This document provides information about homocystinuria, an inborn error of metabolism caused by cystathionine β-synthase deficiency. It leads to increased levels of homocysteine and methionine. Symptoms include ectopia lentis, skeletal abnormalities, intellectual disability, and blood clots. Treatment involves a low-protein, methionine-restricted diet and supplementation with vitamins B6, folate, betaine to convert homocysteine to cystathionine. Early diagnosis and treatment can prevent complications and allow for normal growth.
This document provides information about newborn screening disorders in Kuwait, including:
- It describes the 22 disorders in Kuwait's newborn screening panel, which include amino acid disorders, fatty acid disorders, organic acid disorders, and endocrine disorders.
- Clinical and treatment principles are summarized for each disorder, focusing on preventing developmental delays, neurological damage, comas and death.
- Factors that can cause false positive or negative screening results are outlined to improve accuracy of detection for each condition.
This document provides information about newborn screening disorders in Kuwait, including:
- It describes the 22 disorders in Kuwait's newborn screening panel, which include amino acid disorders, fatty acid disorders, organic acid disorders, and endocrine disorders.
- Clinical and treatment principles are outlined for each disorder, focusing on preventing developmental delays, neurological damage, comas and death.
- Factors that can cause false positive or negative screening results are identified to improve accuracy of detection.
iap-ahmedabad-inborn error of metabolismNilu Panch
This document discusses the approach to diagnosing and managing inborn errors of metabolism in neonates presenting with non-specific signs and symptoms. It outlines common signs and symptoms of IEMs including respiratory, cardiac, gastrointestinal, and neurological issues. It describes categories of IEMs and how to recognize metabolic acidosis, hyperammonemia, and hypoglycemia as presentation of underlying IEMs. Initial management involves stabilizing the patient through treatments like sodium bicarbonate, removing organic acids and ammonia through hemodialysis, and providing carnitine supplementation. Specific disorders discussed include organic acidemias and urea cycle disorders. Long term treatment depends on the specific diagnosed IEM and involves dietary management, medication
This document provides guidance for acute gastroenterology issues commonly seen in acute medical units. It summarizes guidelines on screening for alcohol use, appropriate blood transfusion levels for GI bleeds, paracetamol overdose treatment, and safely refeeding underweight patients to avoid complications.
This document discusses the diagnosis and management of inborn errors of metabolism (IEM) in neonates. Key points include:
- IEM are individually rare but collectively affect about 1 in 5,000 live births.
- Presentation can range from gradual to sudden to catastrophic and may mimic other conditions like infection.
- Initial labs should check for metabolic acidosis, hyperammonemia, and hypoglycemia to help identify treatable disorders.
- Life-threatening conditions require stabilizing the neonate before identifying the specific IEM through additional tests and specialist consultation. Management aims to correct acidosis/electrolytes, provide calories, remove toxic metabolites, and treat any underlying precipitants
This document provides an overview of the approach and management of inborn errors of metabolism. It discusses the incidence, clinical presentation, investigations, and management of various metabolic disorders. Key points include:
- Metabolic disorders are caused by enzyme deficiencies or abnormalities that disrupt normal metabolism. They are often inherited in an autosomal recessive pattern.
- Clinical features can include encephalopathy, liver disease, dysmorphic features, cardiac issues, and more nonspecific signs like jaundice or hypoglycemia. Laboratory tests help evaluate for issues like metabolic acidosis, hyperammonemia, or abnormal organic acids.
- Management involves stabilizing the patient, addressing acute issues like seizures or infections, implementing dietary modifications
This document discusses inborn errors of metabolism. It begins by defining metabolism as the breakdown and building up of molecules through catabolic and anabolic pathways, facilitated by enzymes. Inborn errors of metabolism are disorders caused by mutations that block normal metabolic pathways, resulting in toxic metabolites. The document then classifies different types of inborn errors affecting amino acid, carbohydrate, lipid, protein, and pigment metabolism. It outlines patterns of clinical presentation including encephalopathy, liver disease, dysmorphic features, and neurological symptoms. The document stresses the importance of early metabolic investigations for treating inborn errors.
This document provides information about newborn screening disorders in Kuwait, including:
- It describes the 22 disorders in Kuwait's newborn screening panel, which include amino acid disorders, fatty acid disorders, organic acid disorders, and endocrine disorders.
- Clinical and treatment principles are summarized for each disorder, focusing on preventing developmental delays, neurological damage, comas and death.
- Factors that can cause false positive or negative screening results are outlined to improve accuracy of detection for each condition.
This document provides information about newborn screening disorders in Kuwait, including:
- It describes the 22 disorders in Kuwait's newborn screening panel, which include amino acid disorders, fatty acid disorders, organic acid disorders, and endocrine disorders.
- Clinical and treatment principles are outlined for each disorder, focusing on preventing developmental delays, neurological damage, comas and death.
- Factors that can cause false positive or negative screening results are identified to improve accuracy of detection.
iap-ahmedabad-inborn error of metabolismNilu Panch
This document discusses the approach to diagnosing and managing inborn errors of metabolism in neonates presenting with non-specific signs and symptoms. It outlines common signs and symptoms of IEMs including respiratory, cardiac, gastrointestinal, and neurological issues. It describes categories of IEMs and how to recognize metabolic acidosis, hyperammonemia, and hypoglycemia as presentation of underlying IEMs. Initial management involves stabilizing the patient through treatments like sodium bicarbonate, removing organic acids and ammonia through hemodialysis, and providing carnitine supplementation. Specific disorders discussed include organic acidemias and urea cycle disorders. Long term treatment depends on the specific diagnosed IEM and involves dietary management, medication
This document provides guidance for acute gastroenterology issues commonly seen in acute medical units. It summarizes guidelines on screening for alcohol use, appropriate blood transfusion levels for GI bleeds, paracetamol overdose treatment, and safely refeeding underweight patients to avoid complications.
This document discusses the diagnosis and management of inborn errors of metabolism (IEM) in neonates. Key points include:
- IEM are individually rare but collectively affect about 1 in 5,000 live births.
- Presentation can range from gradual to sudden to catastrophic and may mimic other conditions like infection.
- Initial labs should check for metabolic acidosis, hyperammonemia, and hypoglycemia to help identify treatable disorders.
- Life-threatening conditions require stabilizing the neonate before identifying the specific IEM through additional tests and specialist consultation. Management aims to correct acidosis/electrolytes, provide calories, remove toxic metabolites, and treat any underlying precipitants
This document provides an overview of the approach and management of inborn errors of metabolism. It discusses the incidence, clinical presentation, investigations, and management of various metabolic disorders. Key points include:
- Metabolic disorders are caused by enzyme deficiencies or abnormalities that disrupt normal metabolism. They are often inherited in an autosomal recessive pattern.
- Clinical features can include encephalopathy, liver disease, dysmorphic features, cardiac issues, and more nonspecific signs like jaundice or hypoglycemia. Laboratory tests help evaluate for issues like metabolic acidosis, hyperammonemia, or abnormal organic acids.
- Management involves stabilizing the patient, addressing acute issues like seizures or infections, implementing dietary modifications
This document discusses inborn errors of metabolism. It begins by defining metabolism as the breakdown and building up of molecules through catabolic and anabolic pathways, facilitated by enzymes. Inborn errors of metabolism are disorders caused by mutations that block normal metabolic pathways, resulting in toxic metabolites. The document then classifies different types of inborn errors affecting amino acid, carbohydrate, lipid, protein, and pigment metabolism. It outlines patterns of clinical presentation including encephalopathy, liver disease, dysmorphic features, and neurological symptoms. The document stresses the importance of early metabolic investigations for treating inborn errors.
Organic acidemias are a group of disorders characterized by excess excretion of non-amino organic acids in urine due to defects in amino acid metabolism. Common presentations include acute overwhelming illness in neonates or recurrent metabolic crises in infants leading to developmental delay, seizures, and dystonia or choreoathetosis. Symptoms represent toxic encephalopathy and include lethargy, coma, vomiting, and seizures. Laboratory findings include metabolic acidosis, ketosis, and elevated organic acids in urine. Examples of organic acidemias with typical presentations are methylmalonic acidemia, propionic acidemia, and isovaleric acidemia.
This document summarizes information presented by two public health nutrition students about Glycogen Storage Disease type 1 (von Gierke's disease). It defines GSD1 as a genetic metabolic disorder caused by an inability to break down glycogen into glucose. This puts patients at risk for hypoglycemia. The major forms are type 1a, caused by a deficiency in glucose-6-phosphatase, and type 1b, caused by a defect in glucose-6-phosphate translocase. Successful treatment requires maintaining normal blood glucose through frequent intake of complex carbohydrates. Left untreated, GSD1 can cause serious health issues; but with proper nutrition management, patients can experience normal growth and development.
This document discusses inborn errors of metabolism, which are inherited disorders caused by defects in metabolic enzyme pathways. It provides details on the presentation, evaluation, differential diagnosis, emergency treatment and management of several specific metabolic conditions. Key points include: inborn errors can present from infancy to adulthood; evaluation involves medical history, physical exam and laboratory tests; treatment focuses on stabilizing the patient, identifying and eliminating toxic metabolites, and providing supportive care and diet management. Congenital adrenal hyperplasia is discussed as an example of an inborn error presenting as an adrenal crisis in infants.
This document discusses inherited metabolic disorders (IMDs), also known as inborn errors of metabolism. IMDs are caused by enzyme deficiencies that disrupt normal metabolism, leading to the accumulation of toxic substrates. Common symptoms include neurological deterioration, metabolic acidosis, hypoglycemia, and more. The document focuses on phenylketonuria (PKU) and galactosemia as examples. PKU is caused by a lack of the enzyme phenylalanine hydroxylase, causing phenylalanine to accumulate and damage the brain if left untreated. Galactosemia results from a lack of the GALT enzyme, causing galactose toxicity if dairy is consumed. Both require life-long dietary restrictions to restrict intake of
The document summarizes guidelines for diagnosing inborn errors of metabolism (IEM) presenting in neonates from AIIMS, Delhi. It outlines key clinical pointers towards IEM like family history or consanguinity. Initial investigations should include blood gases, glucose, ammonia and lactate levels. Based on results, IEM can be categorized as urea cycle defects, organic acidemias or others. Confirmatory tests include urine organic acids analysis, plasma amino acids and acylcarnitine profiles. Prompt diagnosis and management is important as outcomes depend on rapid detection and treatment of underlying causes like hyperammonemia.
Inborn errors of metabolism are genetic diseases caused by defects in single enzymes involved in metabolic pathways. This leads to toxic accumulation of substrates or deficiencies in essential compounds. Garrod hypothesized these disorders were due to errors in intermediate metabolism. Examples include disorders of carbohydrate, amino acid, fatty acid, and mitochondrial metabolism. Symptoms depend on the specific pathway affected and can include hypoglycemia, lactic acidosis, and developmental delays. Treatment focuses on preventing toxic accumulations and supplementing deficient compounds.
This document summarizes various inborn errors of metabolism, including:
- Disorders of amino acid metabolism such as phenylketonuria (PKU), tyrosinemia, maple syrup urine disease (MSUD), homocystinuria, and nonketotic hyperglycinemia.
- Urea cycle defects which result in abnormal nitrogen metabolism and elevated ammonia levels.
- Disorders of organic acid metabolism including propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and glutaric aciduria type 1.
- A disorder of fatty acid metabolism, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), is also mentioned.
This document discusses the diagnosis and presentation of inborn errors of metabolism. It begins by defining inborn errors of metabolism as inherited enzyme deficiencies that disrupt normal metabolism. There are three main types of clinical presentation: silent disorders, acute metabolic crises, and progressive neurological deterioration. For diagnosis, the document outlines important history and examination factors and provides guidance on initial laboratory tests and specialized investigations. Common metabolic presentations like metabolic acidosis and hypoglycemia are reviewed. Specific disorders are then discussed in terms of their typical diagnostic considerations and laboratory findings.
This document discusses diabetes mellitus, including its increasing prevalence worldwide driven by obesity and reduced activity. It covers the classification, pathogenesis, symptoms, diagnosis and management of both type 1 and type 2 diabetes. Key points include the roles of insulin and insulin resistance in the different types of diabetes, long-term complications involving microvascular and macrovascular damage, and treatment involving lifestyle modifications and medications like metformin, insulin, and other anti-diabetic drugs. Hypoglycemia, ketoacidosis, and other acute complications are also summarized.
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.
Inborn errors of metabolism are genetic disorders that prevent the body from properly breaking down certain nutrients. There are several types of inborn errors of metabolism described in the document. Garrod first proposed the "one gene-one enzyme" hypothesis to explain these disorders, where defects in specific enzymes cause the buildup of nutrients. Examples provided include galactosemia, phenylketonuria (PKU), tyrosinemia, maple syrup urine disease, homocystinuria, and others. Galactosemia prevents breaking down the sugar galactose, leading to complications without treatment. PKU increases phenylalanine levels, causing intellectual disabilities if untreated. Tyrosinemia disrupts tyrosine breakdown and can damage organs
This document provides information on inborn errors of purine and pyrimidine metabolism. It defines key enzymes involved in purine degradation and salvage pathways such as adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, and adenosine deaminase. It also discusses disorders that result from defects in these enzymes, including the causes and effects of lesions in the purine nucleotide cycle. Additionally, it describes uric acid formation from hypoxanthine and xanthine, and the role of the UMP synthase complex in pyrimidine synthesis. Overall, the document outlines the normal metabolic pathways of
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
This document provides an overview of metabolic diseases in children. It begins by defining inborn errors of metabolism and their causes. The document then discusses patterns of inheritance and classifications of different types of metabolic diseases affecting amino acid, carbohydrate, lipid, and protein metabolism. Signs and symptoms of various metabolic diseases are outlined. The document concludes by covering investigations and treatment approaches for metabolic diseases in children.
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
The document discusses the ketogenic diet, which is a high-fat, low-carbohydrate diet used to treat intractable epilepsy. It aims to decrease seizures by putting the body into a state of ketosis. The diet has shown to be effective in reducing seizures in 38% of patients after 3 months compared to 6% of control patients. It can be implemented as a classical 4:1 or 3:1 ratio diet, or as a medium chain triglyceride diet, with no difference in efficacy between the two. Strict monitoring of growth, blood tests, seizures and ketone levels is needed when a patient is on the ketogenic diet.
Nutritional refeeding syndrome kwashiorkar and marasmus indore pedicon 2014Rajesh Kulkarni
This document provides information on the management of severe acute malnutrition (SAM) in children, including refeeding syndrome. It describes a case of an 18-month-old boy admitted with SAM who deteriorated on the third day of treatment. It then discusses refeeding syndrome, its pathophysiology, clinical manifestations, and electrolyte deficiencies. Guidelines are provided for monitoring patients and correcting electrolyte abnormalities during nutritional rehabilitation. The document outlines protocols for the stabilization and rehabilitation phases of SAM treatment, including feeding amounts and micronutrient supplementation.
Obesity- Metabolic alterations, complications and treatmentNamrata Chhabra
The document discusses complications and treatment of obesity. It summarizes that obesity affects almost all systems of the body and is associated with various comorbidities related to cardiology, dermatology, endocrinology, gastrointestinal, neurology, oncology, metabolism, and psychology. The prognosis of obesity is usually poor, increasing risks of various diseases. Obesity can be treated through diet, physical exercise, behavioral modification, medications, and bariatric surgery.
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
Protein which are major component of our diet have amino acid as their precursor and also act as important energy source. Any imbalance in the metabolism of these amino acid cause disorders
Lesson 7.1 inborn errors of metabolism princesa2000
This document discusses inborn errors of metabolism (IEMs), which are genetic disorders caused by defects in metabolic pathways. It covers:
- Classification of IEMs including disorders of carbohydrate, protein, lipid, and nucleic acid metabolism.
- Presentation of IEMs in newborns including non-specific symptoms like vomiting and seizures.
- Diagnosis through family history, physical exam, and simple lab tests to check for metabolic acidosis.
- Treatment options like dietary restrictions, supplements, and gene therapy depending on the specific IEM.
