and therapeutic strategies Khalid M. Sumaily and Ahmed H.
Mujamammi
✘ Validity and reliability of the 13C-methionine breath test for the detection of
moderate hyperhomocystinemia in Mexican adults Jorge Maldonado-
Hernández
✘ Newborn screening for Tyrosinemia type 1 using succinylacetone – a
systematic review of test accuracy Chris Stinton,1 Julia Geppert,1 Karoline
Freeman,1 Aileen Clarke,1 Samantha Johnson,2 Hannah Fraser,1 Paul
113