Organic acidemias are a group of disorders characterized by excess excretion of non-amino organic acids in urine due to defects in amino acid metabolism. Common presentations include acute overwhelming illness in neonates or recurrent metabolic crises in infants leading to developmental delay, seizures, and dystonia or choreoathetosis. Symptoms represent toxic encephalopathy and include lethargy, coma, vomiting, and seizures. Laboratory findings include metabolic acidosis, ketosis, and elevated organic acids in urine. Examples of organic acidemias with typical presentations are methylmalonic acidemia, propionic acidemia, and isovaleric acidemia.
This document summarizes information presented by two public health nutrition students about Glycogen Storage Disease type 1 (von Gierke's disease). It defines GSD1 as a genetic metabolic disorder caused by an inability to break down glycogen into glucose. This puts patients at risk for hypoglycemia. The major forms are type 1a, caused by a deficiency in glucose-6-phosphatase, and type 1b, caused by a defect in glucose-6-phosphate translocase. Successful treatment requires maintaining normal blood glucose through frequent intake of complex carbohydrates. Left untreated, GSD1 can cause serious health issues; but with proper nutrition management, patients can experience normal growth and development.
This document discusses inborn errors of metabolism, which are inherited disorders caused by defects in metabolic enzyme pathways. It provides details on the presentation, evaluation, differential diagnosis, emergency treatment and management of several specific metabolic conditions. Key points include: inborn errors can present from infancy to adulthood; evaluation involves medical history, physical exam and laboratory tests; treatment focuses on stabilizing the patient, identifying and eliminating toxic metabolites, and providing supportive care and diet management. Congenital adrenal hyperplasia is discussed as an example of an inborn error presenting as an adrenal crisis in infants.
This document discusses inherited metabolic disorders (IMDs), also known as inborn errors of metabolism. IMDs are caused by enzyme deficiencies that disrupt normal metabolism, leading to the accumulation of toxic substrates. Common symptoms include neurological deterioration, metabolic acidosis, hypoglycemia, and more. The document focuses on phenylketonuria (PKU) and galactosemia as examples. PKU is caused by a lack of the enzyme phenylalanine hydroxylase, causing phenylalanine to accumulate and damage the brain if left untreated. Galactosemia results from a lack of the GALT enzyme, causing galactose toxicity if dairy is consumed. Both require life-long dietary restrictions to restrict intake of
The document summarizes guidelines for diagnosing inborn errors of metabolism (IEM) presenting in neonates from AIIMS, Delhi. It outlines key clinical pointers towards IEM like family history or consanguinity. Initial investigations should include blood gases, glucose, ammonia and lactate levels. Based on results, IEM can be categorized as urea cycle defects, organic acidemias or others. Confirmatory tests include urine organic acids analysis, plasma amino acids and acylcarnitine profiles. Prompt diagnosis and management is important as outcomes depend on rapid detection and treatment of underlying causes like hyperammonemia.
Inborn errors of metabolism are genetic diseases caused by defects in single enzymes involved in metabolic pathways. This leads to toxic accumulation of substrates or deficiencies in essential compounds. Garrod hypothesized these disorders were due to errors in intermediate metabolism. Examples include disorders of carbohydrate, amino acid, fatty acid, and mitochondrial metabolism. Symptoms depend on the specific pathway affected and can include hypoglycemia, lactic acidosis, and developmental delays. Treatment focuses on preventing toxic accumulations and supplementing deficient compounds.
This document summarizes various inborn errors of metabolism, including:
- Disorders of amino acid metabolism such as phenylketonuria (PKU), tyrosinemia, maple syrup urine disease (MSUD), homocystinuria, and nonketotic hyperglycinemia.
- Urea cycle defects which result in abnormal nitrogen metabolism and elevated ammonia levels.
- Disorders of organic acid metabolism including propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and glutaric aciduria type 1.
- A disorder of fatty acid metabolism, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), is also mentioned.
This document discusses the diagnosis and presentation of inborn errors of metabolism. It begins by defining inborn errors of metabolism as inherited enzyme deficiencies that disrupt normal metabolism. There are three main types of clinical presentation: silent disorders, acute metabolic crises, and progressive neurological deterioration. For diagnosis, the document outlines important history and examination factors and provides guidance on initial laboratory tests and specialized investigations. Common metabolic presentations like metabolic acidosis and hypoglycemia are reviewed. Specific disorders are then discussed in terms of their typical diagnostic considerations and laboratory findings.
This document discusses diabetes mellitus, including its increasing prevalence worldwide driven by obesity and reduced activity. It covers the classification, pathogenesis, symptoms, diagnosis and management of both type 1 and type 2 diabetes. Key points include the roles of insulin and insulin resistance in the different types of diabetes, long-term complications involving microvascular and macrovascular damage, and treatment involving lifestyle modifications and medications like metformin, insulin, and other anti-diabetic drugs. Hypoglycemia, ketoacidosis, and other acute complications are also summarized.
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.
Inborn errors of metabolism are genetic disorders that prevent the body from properly breaking down certain nutrients. There are several types of inborn errors of metabolism described in the document. Garrod first proposed the "one gene-one enzyme" hypothesis to explain these disorders, where defects in specific enzymes cause the buildup of nutrients. Examples provided include galactosemia, phenylketonuria (PKU), tyrosinemia, maple syrup urine disease, homocystinuria, and others. Galactosemia prevents breaking down the sugar galactose, leading to complications without treatment. PKU increases phenylalanine levels, causing intellectual disabilities if untreated. Tyrosinemia disrupts tyrosine breakdown and can damage organs
This document provides information on inborn errors of purine and pyrimidine metabolism. It defines key enzymes involved in purine degradation and salvage pathways such as adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, and adenosine deaminase. It also discusses disorders that result from defects in these enzymes, including the causes and effects of lesions in the purine nucleotide cycle. Additionally, it describes uric acid formation from hypoxanthine and xanthine, and the role of the UMP synthase complex in pyrimidine synthesis. Overall, the document outlines the normal metabolic pathways of
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
This document provides an overview of metabolic diseases in children. It begins by defining inborn errors of metabolism and their causes. The document then discusses patterns of inheritance and classifications of different types of metabolic diseases affecting amino acid, carbohydrate, lipid, and protein metabolism. Signs and symptoms of various metabolic diseases are outlined. The document concludes by covering investigations and treatment approaches for metabolic diseases in children.
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
The document discusses the ketogenic diet, which is a high-fat, low-carbohydrate diet used to treat intractable epilepsy. It aims to decrease seizures by putting the body into a state of ketosis. The diet has shown to be effective in reducing seizures in 38% of patients after 3 months compared to 6% of control patients. It can be implemented as a classical 4:1 or 3:1 ratio diet, or as a medium chain triglyceride diet, with no difference in efficacy between the two. Strict monitoring of growth, blood tests, seizures and ketone levels is needed when a patient is on the ketogenic diet.
Nutritional refeeding syndrome kwashiorkar and marasmus indore pedicon 2014Rajesh Kulkarni
This document provides information on the management of severe acute malnutrition (SAM) in children, including refeeding syndrome. It describes a case of an 18-month-old boy admitted with SAM who deteriorated on the third day of treatment. It then discusses refeeding syndrome, its pathophysiology, clinical manifestations, and electrolyte deficiencies. Guidelines are provided for monitoring patients and correcting electrolyte abnormalities during nutritional rehabilitation. The document outlines protocols for the stabilization and rehabilitation phases of SAM treatment, including feeding amounts and micronutrient supplementation.
Obesity- Metabolic alterations, complications and treatmentNamrata Chhabra
The document discusses complications and treatment of obesity. It summarizes that obesity affects almost all systems of the body and is associated with various comorbidities related to cardiology, dermatology, endocrinology, gastrointestinal, neurology, oncology, metabolism, and psychology. The prognosis of obesity is usually poor, increasing risks of various diseases. Obesity can be treated through diet, physical exercise, behavioral modification, medications, and bariatric surgery.
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
Protein which are major component of our diet have amino acid as their precursor and also act as important energy source. Any imbalance in the metabolism of these amino acid cause disorders
Lesson 7.1 inborn errors of metabolism princesa2000
This document discusses inborn errors of metabolism (IEMs), which are genetic disorders caused by defects in metabolic pathways. It covers:
- Classification of IEMs including disorders of carbohydrate, protein, lipid, and nucleic acid metabolism.
- Presentation of IEMs in newborns including non-specific symptoms like vomiting and seizures.
- Diagnosis through family history, physical exam, and simple lab tests to check for metabolic acidosis.
- Treatment options like dietary restrictions, supplements, and gene therapy depending on the specific IEM.
The document discusses glycogen degradation (glycogenolysis). It describes the four enzymes involved - phosphorylase, debranching enzyme, phosphoglucomutase, and glucose-6-phosphatase. Phosphorylase breaks down glycogen into glucose-1-phosphate. The debranching enzyme and phosphorylase work together to further degrade glycogen. Phosphoglucomutase converts glucose-1-phosphate to glucose-6-phosphate which can then be used for energy or converted to glucose by glucose-6-phosphatase in the liver. The pathway provides glucose between meals and for anaerobic activity.
The document summarizes the regulation of glycogen metabolism. Key points include:
- Glycogen synthesis (glycogenesis) and breakdown (glycogenolysis) are reciprocally regulated through phosphorylation/dephosphorylation of glycogen synthase and glycogen phosphorylase enzymes by hormones like insulin and glucagon.
- Insulin promotes glycogenesis by stimulating dephosphorylation while glucagon promotes glycogenolysis by stimulating phosphorylation via the cAMP pathway.
- Regulation allows the storage of glucose as glycogen when blood glucose is high and the release of glucose from glycogen when blood glucose is low to maintain homeostasis.
Glycogen is a readily available storage form of glucose found mainly in the liver and muscle. It is synthesized through glycogenesis, which involves four steps - activation of glucose to UDP-glucose, initiation using the primer glycogenin, elongation by glycogen synthase adding glucose units via alpha-1,4 glycosidic bonds, and branching every 7-10 units via alpha-1,6 bonds by branching enzyme. Glycogen synthesis requires two enzymes - glycogen synthase which elongates the chain and branching enzyme which introduces branches, and continues till sufficient glycogen is synthesized or glucose is no longer available.
The hexose monophosphate shunt (HMP) pathway is an alternative pathway to glycolysis that occurs in the cytoplasm of liver, adipose tissue, and red blood cells. It has two phases: an oxidative phase that produces NADPH and a non-oxidative phase that generates pentoses and glycolytic intermediates. The HMP pathway is important because it provides NADPH for reductive biosynthesis, pentoses for nucleotide and coenzyme synthesis, and intermediates that can re-enter glycolysis or gluconeogenesis.
ATP is the most important form of chemical energy in cells. It is a nucleoside triphosphate containing adenine, ribose, and three phosphate groups. ATP is considered the universal energy currency of cells because it can easily donate a single phosphate, two phosphates, or its entire adenosine group to drive various energy-requiring cellular reactions and processes. ATP is regenerated through substrate-level phosphorylation during glycolysis and the citric acid cycle, as well as oxidative phosphorylation in the mitochondria. When ATP is hydrolyzed, energy is released to power cellular work.
Alcohol induced metabolic alterations - A Case based discussionNamrata Chhabra
This document describes a case study of a 60-year-old male alcoholic who was brought to the hospital in serious condition. Laboratory tests revealed hypoglycemia, lactic acidosis, hyperuricemia, and other metabolic alterations. The patient's history of alcoholism and cirrhosis indicated that the metabolic derangements were due to alcohol-induced impairments in gluconeogenesis and tricarboxylic acid cycle function, leading to reduced glucose availability, increased lactate production, and impaired uric acid excretion. The patient was diagnosed with cirrhosis, portal hypertension, bleeding varices, sepsis, shock, renal failure, and other complications of long-term heavy alcohol use and malnutrition.
This document discusses metabolic disorders caused by inborn errors of metabolism. It explains that these disorders occur when the body is unable to break down nutrients normally due to defects in enzymes involved in metabolic pathways. This leads to toxic buildup of substrates that can damage tissues if not treated early. Specific disorders discussed include phenylketonuria, maple syrup urine disease, homocystinuria, citrullinemia, and tyrosinemia. The document emphasizes the importance of newborn screening to detect these disorders before symptoms appear in order to start early treatment and prevent negative health outcomes.
Pegnancy and liver disease BY DR KANDYAjay Kandpal
This document discusses various physiological changes in pregnancy and how they relate to common pregnancy-related liver conditions. It begins by outlining relevant increases in body water, cardiac output, and plasma volume during pregnancy. It then examines specific conditions like hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, HELLP syndrome, and acute viral hepatitis-E. For each condition, it discusses etiology, clinical features, management, and outcomes. The document provides a concise yet informative review of how physiology and pathology intersect in relation to the liver during pregnancy.
Hyperemesis gravidarum is a severe form of nausea and vomiting during pregnancy that can cause dehydration, weight loss, and nutritional deficiencies if left untreated. It occurs in 0.3-3% of pregnancies and is more common in young, primigravid women. The exact cause is unknown but may involve high pregnancy hormone levels. Symptoms include persistent vomiting and inability to keep food or liquids down. Treatment focuses on rehydration, electrolyte replacement, antiemetics, nutritional supplementation to prevent complications like Wernicke's encephalopathy. With supportive treatment, prognosis is generally good but uncontrolled vomiting can lead to low birth weight or other issues.
- The patient is a 9-year-old girl who was diagnosed with hypoparathyroidism at age 2 and Addison's disease at age 8. She presents symptoms of both conditions.
- She likely has polyglandular autoimmune syndrome type 1, a rare disorder caused by AIRE gene mutations where patients develop multiple autoimmune endocrine conditions, most commonly involving the parathyroid glands, adrenal glands, and gonads.
- Her conditions are treated with hydrocortisone and fludrocortisone replacement for adrenal insufficiency and calcium and calcitriol supplementation for hypoparathyroidism. Close monitoring of her treatment is needed to
A urea cycle disorder (UCD) is an inherited disease that affects how the body removes the waste that is made from breaking down protein.
A very short and to the point presentation to understand.
This document discusses hyperemesis gravidarum, a severe form of nausea and vomiting during pregnancy. It begins by defining hyperemesis gravidarum and listing its risk factors, which include high levels of hCG and estrogen, primigravidity, and a history of this condition. The document then covers signs and symptoms, pathogenesis, diagnosis, and both outpatient and inpatient management. Outpatient management involves medications, dietary changes, and lifestyle adjustments while inpatient management focuses on IV rehydration and electrolyte replacement, antiemetics, and monitoring until discharge criteria are met. Complications are also outlined.
The document discusses malnutrition in critical illness and factors that favor its development. It outlines the consequences of malnutrition, including impaired immune function, wound healing, organ dysfunction, and increased risk of death. The document provides guidelines on nutritional assessment and determining energy and protein requirements in critical illness. It discusses the benefits of early enteral nutrition over parenteral nutrition.
The document outlines the agenda and content for a class on the endocrine system and diabetes mellitus. The class will review the hypothalamic-pituitary control of hormones, hypo- and hyper- functions of endocrine glands, the anatomy and physiology of the endocrine pancreas, classifications of diabetes, and the pathophysiology and clinical manifestations of type 1 and type 2 diabetes. Key differences between type 1 and type 2 diabetes will also be discussed.
This document provides an overview of inborn errors of metabolism (IEM). It discusses that IEM have an overall incidence of 1 in 1000 to 1 in 2000 births. The most common presentation is sepsis in 30% of cases. IEM are classified based on the defective metabolic pathway, such as amino acid metabolism defects, carbohydrate metabolism defects, and organic acidemias. Clinical pointers for suspected IEM include deterioration after apparent normalcy, hypoglycemia, metabolic acidosis, abnormal urine odor, and dysmorphic features. Evaluation of neonates involves blood tests, blood gases, glucose and ammonia levels, urine analysis, and plasma amino acid analysis to identify specific disorders. Management involves identifying and limiting the offending substance
This document discusses Dr. Patrick Garrett's approach to restoring fertility through lifestyle and dietary interventions. It begins with an introduction to Dr. Garrett and his qualifications. It then covers normal female hormone physiology and the menstrual cycle. It discusses various causes of amenorrhea and anovulation, including hypothalamic issues, hyperprolactinemia, premature ovarian failure, PCOS, and other disorders. For each condition, it outlines a lifestyle-based treatment approach focusing on diet, herbal remedies, exercise, stress management, and eliminating endocrine disruptors to restore normal hormone functioning and fertility.
This document discusses diabetes mellitus and provides classifications and types of diabetes. It covers:
1. Diabetes is characterized by hyperglycemia due to defects in insulin secretion or insulin resistance. It is classified into type 1, type 2, and other specific types.
2. Less common types of diabetes in children include type 2 diabetes, monogenic diabetes, neonatal diabetes, mitochondrial diabetes, and cystic fibrosis related diabetes.
3. Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells leading to insulin deficiency. It has both genetic and environmental risk factors.
Inborn errors of metabolism are rare genetic disorders where the body cannot properly break down food into energy due to defects in enzymes. Phenylketonuria is provided as an example, where a defect in the enzyme phenylalanine hydroxylase prevents the breakdown of phenylalanine, causing it to accumulate to toxic levels and resulting in issues like intellectual disability if left untreated. Treatment involves a low-phenylalanine diet from infancy onwards.
This document discusses nutrition and fasting in chronic liver disease. It outlines several metabolic changes that occur in chronic liver disease, including decreased glycogen stores and glucose intolerance. It provides general nutrition guidelines for patients with liver disease, recommending adequate calories, proteins, vitamins and minerals. It discusses the benefits of fasting, including detoxification, reduced inflammation, blood sugar and weight loss. However, it notes fasting can worsen conditions in some patients and is not advised for all cases of liver disease.
Dr. Patrick Garrett is a chiropractor and functional medicine practitioner who specializes in reversing acute and chronic conditions naturally, including migraines. He discusses various triggers for migraines such as food sensitivities, dietary amines, chemical additives, and lifestyle factors. Rather than relying on medications which can cause side effects and rebound headaches, Dr. Garrett recommends a lifestyle approach including an anti-inflammatory diet rich in omega-3s, magnesium, B vitamins, and supplements like magnesium, ginger, and butterbur to help cure and prevent migraines.
MSUD is metabolic genetic error . It happens due to lack of an enzyem that degrades specific amino acids
Homocystinuria is also a metbolic genetic error due to an enzyme defficiency it leads to an accumulation of homocystein and related chemical in the blood
This document provides information on various metabolic inborn errors including phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia, galactosemia, glycogen storage diseases, and Niemann-Pick disease. It defines metabolic inborn errors as disorders caused by single gene defects that block metabolism. For each condition, it describes the genetic cause, signs and symptoms, diagnosis, and treatment. The document is presented as part of a biochemistry assignment on metabolic inborn errors for a health sciences university in Central America.
This document discusses nutrition and immunonutrition in the intensive care unit (ICU). It covers the physiological stress of critical illness, consequences of malnutrition, evidence for early enteral feeding and risks of overfeeding. It also discusses immunonutrition strategies like glutamine, probiotics, arginine and omega-3 fatty acids which may help modulate the immune response and reduce infections in critically ill patients. Unanswered questions remain around optimal delivery of specific nutrients to different patient groups.
This document discusses nutrition and immunonutrition in the ICU. It notes that critical illness causes physiological stress, organ failure, and immune suppression. Poor nutrition in the ICU increases morbidity, mortality, and hospital stay. While early enteral feeding is best, trials of nutrition in the ICU have been small and inconclusive. Guidelines recommend screening patients and providing either enteral or parenteral nutrition to malnourished patients. Immunonutrition aims to modulate the immune response with specific nutrients.
This document lists numerous genes and their associated phenotypes and inheritance patterns. It provides the gene name, associated OMIM number and phenotype, and whether the condition is autosomal recessive, autosomal dominant, or X-linked recessive. The document contains over 100 gene entries in this format.
The document lists various genes that can be analyzed using next-generation sequencing (NGS) panels for newborn screening results. It includes genes related to inborn errors of metabolism (IEM), endocrinology (EPI), neurology, ophthalmology (OPTH), hematology (Hema), and cardio-vascular disorders. The genes are associated with newborn screening results from tandem mass spectrometry and DELFIA laboratories in Kuwait for conditions such as hypothyroidism, congenital adrenal hyperplasia, galactosemia, phenylketonuria, and homocystinuria.
This document provides a guide for non-genetic medical doctors to understand next generation sequencing (NGS) reports. It explains that NGS is used in clinical diagnostic testing to sequence a patient's genome and identify genetic variants, which can be benign, pathogenic, or of uncertain significance. The document outlines how variants are classified and discusses limitations of testing. It also describes what primary findings related to a patient's symptoms and secondary findings unrelated to symptoms may be reported.
Kuwait has established a national newborn screening program that screens all newborns for 22 disorders using tandem mass spectrometry and other methods. The program started in 2005 screening high-risk newborns for 2 disorders and expanded over time, becoming a universal screening program in 2014 that screens over 60,000 newborns annually across both governmental and private hospitals. The screening helps detect treatable genetic disorders early to improve newborn health outcomes and reduce disability and disease burden. Challenges in implementing the program were addressed through strategic planning, leadership, education, and integrating screening into the public health system to ensure sustainability.
This document provides an annual report on Kuwait's newborn screening program for 2018. It includes statistics on the number of samples received and tested, the screening panel used, positive results, confirmed cases, and performance indicators. A total of 59,655 samples were received in 2018 from various hospitals in Kuwait. Of these, 931 screened positive for various conditions. Further testing confirmed 67 cases across different metabolic disorders and endocrine conditions. Key performance metrics like detection rate, false positive rate, and positive predictive value are provided. The report concludes by thanking the newborn screening team and various doctors for their efforts in the program's success.
This document discusses newborn screening results for biotinidase deficiency in Kuwait between 2015-2018. It found that 1 in 1,030 neonates screened had partial or profound biotinidase deficiency. Only 3% of those referred for additional testing had profound deficiency. The most common mutation detected was c.[1330G>C] (p.(Asp444His)), considered a mild form. While screening was effective at detecting profound cases, it identified a large number of false positives and partially deficient cases. The program aims to identify only those with profound deficiency at risk of severe symptoms.
Next generation sequencing (NGS) provides faster and cheaper DNA sequencing compared to previous methods. NGS involves massively parallel sequencing of millions of DNA fragments simultaneously. This produces huge amounts of data that require specialized computational analysis tools. NGS has led to important discoveries in genomics and applications in medicine, agriculture, and other fields by revealing genetic information underlying various biological systems and traits.
The document discusses newborn screening and strategies to reduce false positive results. It explains that screening tests are meant to identify babies who may have a condition, not to diagnose them definitively. Many babies with out-of-range screening results turn out to be healthy after further testing. To reduce false positives, some programs use two-tiered testing, where a second, more specific test is performed to help distinguish true from false positives found on the initial screen. Using two-tiered testing and optimizing cutoff levels for screening tests can help improve newborn screening programs by reducing unnecessary follow-up testing and anxiety while still effectively identifying babies who need treatment.
This document provides an annual report on Kuwait's national newborn screening program for 2016. It summarizes screening statistics including the number of samples received and screened (57,951 total), the number of positive results (986), and confirmed cases (112). It also outlines the screening panel of tests performed, monthly screening volumes, demographic information on screened newborns, and performance indicators for the screening program such as false positive rate and positive predictive values. In summary, the report analyzes the results and outcomes of Kuwait's national newborn screening efforts for 2016.
This document discusses newborn screening markers for autosomal recessive conditions. It notes that phenylalanine levels greater than 120 uMl/L or a phenylalanine to tyrosine ratio greater than 2 could indicate issues. These markers are measured via tandem mass spectrometry.
This document summarizes a study analyzing screening results for congenital hypothyroidism in newborns in Kuwait between 2014 and 2016. Initially, a single TSH cutoff was used but resulted in a high false positive rate of 1 true positive for every 30 false positives. In 2015, the researchers introduced age-dependent TSH cutoffs based on the natural TSH surge in the first few days of life. This reduced the false positive rate significantly to 1 true positive for every 733 screened, demonstrating that age-dependent cutoffs improved the positive predictive value of the TSH screening test.
The Kuwait National Newborn Screening Program screens newborns in Kuwait for 22 treatable genetic and metabolic disorders. The screening is done between 48-72 hours after birth, targeting approximately 60,000 babies born in Kuwait each year. Newborn blood samples are collected at hospitals and newborn screening offices, analyzed at the Kuwait Medical Genetic Center, and if initial results are positive a confirmatory sample is sent to the Al-Sabah Biochemistry Lab. In 2015, 1 in 330 newborns screened was found to have a treatable condition, allowing them to receive early treatment and grow up healthy.
These lecture slides, by Dr Sidra Arshad, offer a simplified look into the mechanisms involved in the regulation of respiration:
Learning objectives:
1. Describe the organisation of respiratory center
2. Describe the nervous control of inspiration and respiratory rhythm
3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
5. Explain the role of Hering-Breur inflation reflex in regulation of inspiration
6. Explain the role of central chemoreceptors in regulation of respiration
7. Explain the role of peripheral chemoreceptors in regulation of respiration
8. Explain the regulation of respiration during exercise
9. Integrate the respiratory regulatory mechanisms
10. Describe the Cheyne-Stokes breathing
Study Resources:
1. Chapter 42, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 36, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 13, Human Physiology by Lauralee Sherwood, 9th edition
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Our backs are like superheroes, holding us up and helping us move around. But sometimes, even superheroes can get hurt. That’s where slip discs come in.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Ear and its clinical correlations By Dr. Rabia Inam Gandapore.pptx
Fact sheets
1. Ist edition by dr.amir abdelazim ahmed
Rapid
Notes
Information for DOCTORS about the
Disorders included in the Kuwait’
Newborn Screening Panel
By
Dr.Amir Abdelazim Ahmed
Clinical pathology specialist
Kuwait newborn screening laboratories
2. Ist edition by dr.amir abdelazim ahmed
Content :
Subject
1 Panel of newborn screening program in
Kuwait
2 Summary for conditions affect newborn
screening results
3 Table for notes in clinical and therapeutic
principles
4 Amino acid disorders
5 Fatty acid disorders
6 Organic acid disorders
7 Endocrine disorders
8 Galactosemia
3. Ist edition by dr.amir abdelazim ahmed
Panel of 22 disorders
Amino Acidemias :
Phenylketonuria (PKU)
Maple syrup urine disease (MSUD)
Homocystinuria (Cystathionine synthase def.)
Citrullinemia (ASA synthase deficiency )
Tyrosinemia (Type 1)
Argininosuccinic Aciduria (ASA Lyase deficiency)
Organic Acidemias :
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Isovaleric Acidemia (IVA)
Glutaric Acidemia Type I (GA-I)
3-methylcrotonyl-CoA Carboxylase deficiency (3MCC)
Beta Ketothiolase deficiency (Mitochondrial Acetoacetyl CoA Thiolase
deficiency)
Multiple CoA Carboxylase deficiency (MCD)
Fatty Acid Oxidation Defect :
Medium Chain Acyl CoA Dehydrogenase Deficiency (MCAD)
Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCAD)
Long Chain Hydroxy Acyl Dehydrogenase (LCHAD)
Trifunctional Protein Deficiency (TFP)
3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (3HMG)
Galactosemia
Biotinidase Deficiency
Endocrine Disorders :
Congenital Hypothyrodism
Congenital Adrenal Hyperplasia
7. Ist edition by dr.amir abdelazim ahmed
disorders Appearance
of
symptoms
Risk
of
crisis
Screening
time
Factors causing false
positive results
Factors causing false
negative results
Congenital
hypothyroidism
first year of life,
early treatment
prevents mental
retardation,
developmental
delays
12 - 72 hr and
2 - 6 weeks
TSH surge in first 12-24 hours
topical iodine on baby or
breastfeeding mother
maternal hyperthyroidism treated
with propylthiouracil,
acute illness until recovered
iodine deficiency
delayed rise of TSH in affected
infants, particularly if preterm
(immature hypothalamicpituitary-
thyroid axis)
dopamine therapy (suppresses
TSH)
steroid treatment (suppresses
TSH & T4)
Congenital
adrenal
hyperplasia
first week of life yes 12 - 48 hr and
2 - 4 weeks
preterm birth or LBW
sick or stressed infant
mother with CAH and elevated
17-OHP
early collection (<24 hr of age)
maternal steroid treatment
steroid (dexamethasone)
treatment in infant
Biotindase 1 week – 10
years of age
(most show
Symptoms
between 3 – 6
months of age)
birth - 72 hr heat with humidity damage to
specimen
prematurity
liver disease
, jaundice
transfusion of plasma or other
blood products
Galactosemia first week of life yes birth - 48 hours heat damage to specimen,
age of specimen (received by lab
more than 4 – 5 days after collection)
red blood cell transfusion
PKU 6 - 8 months of
age
(irreversible brain
damage happens
if
treatment is not
started in first
weeks
of life)
24 - 48 hours parenteral nutrition
liver dysfunction or immaturity
maternal PKU or hyperphe
uncontrolled by diet or medication
early collection (<24 hours of
age) or collection only a few
hours after transfusion or
discontinuation of ECMO
MSUD first two weeks of
life
yes 24 - 48 hours parenteral nutrition
liver dysfunction or immaturity
early collection (<24 hours of
age) or collection only a few
hours after transfusion or
discontinuation of extra corporeal
membrane oxygenation
HCY 3 - 7 days parenteral nutrition
liver dysfunction or immaturity
early collection, pyridoxine
responsive cases are not
identified by NBS
CIT &
ASA
first two weeks of
life
yes 24 - 48 hours parenteral nutrition
liver dysfunction or immaturity
early collection or collection only
a few hours after transfusion
ordiscontinuation of extra
corporeal membrane
oxygenation
TYR 1 3 – 4 months of
age
(liver is damaged
by
that time)
more than 1
week of age
liver dysfunction or immaturity
FAO
disorders
first few days to
months or years
(more easily
detected during
acute illnesses or
during times of
increased energy
need)
yes birth - 48 hours carnitine supplementation, MCT oil
fatty liver of pregnancy or HELLP
syndrome* can cause elevated even
chain acylcarnitines
MCD,
MMAs,
PA
yes 24 - 48 hours maternal Vitamin B12 deficiency
Organic
acid
disorders
first two weeks of
life
yes 24 - 48 hours parenteral nutrition
IVA first two weeks of
life
yes 24 - 48 hours pivalic acid antibiotic therapy
3MCC yes 24 - 48 hours asymptomatic mother with
3MCC, unaffected infant
8. Ist edition by dr.amir abdelazim ahmed
Chronic Neurological Diseases Life Threatening Diseases
Phenylketonuria Medium chain acyl-CoA dehydrogenase
deficiency
Glutaric acidemia type 1 Very Long chain acyl-CoA dehydrogenase
deficiency
Biotindase Deficiency 3Methyl 3-hydroxyglutarayl CoA lyase deficiency
Multiple Carboxylase Deficiency Isovaleric Acidemia
Congenital Hypothyroidism Maple Syrup Urine Disease
Multi Organ Diseases Argininosuccinic aciduria
Citrullinemia
Methyl malonic acidemia
Homocystinuria Propionic acidemia
Long Chain 3hydroxy acyl-CoA dehydrogenase
deficiency
B-ketothiolase deficiency
Congenital adrenal hyperplasia
Trifunctional protein deficiency
Liver Diseases
Tyrosinemia type 1
Galactosemia
9. Ist edition by dr.amir abdelazim ahmed
Abnormal screening results
Retest same filter paper
Confirmatory testing
Consult specialist
10. Ist edition by dr.amir abdelazim ahmed
Disease Primary
Analyte
Measured
Screening Can
Prevent…
Tretmenat
Argininosuccinic Acidemia
(ASA)
Citrulline …developmental
delay , seizures , coma
, death
Avoid fasting , low
protein diet , medication
Β-Ketothiolase (BKT)
Deficency
C5OH … brain damage ,
developmental delay ,
coma , death
Avoid fasting , low
protein and fat diet ,
medication
Biiotindase Deficency Biotindase … developmental
delay , hypotonia ,
seizures , skin , rash ,
hair loss , death
Biotin (vitamin)
supplementation
Citrullinemia Cirtulline … developmental
delay , seizures , coma
, death
Low protein diet , avoid
fasting , medication
Congenital Adrenal
Hyperplasia (CAH)
17-OH
progesterone
… salt-wasting crises ,
death
Hormone and mineral
replacement
Congenital
Hypothyroidism
Thyroid
hormones
… severe and
irreversible
developmental delay ,
failure to thrive
Hormone replacement
Galactosemia Galactose -1-
phosphate
uridyl
transferase
(GALT)
… failure to thrive ,
liver damage , sepsis,
death
Galactose restricted diet
Glutaric Acidemia Type I
(GAI)
C5DC … developmental
delay , spasticity ,
encephalopathy ,
coma , death
Avoid fasting , low
protein diet , medication
Homocystinuria Methionine … developmental
delay , lens
dislocation ,
thrombosis
Low methionine diet ,
medication , dietary
supplementation
3-Hydroxy-3-
methylglutaryl CoA Lyase
Deficiency
C5OH … brain damage ,
developmental delay ,
death
Avoid fasting , low
protein and fat diet ,
carnitine
supplementation
Isovaleric Acidemia (IVA) C5 … encephalopathy ,
neurological damage,
coma , death
Avoid fasting , low
protein diet , medication
LCHAD Deficiency C16OH … cardiomyopathy ,
seizures ,
developmental delay ,
coma , death
Avoid fasting , diet low in
long –chain fats
Maple Syrup Urine
Disease (MSUD)
Leucine
/isoleucine
.. failure to thrive ,
seizures ,
developmental delay ,
coma , death
Low protein diet , avoid
fasting ,
11. Ist edition by dr.amir abdelazim ahmed
MCAD Deficiency C8 … seizures , coma ,
dudden death
Avoid fasting , aggressive
treatment of illness
3-Methylcrotonyl-CoA
Carboxylase Deficiency
C5OH …failure to thrive ,
seizure , coma , death
Avoid fasting ,
medications , low
protein diet ,
supplementation
Methylmalonic Acidemia
(mutase deficiency and
cobalamin defects)
C3 … failure to thrive ,
encephalopathy ,
coma , death
Low protein diet , avoid
fasting ,, vitamin B12
supplementation
Multiiple Carbosylase
Deficency
C3 , C5OH … failure to thrive ,
encephalopathy ,
coma , death
Biotin supplementation
Phenylketonuria Phenylalanine …severe and
irreversible
developmental delay
Phenylalanine restricted
diet , supplementation
Proprioic Acidemia C3 …encephalopathy ,
developmental delay,
coma, death
Avoid fasting , low
protein diet , medication
Trifunctional protein
Deficiency
C16OH ..developmental delay
, failure to thrive ,
cardiomyopathy ,
coma , sudden death
Avoid fasting , diet low in
long chain fats
Tyrosinemia Type I Tyrosine and
Succinylacetone
… liver and kidney
damage and sequelae
, failure to thrive ,
cpagulopathy
Special diet , medication
VLCAD Deficiency C14:1 … developmental
delay and failure to
thrive , hepatomegaly
, cardiomyopathy ,
coma , sudden death
Avoid fasting , special
diet
Legand
Organic acid
disorders
Immune deficiencies
Fatty acid
oxidation
disorders
Endocrine disorders
Amion acid
disorders
12. Ist edition by dr.amir abdelazim ahmed
Amino-acid disorders
HOMOCYSTINURIA
Homocystinuria is an inborn error of the transsulfation pathway which causes an increase in the
levels of homocysteine and methinonine in the blood. It is caused by cystathionine β-synthase (CBS)
deficiency which leads to the inability to convert homocysteine to cystathionine .
Incidence
Very rare
Clinical Manifestation
Patients affected with homocystinuria may present with ectopia lentis which is found in 85% of
patients , skeletal abnormalities such as genu valgus and “marfanoid habitus”, mental retardation
and thromboembolism.
Pathophysiology
Increased homocysteine levels is found to inhibit linking of collagen and elastic tissues which
predisposes zonule generation of the eye predisposing patients to myopia and lens dislocation.5
Skeletal abnormalities are thought to result from damage to fibrillin in patients with cytathionine
β-synthase and due to a reduction in collagen crosslinking6 while the mechanism that contributes
to the atherogenic propensity of hyperhomocystinemia are related to endothelial dysfunction and
injury which leads to platelet aggregation and thrombus formation.7 Chemical abnormalities and
the repeated thromboemolic strokes may contribute to the mental retardation.
13. Ist edition by dr.amir abdelazim ahmed
Inheritance
autosomal recessive
Screening:
increased methionine on MSMS
Confirmatory Testing
Total homocysteine in plasma. Amino acids in plasma, methylmalonic acid in urine and enzyme
study in fibroblasts may be used to confirm the diagnosis.
Prognosis
Early diagnosis and treatment can prevent thromboembolic events and reduce the complications
brought about by increased levels of homocysteine
Treatment of HCY
Treatment is through the dietary restriction of protein and the supplementation of formula lacking
methionine. Vitamin B6, folic acid and betaine are also given.
Preliminary / Initial Management During Metabolic Crisis
Metabolic crises may be caused by illness, prolonged fasting or stressful situations such as SURGERY and
severe infection.
The goal of treatment is to reverse the catabolic state and prevent essential amino acid deficiency.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for methionine and homocystine levels (contact the Biochemical Genetic Laboratory NIH). May request for other
investigations (i.e. CBC, Blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid, may do so up to 1.2 or 1.5X the maintenance
especially if the patient will undergo surgery.
e. Make sure that the patient is well hydrated. Monitor input and output strictly (q6 hours)
f. Start betaine, folic acid and vitamin B6
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with HCY formula to run at maintenance rate
b. Insert IV access. Collect samples for methionine and homocystine level (contact the Biochemical Genetics Laboratory, NIH). May request for other
investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr. Make sure that the patient is well hydrated especially if he will undergo surgery. Monitor input and output
strictly (6 hours)
d. Start betaine, folic acid and vitamin B6
*Children should not be protein restricted for longer than necessary (24-48 hours).
* Inform metabolic doctor on call for further guidance regarding on-going management.
14. Ist edition by dr.amir abdelazim ahmed
Long Term Management
The aim of treatment is to reduce plasma total homocysteine levels to as close to normal as possible
while maintaining normal growth rate. This can be done in the following ways:
Supplementation of Vitamins
Pyridoxine (Vitamin B6)- may start with 50-100mg/day. May progress to 500-1000mg/day guided
by plasma homocysteine and methionine monitoring. About half of patients with CBS deficiency
respond often only partially to large doses of pyridoxine. But since high doses of pyridoxine has
been associated with sensoryneuropathy, it should then be kept at the lowest dose that is able to
achieve a good metabolic control. Doses higher than 250mg/day should be avoided in newborns
and young infants. If patients do not respond to pyridoxine, a low methionine, high cystine diet
must be introduced and continued throughout life.
Folic acid – may start at 5-10 mg/day as response to pyridoxine may also be influenced by folate
depletion Vitamin C supplementation has been shown to ameliorate endothelial dysfunction in CBS
patients suggesting its possible value in reducing the long term risk of atherothrombotic
complications. One may give it at 100mg/ day
Diet
_ Low Methionine Diet- synthetic methionine free amino acid mixtures for infants
_ Supplements of essential fatty acids and carbohydrates are also required
_ After infancy, foods containing proteins low in methionine can be introduced.
Betaine
Betaine is a homocysteine lowering agent (remethylates homocysteine to methionine) that is
especially useful when compliance to the diet is unsatisfactory. One can start at 100mg/kg/day with
a maximum dose of 6-9 grams in adults.
Monitoring of plasma homocysteine and methionine levels
Plasma monitoring of methionine, cysteine, cysteine:homocysteine disulfide and homocysteine
should be done every 3 months. The goal is a plasma homocysteine level of <60umol/L.
15. Ist edition by dr.amir abdelazim ahmed
Key metabolite : Methionine , elevated
Emergency key : Low
Action : Referral to a metabolic center
Confirmation analysis :
Total homocysteine in plasma
Amino acids in plasma
Organic(mwthylmalonic)acids in urine
Mutation analysis
Therapy :
Diet restricted in methionine
Betaine
Pyridoxine in responsive patients
Vitamene B12
Folic acid
Signs and symptoms :
Mental retardation
Dislocation of the lenses
Marfanoid habitus
Osteoporosis
Thromboembolism
Prognosis : Good
References
1 Schulze A, Matern D, Hoffmann GF. Chapter 2: Newborn screening in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric
Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 17-32.
2 Yap S. Homocystinuria due to cystathionine β-synthase deficiency. Orphanet 2005. http://www.orpha.net/data/photo/GBuk-
CbS.pdf Accessed Feb. 16, 2012.
3 Chapter 22 Homocystinuria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford
University Press, 2005 pp 146-151.
4 Cruysburg JR, Boers GHJ, Trijbels FMJ et al. Delay in diagnosis of homocystinuria: retrospective study of consecutive patients.
BMJ 1996;313:1037-1040.
5 Burke JP, O’Keefe M, Bowell R and Naughten ER. Ocular Complications in Homocystinuria – Early and Late Treated. Br J
Ophthalmol. 1989 June; 73 (6):427-431.
6 Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic
and Molecular Bases of Inherited Disease. 8th ed. Vol 2. New York: McGraw-Hill, 2001:2007-2056.
7 Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for
Vascular Disease: Probably Benefits of Increasing Folic Acid Intakes. JAMA 1995l 274:1049-1057.
8 Ueland PM. Homocysteine Species as Components of Plasma Redox Thiol Status. Clin Chem 1995; 41:340-342.
9 Andria G, Fowler B, Sebastio G. Disorders of Sulfur Amino Acid Metabolism. Chapter 22, Inborn Metabolic Diseases 4th edition
eds fernandes, Saudubray, van den Berghe, Walter pp277-278
10 Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of Metabolism) 3rd edition
pp71
16. Ist edition by dr.amir abdelazim ahmed
MAPLE SYRUP URINE DISEASE [MSUD]
Maple syrup urine disease (MSUD) is due to a defect or deficiency of the branched chain ketoacid
dehydrogenase (BCKD) enzyme complex leading to the elevated quantities of leucine, isoleucine,
valine and their corresponding oxoacids in body fluids.1 Accumulation of the latter amino acids will
result in life threatening encephalopathy if not adequately treated.
Incidence
Very rare
Clinical Manifestation
There are different classifications of MSUD based on the enzyme activity and these include:
classical, intermediate, intermittent, thiamine responsive and E-3 deficient MSUD. Classical MSUD
(residual enzyme <2%) is the most severe and common form with symptoms of poor suck, lethargy,
hypo and hypertonia, opisthotonic posturing, seizures and coma developing 4-7 days after birth.1
The characteristic odor of maple syrup may be detected as soon as neurological symptoms develop.
Patients with intermediate MSUD (residual enzyme 3-30%) have gradual neurologic problems
resulting in mental retardation.1 Intermittent form of MSUD go into metabolic crisis when there is
a stressful situation such as infection or after surgery.
Thiamine-responsive MSUD’s clinical symptomatology and metabolic disturbance is ameliorated
once pharmacologic dose of thiamine has been given. E-3 deficient MSUD present with symptoms
similar to those of intermediate MSUD but they also have lactic acidosis.
Pathophysiology
Due to mutations in the gene coding for the branched chain keto-acid dehydrogenase enzyme, the
levels of leucine, valine and isoleucine increase in blood. The increase in leucine may cause
competitive inhibition with other precursors of neurotransmitters causing the neurologic
manifestations.
Inheritance:
autosomal recessive
Screening:
leucine + isoleucine, valine, (leucine + isloeucine)/phe ratio
Confirmatory Testing
Diagnosis is confirmed by detection of the highly increased branched-chain amino acid levels via
quantitative amino acid analysis and/or by increased urinary excretion of α-keto and hydroxyl acids
and branched chain amino acids using gas chromatography-mass spectrometry (GC-MS) and
quantitative amino acid analysis.2
17. Ist edition by dr.amir abdelazim ahmed
Prognosis
Patients with MSUD are now expected to survive, they are generally healthy between episodes of
metabolic imbalance and some attend regular school. However, the average intellectual
performance is clearly below those of normal subjects.
Treatment of MSUD
Treatment is through the dietary restriction of protein and the supplementation of formula lacking leucine,
valine and isoleucine.
Preliminary / Initial Management During Metabolic Crisis
Metabolic crises may be caused by illness, prolonged fasting or stressful situations such as surgery and
severe infection.
The goal of treatment is to lower down the levels of leucine, isoleucine and valine, reverse the catabolic
state and prevent essential amino acid deficiency.
Long term Management
The aim of life long maintenance therapy is to maintain the branched chain amino acid levels at
near normalconcentrations. Regular evaluation of nutritional status, metabolic control, growth
percentiles as well as developmental progress are imperative for a good clinical and cognitive
outcome.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for leucine level, plasma amino acids, blood glucose and urine ketones. May
request for other investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid, may do
so up to 1.2 or 1.5X the maintenance.
e. Start intralipid at 1g/kg/24 hours.
f. Monitor input and output strictly (q6 hours)
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with BCAD formula to run at maintenance rate
b. May give valine at 50mg/kg/day divided into 6 doses and isoleucine 30mg/kg/day divided into 6 doses
c. Insert IV access. Collect samples for leucine level, plasma amino acids, blood glucose and urine ketones. May
request for other investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
e. Monitor input and output strictly (q6 hours)
*Children should not be protein restricted for longer than necessary (24-48 hours).
*If patient does not improve with the initial management (within 12 hours), hemodialysis may be indicated. Monitor
patient clinically, the necessity of hemodialysis will depend on patient’s clinical status.
* Inform metabolic doctor on call for further guidance regarding on-going management.
18. Ist edition by dr.amir abdelazim ahmed
Diet
The major component of the diet is a special formula that do not contain any leucine, isoleucine or
valine but are otherwise nutritionally complete. They contain all the necessary vitamins, minerals,
calories and the other amino acids needed for growth.
They will also be given a formula supplemented with carefully controlled amounts of a protein-
based formula.
The protein-based formula provides the infant with the limited amount of branched chain amino
acids needed to grow and develop normally.
As children with MSUD grow, they continue taking the special formula. They are allowed other
foods which are weighed or measured in the home to supply the prescribed amount of leucine each
day. Typically the MSUD diet does not include any high protein foods such as meat, nuts, eggs, and
most dairy products. Children gradually learn to accept the responsibility for controlling their diets
and generally being on low protein at all times.
Frequent determination of leucine levels are likewise encouraged so that proper dietary
adjustments be done for effective management of the condition.
Special supplements
Occasionally, small amounts of free valine and isoleucine must be added to the amounts provided
by the natural protein because the tolerance for leucine is lower than the other two. Under
conditions of high leucine and low valine and isoleucine levels, a rapid fall of plasma leucine can be
achieved only by combining a reduced leucine intake with a temporary supplement of leucine and
isoleucine.
Treatment of intercurrent decompensations
Acute intercurrent episodes are prevented by being aware of those situations that may induce
protein catabolism. These include intercurrent infections, immunizations, trauma, anesthesia and
surgery. Parents must have at their disposal a semi emergency diet in which natural protein intakes
are reduced by half or an emergency diet in which natural proteins are suppressed. In both, energy
supply is reinforced using carbohydrates and lipids. Solutions containing a mixture of glucose
polymer and lipids can be used. Timely evaluation and intensive treatment of minor illnesses at any
age is essential, as late death attributed to recurrence of metabolic crises with infections has
occurred.
Emergency Protocol for Maple Syrup Urine Disease
Important points to be relayed to the parents over the phone:
1. Avoid delay and bring the child to the hospital at once
2. Bring formula (if known MSUD patient)
3. Bring isoleucine and valine tablets (if known MSUD patient)
4. Ask for child’s current weight
5. Ask about an estimated time of arrival at the ER
19. Ist edition by dr.amir abdelazim ahmed
Alert Emergency Department of the patient’s arrival
1. Talk to the Admitting Officer and Nursing Team Leader
2. Ask them to do an urgent clinical assessment (history and physical examination)
3. *Prepare 12.5% dextrose (maintenance)
4. *Prepare Intralipid 2g/kg/day
5. Collect blood for **plasma amino acids or on dried blood spot. Check for urine ketones. Other
examinations as required.
6. Contact the Physician on call once patient arrives at ER
—————————
* Please prescribe for weight before the patient arrives.
** Collect in green top tube. Transport immediately to Biochemical Genetics Laboratory
Principles of Management
Reversion of catabolism
Start IV infusion using 12.5% dextrose -maintenance + %dehydration (add potassium if serum K is
not high). If the patient is encephalopathic, additional sodium may be required (up to 6
mmols/kg/day). If there is a
concern about cerebral edema (focal neurologic signs or fluctuating level of consciousness) fluids
may need to be restricted.
_ Stop natural protein.
_ Intralipid at 2g/kg/day. This can be infused in the same line peripherally.
_ The patient may also have an enteral emergency sick day regimen, which can be administered
continuously via a nasogastric feeding tube.
_ Treat underlying cause. Treat dehydration, electrolyte imbalance, infection and acidosis
_ Consider dialysis if with acute deterioration of cerebral function consider the following
_ Maintain plasma concentrations of isoleucine and valine more than 200 umol/L
20. Ist edition by dr.amir abdelazim ahmed
Key metabolite : Leucine + isoleucine , valine , elevated
Emergency key : High
Action : Immediate referral to metabolic specialist
Confirmation analysis :
Amino acids in plasma
Organic acid in urine
Enzyme activity in lymphocytes
Mutation analysis
Therapy :
Acute management :
Discontinue natural protein
Provide large amount of calories ,fluids and
electrolytes
Enteral therapy :
Special formula that contains all required
amino acids but is free of leucine , valine and
isoleucine
Signs and symptoms :
Progressive encephalopathy
Maple syrup smell of urine
Mental retardation
Prognosis : Moderate , often mild mental impairment even
in well treated children
References
1 Chapter 24 Maple syrup urine disease. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press, 2005 pp 159-164
2 Hoffman GF and Schulze A. Chapter 7: Organic Acidurias in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric
Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 93-94.
3 Schulze A, Matern D, Hoffmann GF. Chapter 2: Newborn screening in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric
Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 17-32.
4 Wendel U and de Baulny H. branched chain organic acidurias/acidemias. Inborn Metabolic Diseases Chapter 19 4th edition
eds Fernandes, Saudubray, van den Berghe, Walter pp246-256
21. Ist edition by dr.amir abdelazim ahmed
PHENYLKETONURIA [PKU]
Phenylketonuria is a disorder of aromatic amino acid metabolism in which phenylalanine cannot
be converted to tyrosine due to a deficiency or absence of the enzyme phenylalanine hydroxylase.
Phenylalanine hydroxylase requires the co-factor 6-pyruvoyltetrahydropterin or BH4 for activity in
the hydroxylation to tyrosine, absence of this co-factor may present with an increase in plasma
phenylalanine similar to phenylketonuria but is considered a separate disorder.
Incidence
1:15,000 worldwide
Clinical Manifestation
Patients affected with PKU appear normal at birth.2,4 The most important and sometimes the only
manifestation of PKU is mental retardation.2 Patients may present with constitutional, intellectual
and neurologic abnormalities and signs as well as hypopigmentation of the skin and hair and iris
rapidly develop due to impaired metabolism of melanin.4 Seizures occur in a fourth of patients.
The odor of the phenylketonuric patient is that of phenylacetic acid described as mousy, barny, or
musty.
Pathophysiology
PKU results from a deficiency of activity of a liver enzyme, phenylalanine hydroxylase leading to
increased concentrations of phenylalanine in the blood and other tissues.4 Elevated phenylalanine
interfere with myelination, synaptic sprouting and dendritic pruning; and in addition, it
competitively inhibits the uptake of neutral amino acids in the blood-brain barrier causing reduced
tyrosine and tryptophan concentrations thereby limiting the production of neurotransmitters.4
Inheritance
autosomal recessive
Screening
increased phenylalanine levels on MSMS
Confirmatory Testing
The demonstration of decreased enzyme activity is confirmatory. However, in the presence of
increased phenylalanine levels, it is important to differentiate phenylketonuria from a BH4
deficiency. This is accomplished through administration of tetrahydrobiopterin (doses of 2mg/kg
intravenously and 7.5-20mg/kd orally) which leads to a prompt decrease to normal in the
concentration of phenylalanine. Pterin metabolites in urine are likewise useful, demonstrating a
very low biopterin and high neopterin levels.
22. Ist edition by dr.amir abdelazim ahmed
Prognosis
When treatment is started early and performed strictly, motor and intellectual development can
be expected to be near normal.
Tetrahydrobiopterin BH4 Oral Loading Test
Preliminary / Initial Management During Metabolic Crises
Metabolic crises may be caused by illness, prolonged fasting or stressful situations such as surgery and
severe infection.
The goal of treatment is to reverse the catabolic state and prevent essential amino acid deficiency.
23. Ist edition by dr.amir abdelazim ahmed
Long Term Management
Diet
Dietary management is the key to treatment. The diet of patients has four components:
_ complete avoidance of food containing high amounts of phenylalanine;
_ calculated intake of low protein/phenylalanine natural food
_ sufficient intake of fat and carbohydrates to fulfill the energy requirements of the patient and;
_ calculated intake of phenylalanine free amino acid mixture supplemented with vitamins, minerals
and trace elements as the main source of protein.
In young children
At the start of treatment in infants with blood phenylalanine levels above 1200 umol/L, a period
(usually 24-48 hrs) of phenylalanine free milk brings levels down at a rate of 400 umol/l per day. As
levels approach the therapeutic range (120-360umol/L), phenylalanine is then added (around 1-
1.5g/kg/day). Infants with lesser degrees of phenylalanine accumulation need less rigorous
restriction and smooth control is easier to achieve.
The prescription of phenylalanine is adjusted until serial blood levels have stabilized.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for phenylalnine levels. May request for other investigations (i.e. CBC,
blood gas) as
needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid,
may do so up to
1.2 or 1.5X the maintenance.
e. Start Intralipid at 1g/kg/day
f. Monitor input and output strictly (q6 hours)
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with PKU formula to run at maintenance
rate
b. Insert IV access. Collect samples for phenylalanine levels. May request for other investigations (i.e.
CBC, blood gas) as
needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
d. Monitor input and output strictly (q6 hours)
*Children should not be protein restricted for longer than necessary (24-48 hours).
* Inform metabolic doctor on call for further guidance regarding on-going management
24. Ist edition by dr.amir abdelazim ahmed
In older children, adolescents and adults
Given the practical difficulties involved in sustaining a strict low phenylalanine diet, a relaxation of
the diet at some point before adolescence is allowed. It is recommended that older children be
offered the opportunity to remain on a diet that keep blood phenylalanine concentrations ar or
below 700umol/L after mid-childhood and into adulthood.
Phenylalanine levels rise in response to minor events such as intercurrent illness, decline in energy
intake or in growth rate, reduction in the amount of protein substitute and rise in phenylalanine
intake, thus diet should be adjusted as needed.
Managing illness
During illness, children cannot take their prescribed diet. High energy fluids with or without fat
emulsion will help reduce catabolism and are more acceptable to children during time of illness. As
anabolism takes over, it is important to reintroduce phenylalanine allowance to avoid
phenylalanine deficiency as diet is re-established.
Monitoring of phenylalanine levels and growth and development
Regular monitoring of phenylalanine levels (at least monthly or more frequent depending on the
clinical status of patient) should be done religiously. There is evidence that raising blood
phenylalanine concentrations is associated with reversible impairments in neuropsychological
performance, thus assessment of mental development should likewise be enforced. The risk of
maternal phenylketonuria in adolescent girls and women of reproductive age should also be
emphasized as this risk increases linearly in proportion to maternal phenylalanine concentrations.
Defects of Biopterin Metabolism (i.e. 6 Pyruvoyltetrahydrobiopterin synthase deficiency)
There is no diet restriction in these types of disorders. The following medications should be given:
_ Tetrahydrobiopterin: 5-10 mg/kg/day
L-Dopa 8-12 mg/kg/day (neonates 1-3mg/kg/day, infants 4-7 mg/kg/day)
_ 5-OH-tryptophan (max 6-9mg/kg/day)
Key metabolite : Phe , elevated
Emergency key : Moderate
Action : Refer to metabolic specialist
Confirmation analysis : Amion acid in plasma
Pterin analysis in urine
DHPR-activity in DBS
Therapy : Phe restricted diet
Signs and symptoms : Severe mental retardation –seizures
Prognosis : Excellent , normal development
25. Ist edition by dr.amir abdelazim ahmed
References
1Chapter 20: Phenylketonuria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford
University Press, 2005 pp 127-133.
2Chapter 21 Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin. Nyhan WL, Barshop BA and Ozand P.
Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 136-145
3Burgard P, Lui X, Hoffmann GF. Chapter 13: Phenylketonuria in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric
Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 163-168.
4Kaye CI and the Committee on Genetics. Newborn screening fact sheets. Pediatrics 2006;118:934-963.
5 Walter JH, Lee P, Burgard P, Hyperphenylalaninemia. Inborn Metabolic Diseases Chapter 17 4th edition eds Fernandes,
Saudubray, van den Berghe, Walter pp224-226
6 Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of Metabolism) 3rd edition
pp 153.
Analyte phenylalanine
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 120 uM/L
Flurometeric (DELFIA) - cutoff 3.5 ug/dl
Differential
diagnosis
Phenylketonuria (Classical PKU);
non-PKU mild hyperphenylalaninemia; pterin defects;
Transient hyperphenylalaninemia.
False positive Prematurity , weight , nutrituion, health status and treatment at time of specimen collection
Screen must be 24-48 hr after feeding of protein to decrease false negative
Clinical
presentation
PKU : Asymptomatic in the neonate. If untreated PKU will cause irreversible mental retardation,
hyperactivity, autistic-like features, and seizures and hyperactivity, eczematoid rash unpleasant
odor microcephaly and prominent maxilla. Treatment will usually prevent these symptoms.
Pterin defects cause early severe neurologic disease (developmental delay/seizures) and require
specific therapy.
Diagnostic
evaluation and
confirmatory
test
Classic PKU: Plasma amino acid analysis which shows increased phenylalanine without
increased tyrosine (increased phenylalanine:tyrosine ratio). Identification of phenyl ketones in
urine by ferric chloride , Deficiency of BH4 cofactor must be ruled out
Urine pterin analysis(neopterin&biopetrin) and red blood cell DHPR assay will identify pterin
defects.plasma , Consider PAH mutation testing. phenylalanine slight increase and no excretion
to phenyl ketones , BH4 loading test :patient with BH4 deficiency show normalize of phenylalanine
level after 4 hrs from the loading dose of BH4
Causes and
mechanism
In classic PKU the phenylalanine from ingested protein cannot be metabolized to tyrosine because
of deficient liver phenylalanine hydroxylase (PAH). This causes elevated phenylalanine.
Pterin defects result from deficiency of tetrahydrobiopterin (BH4), the cofactor for PAH and other
hydroxylases. This produces not only increased phenylalanine but also neurotransmitter
deficiencies.
Genetics PKU is caused by a mutation in a gene on chromosome 12
Prenatal diagnosis
Prevalence 1:15000 (turkey has highest rate)
Action for
result
Contact family immediately to evaluate baby and provide basic information about PKU and
dietary management and initiate confirmatory test and refer to metabolic specialist
Treatment Phenylalanine – restricted diet (such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk
and other dairy products. Starchy foods, such as potatoes, bread, pasta, and corn)
Oral administration of the cofactor tetrahydrobiopterin BH4
26. Ist edition by dr.amir abdelazim ahmed
TYROSINEMIA
There are 2 clinically recognized types of tyrosinemia.
Type I (hepatorenal) is characterized by liver toxicity from increased concentrations of tyrosine.
There is anssociated renal tubular defects and peripheral neuropathy. There is also a high risk for
hepatocellular carcinoma. The deficient enzyme is fumarylacetoacetase.
Type II (oculocutaneous) tyrosinemia exhibits with corneal lesions and hyperkeratosis of palms and
soles. It is caused by the deficiency of the enzyme, tyrosine aminotransferase.
Incidence
Very rare
Clinical Manifestation
Tyrosine-I is usually asymptomatic in newborns, but if left untreated it affects liver, kidney, bone,
and peripheral nerves. Two patterns are reported: an acute or chronic form. The acute form
presents with acute hepatic decompensation where infants are noted to have jaundice, abdominal
distention, failure to thrive, ascites and hepatomegaly, renal disease is also prominent and a “boiled
cabbage” odor in urine is observed; the chronic liver disease feature is that of hepatic cirrhosis.
Tyrosinemia type II is a distinctive oculocutaneous syndrome. Eye findings can be limited to
lacrimation, photophobia, and redness. Cutaneous lesions includepainful nonpruritic blisters or
erosions that crust and become hyperkeratotic. Mental retardation is also an infrequent finding.
Pathophysiology
In type I, the deficient enzyme, fumarylacetoacetase catalyzed the last step in tyrosine degradation.
The increased concentrations of tyrosine and its metabolites is postulated to inhibit many transport
functions and enzymatic activities.
In type II, deficiency of the rate limiting enzyme tyrosine transaminase in tyrosine catabolism leads
to accumulation of tyrosine, phenolic acids, tyramine in the blood ad urine.1
Inheritance
autosomal recessive
Screening
increased tyrosine and succinylacetone for type I; increased tyrosine for type II
Confirmatory Testing
Confirmation can be done through plasma amino acid levels (increased tyrosine) and urine
metabolic screening (increased succinylacetone).
27. Ist edition by dr.amir abdelazim ahmed
Prognosis
If untreated, death from liver failure may occur in the first year of life for hepatorenal tyrosinemia.
Treatment of Tyrosinemia
Treatment is through the dietary restriction of protein and the supplementation of formula lacking
tyrosine. Patients are also given nitisinone (NTBC) which is an inhibitor of p-hydroxyphenylpyruvate
dioxygenase as maintenance medication.
Preliminary / Initial Management During Metabolic Crisis
Metabolic crises may be caused by illness, high consumption of protein, prolonged fasting or stressful
situations such as surgery and severe infection. The goal of treatment is to control level of tyrosine, correct
bleeding parameters, reverse the catabolic state and prevent essential amino acid deficiency.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem except medications
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for blood glucose, plasma amino acids, liver function tests,
coagulation studies and urine succinylacetone. May request for other investigations (i.e. CBC, blood gas)
as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid,
may do so up to 1.2 or 1.5X the maintenance.
e. Start nitisinone (2mg/kg) per orem.
f. Monitor input and output strictly (6 hours)
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with tyrosine free formula to run at
maintenance rate
b. Start nitisinone (2mg/kg) per NGT
c. Insert IV access. Collect samples for blood glucose, plasma amino acids, liver function tests,
coagulation studies and urine succinylacetone. May request for other investigations (i.e. CBC, blood gas)
as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
e. Monitor input and output strictly (q6 hours)
*Children should not be protein restricted for longer than necessary (24-48 hours).
* Inform metabolic doctor on call for further guidance regarding on-going management.
28. Ist edition by dr.amir abdelazim ahmed
Long Term Management
Tyrosinemia type I
Treatment options for tyrosinemia I include dietary therapy (restriction of phenylalanine and
tyrosine), liver transplantation and use of the pharmacologic agent 2(2-nitro-4-trifluoro-
methylbenzoyl)-1,3-cyclohexanedione or NTBC.
NTBC
The rationale for the use of NTBC is to block tyrosine degradation at an early step so as to prevent
production of toxic down stream metabolites such as fumarylacetoacetate, maleylacetoacetate
and succinylacetone. It is recommended at an initial dose of 1 mg/kg/day. The risk of hepatocellular
carcinoma appears to be much reduced in patients started early on NTBC treatment (before 6
months of age).
Diet
Dietary restriction of phenylalanine and tyrosine is necessary to prevent the known adverse effects
of hypertyrosinemia. Tyrosine levels are aimed between 200-400 umol/L using a combination of a
protein restricted diet and phenylalanine and tyrosine free amino acid mixtures.
Supportive therapy
In the acutely ill patient, supportive treatment is essential. Clotting factors, albumin, electrolytes
and acid/base balance should be closely monitored and corrected as necessary. Tyrosine and
phenylalanine intake should be kept to a minimum during acute decompensation. Addition of
vitamin D may be required to treat rickets.
Infections should be treated aggressively.
Monitoring of patients on NTBS should include regular blood tests for liver function, blood counts,
clotting studies, alpha feto protein, tests of renal and tubular function, hepatic imaging and plasma
amino acid profile.
Blood levels of phenylalanine and tyrosine should be checked every 3 months and the diet should
be supervised regularly.
Tyrosinemia type II
Diet
Treatment consists of phenylalanine and tyrosine restricted diet and the skin and eye symptoms
resolve within weeks of treatment. In general, skin and eye symptoms do not occur at tyrosine
levels <800umol/L, however, as hypertyrosinemia may be involved in the pathogenesis of
neurodevelopmental symptoms, it may be beneficial to maintain much lower levels. Growth and
nutritional status should be regularly monitored.
29. Ist edition by dr.amir abdelazim ahmed
Key metabolite : Tyrosine ( &succinylacetone in TYR I)
Emergency key : Moderate
Action : Referral to metabolic specialist
Confirmation analysis :
Plasma anino acids
Serum alpha-fetoprotein
Succinylacetone in urine
Therapy :
2-nitro-4-trifluoromethylbenzoyl-3-
cyclohexanedione NTBC
Dietary restriction of phenylalanine and
tyrosine
Signs and symptoms :
Acute or chronic liver failure
Tubulopathy – peripheral neuropathy
Porphyria like crisis
Vomiting , lethargy , diarrhea
Failure to thrive - rickets
Hepatocellular carcinoma
Prognosis : Good if start treatment early
Note of caution :
- Tyrosine also elevated in liver diseases ,
prematurity ,tyrosinemiaII and III and
infection
- Tyrosine may be normal in an
appreciable number of tyrosinemia I
causing false negative results
- Humidity and heat and exposure to EDTA
denature the enzyme causing false
positive
References
1Kaye C. Newborn screening fact sheets.2006 Pediatrics 118:3 pp e960-962
2 Chapter 26: Hepatorenal tyrosinemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press, 2005 pp 175-179.
30. Ist edition by dr.amir abdelazim ahmed
Analyte Tyrosine
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 229 uM/L
Differential
diagnosis
Tyrosinemia I (hepatorenal);
tyrosinemia II (oculocutaneous , Richer-Hanhart syndrome);
tyrosinemia III;
transient hypertyrosinemia;
liver disease.
False positive In first two weeks infants who receive high protein diets and premature baby due to delay
maturation of 4-HPPD enzyme always show positive screen for PKU (transient hypertyrosenemia)
Clinical
presentation
Tyrosinemia I is usually asymptomatic in the neonate. If untreated, it will cause liver
disease and cirrhosis early in infancy, peripheral neuropathy ,renal failure and mortality 60%
Tyrosinemia II is asymptomatic in the neonate but will cause hyperkeratosis of the skin, corneal
ulcers, and in some cases, mental retardation
Tyrosinemia III show developmental delay ,seizures and no liver or renal abnormalites
Diagnostic
evaluation and
confirmatory
test
Plasma amino acid analysis will show increased tyrosine in all of the tyrosinemias.
Urine organic acid analysis may reveal increased succinylacetone in tyrosinemia I.
Assay tyrosine aminotransferase activity in liver or by DNA analysis for gene mutation
Measure plasma level for 4-hydroxyphenylpyruvic acid and urine level for 4-hydroxyphenylacetic
acid and can confirmed by assay activity of 4-HPPD liver biopsy or mutation of 4-HPPD gene
Causes and
mechanism
Herediary :
Tyrosinemia I :deficiency of fumarylacetoacetate hydrolase FAH (autosomal recessive)
tyrosine accumulate from ingested protein and phenylalanine metabolism cannot be metabolized
by FAH to fumaric acid and acetoacetic acid. The resulting fumarylacetoacetate accumulates and
is converted to succinylacetone, the diagnostic metabolite, which is liver toxic and leads to
elevated tyrosine.
Tyrosinemias II :deficiency of tyrosine aminotransferase (A.R)
Tyrosinemias III : deficiency of 4-hydroxyphenpyruvate dioxygenase 4-HPPD (A.R)
Acquired :
Severe hepatocellular dysfunction
Scurvy (vitamin c is the cofactor for enzyme 4-HPPD)
hyperthyroidism
Genetics FAH has been mapped to chromosome 15q
Tyrosine aminotransferase mapped to chromosome 16q
4-HPPD mapped to chromosome 12q24-qter
Prenatal diagnosis DNA analysis can be used to test specific mutation and measure succinylacetone in amniotic fluid
Prevalence Worldwide : Tyrosinemia I : 1:100,000
Action for
result
Contact family to evaluate baby and provide basic information about tyrosinemia and initiate
confirmatory test and refer to metabolic specialist
Treatment Diet low in phenylananine and tyrosine
Nitisinone which inhibit tyrosine degradation at 4-HPPD
Vitamin c as cofactor for 4-HPPD
Liver transplantation in hepatocellular disease
31. Ist edition by dr.amir abdelazim ahmed
UREA CYCLE DEFECTS
CITRULLINEMIA
Citrullinemia is an inborn error of metabolism resulting from the deficiency of argininosuccinate
synthetase, an enzyme present in all tissues but the level of which is highest in the liver where it
functions in the urea cycle.
Incidence
Very rare
Clinical Manifestation
Following a brief hiatus in which the newborn appears normal, anorexia, vomiting and lethargy
develop followed rapidly by progression to deep coma. The symptoms mimic that of sepsis and
affected newborns present with severe lethargy, poor feeding to respiratory distress, jitteriness
and seizures.
A late onset form may occur as late as 20 years old and present as symptoms such as slurred speech,
irritability, insomnia or delirium.
32. Ist edition by dr.amir abdelazim ahmed
Pathophysiology
Argininosuccinate synthetase is an enzyme that converts citrulline to argininosuccinate, the
absence of which causes an increase in plasma citrulline and ammonia levels.3
Inheritance
autosomal recessive
Screening
increased citrulline and low arginine on MSMS
Confirmatory Testing
Confirmatory testing may be done through the demonstration of amino acids in plasma (decreased
arginine and high citrulline), presence of orotic acid in urine and increased levels of ammonia in
blood.
Prognosis
Prognosis for intellectual development depends on the nature of the initial hyperammonemia
especially its duration or those of recurrent episodes.
Key metabolite : Citrulline ,elevated
Emergency key : High
Action : Immediate referral to metabolic specialist
Confirmation analysis :
Amino acids in plasma
Blood ammonia
Orotic acid in urine
Mutation analysis
Therapy :
Low protein diet
L-arginine - sodium benzoate
Sodium phenylbutyrate
Hemodialysis or hemofiltration
Liver transplantation
Signs and symptoms :
Hyper ventilation
Vomiting - hypothermia
Hyperammonemic encephalopathy rapidly
progressing to coma ,cerebral edema and death
Prognosis : Poor in neonatal cases unless early liver
transplant is performed
Moderate in intermittent cases
Note of caution : Consider to stop therapy after prolonged
hyperammonemia
33. Ist edition by dr.amir abdelazim ahmed
ARGININOSUCCINIC ACIDEMIA
Argninosuccinate lyase or argininosuccinase catalyzes the conversion of the argininosuccinate
formed from citrulline and aspartate to fumarate and arginine.5
Incidence
rare
Clinical Manifestation
Neonatal onset disease presents with severe hyperammonemic coma within the first few days of
life with an overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy or
irritability and tachypnea to seizures, coma and respiratory arrest; late onset disease are less acute
and more subtle often precipitated by stress such as infection and anesthesia.
A unique finding in patients is the presence of trichorrhexis nodosa where hair is very friable and
breaks off easily.
Pathophysiology
Argininosuccinate lyase deficiency causes the accumulation of citrulline and decreasethe levels of
arginine, the last compound of the urea cycle prior to the splitting off of urea.6 This causes the
increased ammonia levels in blood that is responsible for the signs and symptoms observed.
Inheritance:
autosomal recessive
Screening
elevated citrulline, low arginine on MSMS
Confirmatory Testing
Confirmation may be done through amino acids (elevated citrulline, low arginine, high
argininosuccinate) in plasma , increased ammonia in blood, increased orotic acid in urine and
enzyme studies in erythrocytes or fibroblasts.
Prognosis
Prognosis for intellectual development depends on the nature of initial hyperammonemia,
especially its duration or the nature of recurrent episodes.
34. Ist edition by dr.amir abdelazim ahmed
Key metabolite : Citrulline ,elevated
Emergency key : High
Action : Immediate referral to metabolic specialist
Confirmation analysis :
Amino acids in plasma
Blood ammonia
Orotic acid in urine
Enzyme activity in erythrocytes
Therapy :
Low protein diet
L-arginine (high dose ) - sodium benzoate
Sodium phenylbutyrate
Hemodialysis or hemofiltration
Liver transplantation
Signs and symptoms :
Lethargy - hyperventilation
Vomiting - hypothermia
Hyperammonemic encephalopathy progressing
to coma ,cerebral edema and death
Prognosis : Moderate : hyperammonemia easy to control
but mental retardation will develop in most
cases
Treatment of UCDs
Treatment is through the dietary restriction of protein and the supplementation of a protein free formula.
Sodium benzoate, an ammonia scavenger, is given as well as arginine supplementation.
Preliminary / Initial Management During Metabolic Crises
Metabolic crises may be caused by an excess intake of protein, illness, prolonged fasting or stressful
situations such as surgery and severe infection. The goal of treatment is to reverse the catabolic state and
prevent essential amino acid deficiency.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for serum ammonia. May request for other investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid, may do so up to 1.2 or 1.5X the maintenance.
e. Start IV sodium benzoate loading dose (250mg/kg) to run for four hours
f. Start IV arginine loading dose (250mg/kg) to run for four hours
g. Monitor input and output strictly (6 hours)
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with protein free formula to run at maintenance rate
b. Insert IV access. Collect samples for serum ammonia. May request for other investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
d. Start IV sodium benzoate loading dose (250mg/kg) to run for four hours
e. Start IV arginine loading dose (250mg/kg) to run for four hours
f. Monitor input and output strictly (q6 hours)
*Children should not be protein restricted for longer than necessary (24-48 hours).
*If patient does not improve with the initial management (within 12 hours), hemodialysis may be indicated. Monitor patient clinically, the necessity of hemodialysis will depend on patient’s
clinical status.
* Inform metabolic doctor on call for further guidance regarding on-going management.
35. Ist edition by dr.amir abdelazim ahmed
Long Term Management
Diet
Most patients require a low protein diet. Many suggest severe protein restriction but in early
infancy, patients may need > 2 g/kg/day during phases of rapid growth. The protein intake usually
decreases to approximately 1.2-1.5 g/kg/day during pre-school years and 0.8-1 g/kg/day in late
childhood. After puberty, the quantity of natural protein may be less than 0.5 g/kg/day. However,
it should be emphasized that there is considerable variation in the needs of individual patients.
Some patients may not take their full protein allowance and some may not achieve good nutrition
with restriction of natural protein, thus replacement with an essential amino acid mixture, giving
up to 0.7 g/kg/day be added to the dietary regimen.
Alternative pathways for nitrogen excretion
The effect of giving the following drugs is that nitrogen will be excreted in compounds other than
urea, thus the load of the urea cycle is reduced.
_ Sodium Benzoate 250-500 mg/kg/day (elimination of 1 mol NH3 per mol of glycine)
_ Phenylbutyrate 250-500 mg/kg/day (elimination of 2 mol NH3 per mol of glutamine)
Replacement of deficient nutrients
Arginine is normally a nonessential amino acid, because it is synthesized within the urea cycle. For
this reason, all patients with urea cycle disorders are likely to need a supplement of arginine to
replace what is not synthesized. The aim should be to maintain plasma arginine concentrations
between 50-200 umol/L.
Monitoring
All treatments must be monitored with regular quantitative estimation of plasma ammonia and
amino acids, paying particular attention to the concentration of glutamine and essential amino
acids. The aim is to keep plasma ammonia levels below 80 umol/L and plasma glutamine levels
below 800 umol/L. All diets must be nutritionally complete and must meet requirements for growth
and development.
EMERGENCY MANAGEMENT OF INTERCURRENT HYPERAMMONEMIA IN PATIENTS WITH
UREA CYCLE DISORDERS
Early Diagnosis and Therapy
This is the most important aspect of intercurrent hyperammonemia. Delays are disastrous. A plasma
ammonium level should be done as an emergency procedure on any child with these diseases who exhibits
lethargy or vomiting of any degree, and the metabolic on-call physician should be alerted. Secure IV access
needs to be established without delay.
NB Ammonium needs to be collected in a Lithium Heparin tube, min 0.5 mls and transported IMMEDIATELY
to the laboratory on ICE. Inform laboratory that the specimen is coming.
If the ammonium level approaches three times the upper limits of normal, the ammonium level should be
repeated and plasma obtained for electrolytes, blood gas and quantitative amino acids and urine for
36. Ist edition by dr.amir abdelazim ahmed
metabolic screening tests. Without waiting for the repeat ammonium value, the regimen described below
should be followed as an emergency procedure.
All dietary and intravenous protein intake should be discontinued. Because reduction of body protein
breakdown is desirable a high parenteral caloric intake should be provided from 12.5% glucose and
Intralipid.
Intralipid (20%) should be commenced at a dose of 2gm/kg/day, grading up to 3-4gms/kg/day over the
next 24 hours. Other fluids should be calculated to provide maintenance fluid as indicated by the child’s
condition. Do not delay commencing priming infusion whilst organising maintenance fluids. If there are
signs of cerebral edema this needs to be managed appropriately. Enteral feeding should be recommenced
as soon as the patient is able to tolerate it. This needs to be done in consultation with the metabolic team.
_ Give sodium benzoate up to 500 mg/kg/day-orally or intravenously. If the patient has not received any
medication, give a priming dose of 250 mg/kg in 2-4 hours then 250 mg/kg in the next 20-24 hours
_ Give L-arginine orally or intravenously:
_ Up to 700 mg/kg/day in citrullinemia na argininosuccinic aciduria
_ Up to 150 mg/kg/day in ornithine transcarbamylase deficiency and carbamoyl phosphate synthase
deficiency
_ Plasma levels of ammonium, electrolytes, blood gas should be measured four hours after the completion
of the priming infusion and every eight hours thereafter until plasma ammonium levels are normal or near
normal, or as otherwise directed by the metabolic physician. These drugs may cause urine potassium loss;
the serum potassium level should be monitored and treated as needed.
_ The drugs may cause one or two vomiting episodes, usually towards the end of the 2-3 hour treatment
period. Respiratory alkalosis may occur or be exacerbated during therapy with these drugs.
_ If plasma ammonium level does not decrease within 8 hours urgently discuss the child with the metabolic
physician. It is likely that the child will need hemodialysis.
_ If intracranial pressure is elevated, conventional osmotherapy with mannitol should begin.
Corticosteroids may be contraindicated because they induce negative nitrogen balance.
_ When the ammonium level is stable at normal or near normal levels oral medication may be gradually
added as the intravenous medication is gradually reduced. This should be done in consultation with the
metabolic physician.
References
1Su TS, Bock HGO, Beaudet AL et al. Molecular analysis of argininosuccinate syntehtase deficiency in human fibroblasts. J Clin Invest
1982:70:1334-1339.
2Chapter 31: Citrullinemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press,
2005 pp 210-
213.
3Wasant P, Viprakasit V, Srisomsap C et al. Argininosuccinate synthetase deficiency: mutation analysis in 3 Thai patients. Southeast Asian
J Trop Med Pub
Health 2005;36(3):757-761.
4 Leonard J. Disorders of the urea cycle and related enzymes. Inborn Metabolic Diseases Chapter 18,4th edition eds Fernandes, Saudubray,
van den
Berghe, Walter pp 269-271
5Chapter 32: Argininosuccinic aciduria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford
University Press,
2005 pp 216-219.
6Chen BC, Ngu LH and Zabedah MY. Argininosuccinic aciduria: clinical and biochemical phenotype findings in Malaysian children. Malaysian
J Pathol
2010;32(2):87-95.
7 Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of Metabolism) 3rd edition pp 153.
37. Ist edition by dr.amir abdelazim ahmed
FATTY ACID DISORDER
MEDIUM-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [MCAD]
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common defect of fatty acid
oxidation.
Incidence
rare
Clinical Manifestation
MCAD deficiency has a very wide spectrum of clinical presentations ranging from benign
hypoglycemia to coma
and death. Two presentations have been noted: (1) hypoketotic hypoglycemia or Reye syndrome
which occurs within the first two years of life and (2) the chronic disruption of muscle function
which include cardiomyopathy, weakness, hypotonia and arrhythmia.In addition, MCAD deficiency
38. Ist edition by dr.amir abdelazim ahmed
has been shown to be associated with sudden infant death syndrome (SIDS).4 A “metabolic stress”
such as prolonged fasting often in connection with viral infections is usually required to precipitate
disease manifestations but patients are completely asymptomatic between episodes.
Pathophysiology
MCAD catalyzes the initial step in the β-oxidation of C12-C6 straight chain acyl-CoAs and MCAD
deficiency results in a lack of production of energy from β-oxidation of medium chain fatty acids
and hepatic ketogenesis and gluconeogenesis.
Inheritance
autosomal recessive
Screening
increased octanoylcarnitine on MSMS and a high C10/carnitine ratio
Confirmatory Testing
Urine organic acid profile will show medium chain dicarboxylic aciduria.4 Measurement of the
specific MCAD enzyme activity in disrupted cultures skin fibroblasts, lymphocytes, or tissue biopsies
from muscle can confirm the diagnosis.
Prognosis
Most authors report a mortality rate of 20-25% during the initial decompensation.4 Although the
majority of children survive their initial episode, a significant amount of children who survived and
perhaps children who have experienced clinically unrecognized episodes, suffer from long term
sequelae and about 40% are judged to have developmental delay.2 Long term outcome remains
dependent on constant monitoring for early signs of illness and rapid medical intervention to
prevent complications
Long term management
Avoidance of fasting
It is essential to prevent any period of fasting which would be sufficient to require the use of fatty
acids as fuel.
This can be done by simply ensuring that patients have adequate carbohydrate feeding at bedtime
and do not fast for more than 12 hours overnight. For young babies they should be fed every 3–4
hours with a late night feed continuing until about 9 months of age and they should not fast for
longer than 6 - 8 hours. During inter- current illness (when child has poor appetite, low energy or
excessive sleepiness, vomiting, diarrhea, infection or fever), care should be taken to give extra
feedings of carbohydrate during the night and inform the doctor for the “sick day regimen” which
mainly consists of high energy drink.
39. Ist edition by dr.amir abdelazim ahmed
In a few patients with severe defects in fatty acid oxidation who had developed weakness and/or
cardiomyopathy, addition of continuous intragastric feedings such as the use of uncooked
cornstarch at bedtime might be considered as a slowly released form of glucose.
Diet
Dietary fat restriction is not routine in patients with MCAD deficiency.
Emergency management of patients with MCAD deficiency
When patients with fatty acid oxidation disorders become ill, treatment with intravenous glucose
should be given immediately. Delay may result on sudden death or permanent brain damage. The
goal is to provide sufficient glucose to stimulate insulin secretion to levels that will only suppress
fatty acid oxidation in liver and muscle, but also block adipose tissue lipolysis.
Solutions of 10%dextrose should be used at infusion rates of 10 mg/kg per min or greater to
maintain high to normal levels of plasma glucose, above 100mg/dl. Do not give intravenous lipids
Key metabolite : C8 (octanoyl carnitine ) , elevated
Emergency key : Moderate
Action : Contact family to ascertain clinical condition
and referral to metabolic specialist
Confirmation analysis :
Acylcarnitine profile in DBS/plasma
Carnitine status in plasma/serum
Organic acids in urine
Enzyme activity fibroblasts
Mutation analysis
Therapy : Avoid fasting (L-carnitine supplementation)
Signs and symptoms :
Hypoketotic hypoglycemia
Reye-like syndrome
Lethargy , nausea , vomiting, coma, seizures,
cardiac arrest
Prognosis : excellent
Note of caution : Neonatal manifestation in rare cases
References:
1Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in Sarafoglou K, Hoffman
GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 60-62.
2 Hsu HW, Zytkovicz TH, Comeau AM et al. Spectrum of Medium chain acyl-coA dehydrogenase deficiency detected by
newborn screening. Pediatrics 2008;121:e1108-e1114.
3 Chapter 40: Medium chain acyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic
Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 260-265.
4 Wilson CJ, Champion MP, Collins JE et al. Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch
Dis Child 1999;80:459-462.
5 Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. Inborn
Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
40. Ist edition by dr.amir abdelazim ahmed
Analyte Octanoylcarnitine (C8) (always associated with C6 and C10)
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 0.200 uM/L
Differential
diagnosis
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
False positive The specificity of MS/MS to identify MCAD deficiency appears to be 100%, with a few false negative
results having been reported as a result of inappropriate cut-off selection
False postive may be as marker “octanoylcarnitine” is not specific for MCAD deficiency and is
expected to be elevated in other disorders (i.e., glutaric acidemia type II, and possibly medium-
chain 3-keto acyl-CoA thiolase deficiency) and in newborns treated with valproate or fed a diet rich
in medium-chain triglycerides
Clinical
presentation
MCAD deficiency is usually asymptomatic in the newborn although it can present acutely in the neonate
with hypoglycemia, metabolic acidosis, hyperammonemia, and hepatomegaly. MCAD deficiency is
associated with high mortality unless treated promptly; milder variants exist. Hallmark features include
vomiting, lethargy, and hypoketotic hypoglycemia. Untreated MCAD deficiency is a significant cause
of sudden death.
Prognosis : 25% sudden death in the first attack of illness
Permanent brain injury occur in some patients during attack
Prognosis for survivors without brain damage more than 60%
Diagnostic
evaluation
and
confirmatory
test
Plasma acylcarnitine analysis will show increase C8 ,C10 consistent with MCADD.
Urine organic acid analysis may also show low ketones and high medium chain dicarboxylic
acids (adipic ,suberic and sebacic acids) that derive from microsomal and perioxisomal
omega oxidation of fatty acid
Increase urinary acylglycines (hexanoyl-,suberyl-,3phenylpropionyl glycines)
Diagnosis can be confirmed by mutation analysis of the MCAD gene and determination of
fatty acid B-oxidation in fibroblast and measure MCAD enzyme activity in fibroblast.
In acute attack show hypoketotic hypoglycemia (no metabolic acidemia)
Liver function :elevated ALT,AST and prolonged PT , PTT
Liver biopsy show micro or macro-vesicular steatosis due to triglyceride accumulation
Causes and
mechanism
MCAD deficiency is a fatty acid oxidation (FAO) disorder. Fatty acid oxidation occurs mainly during
prolonged fasting and/or periods of increased energy demands (fever, stress), when energy production
relies increasingly on fat metabolism. In an FAO disorder, fatty acids and potentially toxic derivatives
accumulate because of a deficiency in one of the mitochondrial FAO enzymes.
Genetics Diagnosis can be confirmed by finding the common A985G mutation
Second common mutation T199C has been detected in infants with characteristic acylcarnitines in
newborn screening test
Prenatal
diagnosis
Test of sibling of affected patients important to detect asymptomatic family members as many as
50% of affected patients have never had an episode
Prevalence 1:5000 to 1:17000
Action for
result
Contact family , evaluate baby for poor feeding , lethargy , hypotonia and hepatomegaly , start
confirmatory investigation, educate family to avoid fasting , refer to metabolic specialist
Treatment Acute : 10% dextrose to treat hypoglycemia and suppress lipolysis
Chronic: avoid fasting - restricting dietary fat or treatment with carnitine is controversial
LONG-CHAIN L-3-HYDROXYACYL-CoA DEHYDROGENASE [LCHAD]
Long chain L-3 hydroxyacyl-CoA dehydrogenase (LCHAD) is a component of trifunctional protein.
Isolated LCHAD deficiency catalyzes the third step in the fatty acid oxidation spiral, converting long
chain 3-hydroxyacyl- CoA esters into long chain 3-keto-CoA species by using NAD as a cofactor.
Incidence
Very rare
41. Ist edition by dr.amir abdelazim ahmed
Clinical Manifestation
Patients exhibit moderate or severe multiorgan involvement either neonatally or during the first
two years of life.They may present in the first year of life with hypoketotic hypoglycemia and liver
dysfunction, Reye syndrome- like symptoms, seizures, coma and death.2 By adolescence,
ophthalmologic abnormalities including loss of visual acuity, chorioretinal atrophy, progressive
retinitis pigmentosa and peripheral sensorimotor polyneuropathy may be observed.2,3,4, Up to 40%
of symptomatic patients may have tachycardic arrhythmias, apneic episodes, cardiopulmonary
arrest and unexplained death.2 A strong association has been demonstrated with heterozygous
mothers developing acute fatty liver or pregnancy or hemolysis, elevated liver enzymes and low
platelet count (HELLP) syndrome when carrying an affected fetus.
Pathophysiology
Since the enzyme LCHAD is part of the fatty acid oxidation, a deficiency causes a problem in the
energy utilization of the body which causes the presentation of signs and symptoms as listed above.
Inheritance
autosomal recessive
Screening
elevated C16 (palmitoylcarnitine), 3-hydroxypalmitoylcarnitine, C18, 3-hydroxy-C18-carnitines and
C18:1- hydroxycarnitine 2,3
Confirmatory Testing
Confirmatory testing is done through enzyme assays performed in cultured cells such as skin
fibroblasts. The common mutation G1528C has been identified in affected individuals and may be
used for confirmation.
Prognosis
Patients with LCHAD deficiency who present symptomatically often die during the acute episode
or suffer from sudden, unexplained death and mortality occurs in approximately 38%.
Long term management
Primary goal of treatment is to avoid metabolic stress brought about by infection and long periods
of fasting.
Patients should be given frequent feedings, supplementation with medium chain triglycerides (MCT
formula) and an overnight infusion of cornstarch. Treatment with L-carnitine remains controversial.
Avoidance of fasting
Patients must be ensured to have adequate carbohydrate feeding at bedtime and do not fast for
more than 12 hours overnight. For young babies they should be fed every 3–4 hours with a late
night feed continuing until about 9 months of age and they should not fast for longer than 6 - 8
42. Ist edition by dr.amir abdelazim ahmed
hours. During intercurrent illness, when appetite is diminished, care should be taken to give extra
feedings of carbohydrate during the night. A” sick day regimen” containing high glucose drinks
should be given.
In a few patients with severe defects in fatty acid oxidation who had developed weakness and/or
cardiomyopathy, addition of continuous intragastric feedings such as the use of uncooked
cornstarch at bedtime might be considered as a slowly released form of glucose.
Diet
Sometimes a low fat, high carbohydrate diet is recommended. Food plan is recommended.
Carbohydrates give the body may types of sugar that can be used as energy. In fact, for children
needing this treatment, most food in the diet should be carbohydrates (bread, pasta, fruit, etc.)
and protein (lean meat and low-fat dairy foods).
Any diet changes should be made under the guidance of an experienced dietitian.
People with LCHADD cannot use certain building blocks of fat called “long chain fatty acids”. The
dietitian can help create a food plan low in these fats. Much of the rest of fat in the diet may be in
the form of medium chain fatty acids.
Medium Chain Triglyceride oil (MCT oil) is often used as part of the food plan for people with
LCHADD. This special oil has medium chain fatty acids that can be used in small amounts for energy.
In addition to the above supplements, some doctors suggest taking DHA (docosahexanoic acid)
which may help prevent loss of eyesight.
Avoid prolonged exercise
Long periods of exercise can also trigger symptoms. Problems occurring during or after exercise can
include:
muscle aches, weakness, cramps and reddish-brown color to the urine.
It is advised to have high carbohydrate intake prior to exercise to prevent lipolysis and to restrict
physical activity to levels that are not likely to precipitate an attack of rhabdomyolysis.
Intercurrent illness
Advise parents to refer the child to the doctor if he/she has any of the following:
_ poor appetite
_ low energy or excessive sleepiness
_ vomiting
_ diarrhea
_ an infection
_ a fever
_ persistent muscle pain, weakness, or reddish-brown color to the urine
Children with LCHADD need to eat extra starchy food and drink more fluids during any illness - even
if they may not feel hungry – or they could develop hypoglycemia or a metabolic crisis. When they
become sick, children with LCHADD often need to be treated in the hospital to prevent serious
health problems.
43. Ist edition by dr.amir abdelazim ahmed
Emergency management of patients with LCHAD deficiency
When patients with fatty acid oxidation disorders become ill, treatment with intravenous glucose
should be given immediately. Delay may result on sudden death or permanent brain damage. The
goal is to provide sufficient glucose to stimulate insulin secretion to levels that will only suppress
fatty acid oxidation in liver and muscle, but also block adipose tissue lipolysis.
Solutions of 10%dextrose should be used at infusion rates of 10 mg/kg per min or greater to
maintain high to normal levels of plasma glucose, above 100mg/dl. Do not give intravenous lipids!
Key metabolite : C16OH – C18:OH , elevated
Emergency key : High
Action : Immediate referral to metabolic specialist
Confirmation analysis :
Acylcarnitines in DBS/plasma
Organic acid in urine
CK,liver transamiases
Enzyme activity in lymphocytes
Mutation analysis
Therapy : Diet : restriction of LCT.MCT
Avoid fasting
(careful with L-carnitine supplementation)
Signs and symptoms :
Hypoketotic hypoglycemia cardiomyopathy
Liver disease
Muscular hypotonia
Neuropathy - retinopathy
Exercise intolerance
Muscle pain rhabdomyolysis
Prognosis : Moderate
Patients with a severe phenotype with cardiac
involvement die in the first weeks of life despite
immediate treatment
Note of caution : Mother of an affected fetus may develop acute
fatty liver of pregnancy of HELLP syndrome
References
1 Chapter 42: Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic
Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 272-275.
21Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in Sarafoglou K, Hoffman
GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 60-62.
3Eskelin P and Tyni T. LCHAD and MTP Deficiencies – Two Disorders of Mitochondrial Fatty Acid Beta-Oxidation with Unusual
Features. Cur Ped Rev 2007;3:53-59.
4 Moczulski D, Majak I, Mamczur D. An overview of β-oxidation disorders. Postepy Hig Med Dosw 2009;63:266-277.
5 Gillingham M, Van Calcar S, Ney D et al. Dietary management of long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. A
Case report and survey. J Inherit Metab Dis 1999;22(2):123-131.
6Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. Inborn
Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
7Long chain hydroxyl acyl co-A dehydrogenase deficiency. Available at
http://www.newbornscreening.info/Parents/fattyaciddisorders/LCHADD.html
44. Ist edition by dr.amir abdelazim ahmed
VERY LONG-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [VLCADD]
Very long-chain acyl-CoA dehydrogenase catalyzes the dehydrogenation of C22-C12 straight chain
fatty acids, and because the long chain fatty acids constitute a major proportion of the fatty acids,
VLCAD deficiency is generally a more severe condition than MCAD or SCAD deficiency and multiple
tissues are affected.
Incidence
rare
Clinical Manifestation
The clinical presentation of symptomatic VLCAD deficiency is heterogenous with phenotypes of
different severities.
There are three forms described: (1) severe childhood form with neonatal onset and
cardiomyopathy; (2) milder childhood form with delayed onset of symptoms often triggered by
metabolic stress and presents as hypoketotic hypoglycemia and; (3) adult form which presents with
isolated skeletal muscle involvement with recurrent episode of muscle pain, rhabdomyolysis and
myoglobinuria.
Pathophysiology
VLCAD catalyzes the dehydrogenation of acyl CoA esters of 14-20 carbon length in the first step of
mitochondrial fatty acid oxidation.3,4 VLCAD deficiency results in lack of production of energy from
β-oxidation of longchain fatty acids. Because heart and muscle tissues depend heavily on energy
from long chain fatty acid oxidation, a VLCAD deficiency severely affect these tissues.
Inheritance
autosomal recessive
Screening
elevation of tetradecenoylcarnitine (C14:1) on MSMS
Confirmatory Testing
The enzyme defect can be detected through culture skin fibroblasts.1 The gene for VLCAD has been
clone and sequenced successfully and play a role in diagnosis of this disorder.
Prognosis
Fifty percent of patients die within 2 months of initial symptomatology.4 However, timely and
correct diagnosis leads to dramatic recovery so that early detection could prevent the onset of
arrhythmias, heart failure, metabolic insufficiency and death.
45. Ist edition by dr.amir abdelazim ahmed
Preliminary / Initial Management During Metabolic Crisis
Metabolic crises may be caused by illness, prolonged fasting or stressful situations such as surgery and
severe infection.
The goal of treatment is to reverse the catabolic state and prevent hypoglycemia.
Long term management
Treatment of this disorder include avoidance of fasting by frequent feeding, overnight continuous
feeding, reduction of amount of long chain fat in diet while supplying essential fatty acids in the
form of canola, walnut oil or safflower oil and supplementation with medium chain triglycerides
(MCT).
Avoidance of fasting
Patients must be ensured to have adequate carbohydrate feeding at bedtime and do not fast for
more than 12 hours overnight. For young babies they should be fed every 3–4 hours with a late
night feed continuing until about 9 months of age and they should not fast for longer than 6 - 8
hours. During intercurrent illness, when appetite is diminished, care should be taken to give extra
feedings of carbohydrate during the night. A” sick day regimen” containing high glucose drinks
should be given.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Monitor glucose levels. For patients with VLCAD, collect samples for serum CK. May
request for other investigations (i.e. CBC, Blood gas) as needed. May give fluid boluses if patient
requires.
d. Start D10% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid,
may do so up to 1.2 or 1.5X the maintenance.
e. Monitor input and output strictly (q6 hours). Check for the color of urine.
If unwell and is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with a high glucose formula
b. Insert IV access. Monitor glucose levels. For patients with VLCAD, collect samples for serum CK. May
request for other investigations (i.e. CBC, Blood gas) as needed. May give fluid boluses if patient
requires.
c. Start D10% 0.3 NaCl at 5-10 cc/hr.
d. Monitor input and output strictly (q6 hours). Check for the color of urine.
*Patients with VLCAD may have rhabdomyolysis. Monitor CK levels and hydrate adequately. If CK levels
continually rise, hemodialysis may be indicated.
* Inform metabolic doctor on call for further guidance regarding on-going management.
46. Ist edition by dr.amir abdelazim ahmed
In a few patients with severe defects in fatty acid oxidation who had developed weakness and/or
cardiomyopathy, addition of continuous intragastric feedings such as the use of uncooked
cornstarch at bedtime might be considered as a slowly released form of glucose.
Diet
Sometimes a low fat, high carbohydrate diet is recommended. Food plan is recommended.
Carbohydrates give the body may types of sugar that can be used as energy. In fact, for children
needing this treatment, most food in the diet should be carbohydrates (bread, pasta, fruit, etc.)
and protein (lean meat and low-fat dairy foods).
Any diet changes should be made under the guidance of an experienced dietitian.
People with VLCADD cannot use certain building blocks of fat called “long chain fatty acids”. The
dietitian can help create a food plan low in these fats. Much of the rest of fat in the diet may be in
the form of medium chain fatty acids.
Medium Chain Triglyceride oil (MCT oil) is often used as part of the food plan for people with
VLCADD. This special oil has medium chain fatty acids that can be used in small amounts for energy.
Ask your doctor whether your child needs to have any changes in his or her diet.
Avoid prolonged exercise
Long periods of exercise can also trigger symptoms. Problems occurring during or after exercise can
include:
muscle aches, weakness, cramps and reddish-brown color to the urine.
It is advised to have high carbohydrate intake prior to exercise to prevent lipolysis and to restrict
physical activity to levels that are not likely to precipitate an attack of rhabdomyolysis.
Intercurrent illness
Advise parents to refer the child to the doctor if he/she has any of the following:
_ poor appetite
_ low energy or excessive sleepiness
_ vomiting
_ diarrhea
_ an infection
_ a fever
_persistent muscle pain, weakness, or reddish-brown color to the urine
Children with VLCADD need to eat extra starchy food and drink more fluids during any illness - even
if they may not feel hungry – or they could develop hypoglycemia or a metabolic crisis. When they
become sick, children with VLCADD often need to be treated in the hospital to prevent serious
health problems.
47. Ist edition by dr.amir abdelazim ahmed
Emergency management of patients with VLCAD deficiency
When patients with fatty acid oxidation disorders become ill, treatment with intravenous glucose
should be given immediately. Delay may result on sudden death or permanent brain damage. The
goal is to provide sufficient glucose to stimulate insulin secretion to levels that will only suppress
fatty acid oxidation in liver and muscle, but also block adipose tissue lipolysis.
Solutions of 10%dextrose should be used at infusion rates of 10 mg/kg per min or greater to
maintain high to normal levels of plasma glucose, above 100mg/dl. Do not give intravenous lipids
Key metabolite : C14:1(myrisotoleyl carnitine),elevated
Emergency key : High
Action : Immediate referral to metabolic center
Confirmation analysis :
Acylcarnitine profile in DBS/plasma
Carnitine status in plasma/serum
CK,liver transaminases
Organic acids in urine
Enzyme activity in lymphocytes
Mutation analysis
Therapy : Avoid fasting
In severe cases : dietary restriction of LCT,MCT
Careful with L-carnitine supplementation
Signs and symptoms :
Hypoketotic hypoglycemia
Cardiomayopathy , arrhythmias
Rhabdomyolysis
Liver disease
Prognosis : Generally good(but there are fatal cases)
Note of caution : False negative screening reported world wide
References
1Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in Sarafoglou K, Hoffman
GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 60-62.
2Liebig M, Schymik I, Mueller M et al. Neonatal screening for very long chain acyl-CoA dehydrogenase deficiency: enzymatic
and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics 2006;118(3):1064-1069.
3 Chapter 41: Very long chain acyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic
Diseases 2nd ed. Great Britain: Oxford University Press, 2005 pp 267-270.
4 Wood JC, Mager MJ, Rinaldo P et al. Diagnosis of very long chain acyl-dehydrogenase deficiency from an infant’s newborn
screening card. Pediatrics 2001l108:e19-e21.
5 Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. Inborn
Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
6 Very long chain acyl co-A dehydrogenase deficiency. Available at
http://www.newbornscreening.info/Parents/fattyaciddisorders/VLCADD.html
48. Ist edition by dr.amir abdelazim ahmed
Analyte Tetradeccanoylcarnitine (C14:1) always associated with 3-OH stearoylcarnitine ( C18 OH)
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 0.500 uM/L
Differential
diagnosis
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.
Disorder is sometimes mistaken for Reye syndrome
False positive 75% from newborn staff effort consumed to catch true cases
Clinical
presentation
More severe and earlier than MCAD
VLCAD deficiency may present acutely in the neonate and is associated with high mortality unless
treated promptly; milder variants exist. Features of severe VLCAD deficiency in infancy include
hepatomegaly, cardiomyopathy during acute attack associated with fasting and arrhythmias, lethargy,
hypoketotic hypoglycemia,muscle weakness , rhabdomyolysis and failure to thrive. Treatment is
available.
Diagnostic
evaluation
and
confirmatory
test
Plasma acylcarnitine profile may show increased C14:1 acylcarnitine (and lesser elevations of other
long chain acylcarnitines).
Urinary organic acid profile show nonketotic dicarboxylic aciduria (increase C6-C12)
Assay of enzyme activity of VLCAD in fibroblast
Diagnosis is confirmed by mutation analysis of VLCAD gene and other biochemical genetic tests.
Sudden unexpected death can occur in several patients
Causes and
mechanism
VLCAD deficiency is a fatty acid oxidation (FAO) disorder. Fatty acid oxidation occurs during prolonged
fasting and/or periods of increased energy demands (fever, stress), when energy production relies
increasingly on fat metabolism. In a FAO disorder, fatty acids and potentially toxic derivatives
accumulate because of a deficiency in one of the mitochondrial FAO enzymes.
Genetics ACADVL A gene on chromosome 17p13.1 encodes acyl-Coenzyme A dehydrogenase - autosomal recessive
Prenatal
diagnosis
Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced increased levels
of long-chain acylcarnitines consistent with a deficiency in very-long-chain acyl-CoA dehydrogenase
(VLCAD). Measurements of the enzymatic activity confirmed VLCAD deficiency in amniocytes
Prevalence affect 1 in 40,000 to 120,000 people
Action for
result
Contact family , evaluate baby for poor feeding , lethargy , hypotonia ,arrhythmia and
hepatomegaly , start confirmatory investigation, educate family to avoid fasting , refer to
metabolic specialist
Treatment Avoiding of fasting for more than 10 hours
Continuous intra gastric feeding is useful in some patients
49. Ist edition by dr.amir abdelazim ahmed
TRIFUNCTIONAL PROTEIN [TFP] DEFICIENCY
The mitochondrial trifunctional protein (TFP) is a multienzyme complex of the β-oxidation cycle
composed of four α-subunits harbouring long-chain enoyl-CoA hydratase and long chain L-3-
hydroxyacyl-CoA dehydrogenase and four β-subunits encoding long chain 3-ketoacyl-CoA thoilase.1
General or complete TFP deficiency is defined and occurs when markedly decreased activity of all
three enzymatic components, LCHAD, long chain 2,3 enoyl CoA drasate and LKAT exist.
Incidence
Very rare
Clinical Manifestation
General TFP deficiency has three phenotypes: the lethal phenotype presenting with lethal cardiac
failure or sudden death due to arrhythmias, the hepatic phenotype and the neuromyopathic
phenotype that has lateronset, episodic, recurrent skeletal myopathy with muscular pain and
weakness often induced by exercise or exposure to cold and peripheral neuropathy.
It is important to note that fetuses with complete TFP deficiency can cause maternal liver diseases
of pregnancy.
Pathophysiology
Mitochondrial fatty acid β-oxidation is a major energy-producing pathway.3 Any defect in any
enzyme may cause the characteristic signs and symptoms which include hypoketotic hypoglycemia.
Inheritance
autosomal recessive
Screening
increased C16 and C18 on MSMS
Confirmatory Testing
Confirmatory testing is through the demonstration of decreased enzyme activity on cultured
fibroblasts.Mutations in the HADHA and HADHB gene may result in mitochondrial trifunctional
protein deficiency4 and mayplay a role in confirmation.
Prognosis
Patients with metabolic crises do well unless the hypoglycemia and seizures are prolonged and
cause developmental delay, older onset patients with rhabdomyolysis can reduce episodes
significantly with dietary management and do well.
50. Ist edition by dr.amir abdelazim ahmed
Long term and emergency management
Treatment includes avoidance of fasting, reduced long-chain fat intake, supplementation with
medium chain triglycerides, supplementation with fat-soluble vitamins, and avoidance of other
potential stressors such as prolonged exercise. Emergency management includes administration of
intravenous glucose infusions.
References
1Speikerkoetter U, Khuchua Z, Yue Z et al. General Mitochondrial Trifunctional Protein (TFP) Deficiency as a results of either α
or β-subunit mutations exhibits imilar phenotypes because mutation in either subunit alter TFP complex expression and
subunit turnover. Ped Res 2003l55(2):1-7.
2Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in 14
3 Kamijo T, Wanders RJA, Saudubray JM et al. Mitochondrial Trifunctional Protein Deficiency. J Clin Invest 1994;93:1740-1747.
4Trifunctional protein deficiency. Available at http://ghr.nlm.nih.gov/condition/mitochondrial-trifunctional-protein-
deficiency
5Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. Inborn
Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
Analyte C16OH +/- C18
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 0.500 uM/L
Differential
diagnosis
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency;
Trifunctional protein (TFP) deficiency.
False positive Consider that cefotaxime treatment in the baby or mother may alter lab results.
Clinical
presentation
LCHAD and TFP deficiencies may present acutely and are then associated with high mortality unless
treated promptly. Hallmark features include hepatomegaly, cardiomyopathy, lethargy, hypoketotic
hypoglycemia, elevated liver transaminases, elevated creatine phosphokinase (CPK), lactic acidosis,
and failure to thrive. Rhabdomyolysis (a serious and sometimes fatal complication) may occur. Milder
variants exist.
Diagnostic
evaluation
and
confirmatory
test
Plasma acylcarnitine analysis will show a characteristic pattern consistent with LCHADD or TFP
deficiency.
Urine organic acid analysis may also show an abnormal profile.
Differentiation between both disorders requires further biochemical and molecular genetic testing
Causes and
mechanism
LCHADD and TFP deficiencies are fatty acid oxidation (FAO) disorders. Fatty acid oxidation occurs
during prolonged fasting and/or periods of increased energy demands (fever, stress) after glycogen
stores become depleted and energy production relies increasingly on fat metabolism. Fatty acids and
potentially toxic derivatives accumulate in FAO disorders which are caused by deficiency in one of the
enzymes involved in FAO.
Genetics COMMOM MUTATION IN THE a SUBUNIT , E474Q IS SEEN IN MORE THAN 60% OF LCHAD
Treatment Avoiding fasting stress
Dietary supplements with medium-chain triglyceride oil and docosahexaenoic acid DHA
51. Ist edition by dr.amir abdelazim ahmed
ORGANIC ACID DISORDER
3-METHYLCROTONYL-COA CARBOXYLASE DEFICIENCY [3MCC]
The deficiency of 3-methylcrotonyl CoA carboxylase (3MCC) is a disorder of leucine metabolism
that was first described by Eldjarn et al. in 1970.1 In most instances, it has been found that neonates
who test positive for this condition in expanded newborn screening do not actually have the
condition but instead reflect the increased levels of the metabolites of their mothers.
Incidence
Very rare
52. Ist edition by dr.amir abdelazim ahmed
Clinical Manifestation
There is a broad spectrum of clinical presentation ranging from no symptoms to failure to thrive,
hypotonia, and cardiomyopathy to severe metabolic decompensation with metabolic acidosis and
hypoglycemia. Some patients may have a late presentation (1-3 years old) with an acute episode of
Reye syndrome, massive ketosis, acidosis, lethary, coma leading to a fatal outcome.
Pathophysiology
3-methycrotonyl CoA carboxylase is responsible for the carboxylation of 3-methylcrotonyl-CoA, the
fourth step in leucine catabolism; a deficiency of which causes a disturbance in leucine catabolism.
Inheritance
autosomal recessive
Screening
Increased 3-hydroxyisovaleryl carnitine on MSMS
Confirmatory Testing
An increase in 3-hydroxyisovaleric (3 HIVA) and 3-methylcrotonyl glycine (3 MCG) are found in
urine, confirmatory testing is done through the demonstration of decreased enzyme activity in
cultured fibroblasts.
Prognosis
3-MCC is a common, mostly benign condition; whether treatment with a low-protein diet, carnitine
and glycine supplementation has the potential to change the clinical course in several affected
patients remains to be elucidated.
Long term management
Long term treatment of symptomatic infants based on mildly protein restricted diet results in
general improvement and reduction in the number of exacerbations. It is effective in lowering the
excretion of organic acids which however, never disappears. Glycine supplementation at 175
mg/kg/day increases the excretion of 3 MCG. Carnitine supplementation at 100 mg/kg.day corrects
the very low plasma carnitine levels and increases the excretion of 3 HIVA.
53. Ist edition by dr.amir abdelazim ahmed
Key metabolite : C5OH(3OH isovaleryl-carnitine) , elevated
Emergency key : Low
Action : Referral to metabolic specialist
Confirmation analysis :
Acylcarnitine profile
Carnitine status in plasma /serum
Organic acid in urine
Enzyme activity
Mutation anmalysis
Therapy : Possibly carnitine supplementation
Signs and symptoms :
Benign disorder under risk of decompensation
Prognosis : Good
Note of caution : NBS may detect affected mothers
C5OH not specific to 3MCC deficiency but also
in MCD – Biotindase def. – 3HMG- BKTD
References
1Leonard JV, Seakins JWT, Bartlett K et al. Inherited disorders of 3-methylcrotonyl CoA carboxylation. Arch Dis Child
1981;56:52-59.
2 Chapter 9: 3-methylcrotonyl carboxylase deficiency/3-methylcrtotonyl glycinuria. Nyhan WL, Barshop BA and Ozand P. Atlas
of Metabolic Diseases 2nd
ed. Great Brita3Hoffman GF and Schulze A. Chapter 7: Organic Acidurias in Sarafoglou K, Hoffman GF
and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 93-94.
4 Ficicioglu MD and Payan I. 3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child
detected through newborn screening. Pediatrics 2006;118:2555-2556.
5Wendel U, de Baulny HO. Branched chain organic acidurias/acidemias. Inborn Metabolic Diseases Chapter 19 4th edition eds
Fernandes, Saudubray, van den Berghe, Walter pp 257 in:Oxford University Press, 2005 pp 66-68.