What is a metabolic disease?
Inborn errors of metabolism”
inborn error : an inherited (i.e. genetic) disorder
metabolism : chemical or physical changes in a biological system
Maple syrup urine disease (MSUD) is a rare genetic metabolic disorder caused by a deficiency of the enzyme branched chain alpha ketoacid dehydrogenase, which prevents the body from properly breaking down three amino acids found in protein. This causes a buildup of these amino acids and their byproducts in the body. Symptoms can range from a characteristic maple syrup smell in urine to poor feeding, vomiting, and weight loss. Treatment involves a restricted diet low in these amino acids and use of a special metabolic formula. Management aims to keep amino acid levels from becoming too high or too low to prevent health complications.
Metabolism of Tryptophan and its disorders.Ashok Katta
Tryptophan is an essential aromatic amino acid that can be metabolized through the kynurenine pathway in the liver or the serotonin pathway. The kynurenine pathway produces metabolites that are used for niacin synthesis, the glucogenic pathway, or the ketogenic pathway. The serotonin pathway produces the neurotransmitter serotonin in the brain and gastrointestinal tract. Disorders of tryptophan metabolism can cause symptoms like depression, skin rashes, and neurological issues due to deficiencies in serotonin and niacin.
Metabolism of Sulfur Containing Amino Acids (Methionine, Cysteine, Cystine)Ashok Katta
Methionine and cysteine are sulfur-containing amino acids involved in important metabolic pathways.
Methionine is an essential amino acid that is converted to S-adenosylmethionine (SAM), which acts as a methyl group donor in transmethylation reactions. SAM is also regenerated back to methionine. Cysteine is synthesized from methionine and serine via cystathionine. It can be catabolized through transamination or direct oxidation pathways.
Genetic disorders of methionine and cysteine metabolism include cystinuria, cystinosis, hypermethioninemia, and different types of homocystinurias caused by defects in enzymes involved in
This document summarizes several disorders associated with amino acid metabolism, including albinism, alkaptonuria, and phenylketonuria. Albinism is caused by a lack of melanin pigment due to defects in the tyrosinase enzyme. Alkaptonuria is caused by a defect in the enzyme homogentisate 1,2-dioxygenase, leading to a buildup of homogentisic acid and the darkening of cartilage and urine. Phenylketonuria results from a defect in the enzyme phenylalanine hydroxylase, causing an accumulation of phenylalanine that can lead to intellectual disabilities if left untreated.
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
Maple syrup urine disease (MSUD) is a rare metabolic disorder caused by a deficiency of the enzyme branched-chain keto acid dehydrogenase (BCKDH), which is required to break down the branched-chain amino acids leucine, valine, and isoleucine. This causes an accumulation of these amino acids in the blood and urine, giving urine a characteristic maple syrup smell. MSUD is treated through a carefully controlled diet low in these amino acids and supplementation to maintain metabolic control. Without treatment, MSUD can cause neurological damage and is often fatal within the first month of life.
This document summarizes four lysosomal storage disorders: Niemann-Pick disease, Gaucher's disease, Krabbe's disease, and Farber's disease. Each disease is caused by a defect in an enzyme involved in sphingolipid metabolism, leading to accumulation of specific sphingolipids in tissues. The diseases are characterized by organomegaly, skeletal abnormalities, dermatological issues, neurological impairment, and early mortality.
Maple syrup urine disease (MSUD) is a rare genetic metabolic disorder caused by a deficiency of the enzyme branched chain alpha ketoacid dehydrogenase, which prevents the body from properly breaking down three amino acids found in protein. This causes a buildup of these amino acids and their byproducts in the body. Symptoms can range from a characteristic maple syrup smell in urine to poor feeding, vomiting, and weight loss. Treatment involves a restricted diet low in these amino acids and use of a special metabolic formula. Management aims to keep amino acid levels from becoming too high or too low to prevent health complications.
Metabolism of Tryptophan and its disorders.Ashok Katta
Tryptophan is an essential aromatic amino acid that can be metabolized through the kynurenine pathway in the liver or the serotonin pathway. The kynurenine pathway produces metabolites that are used for niacin synthesis, the glucogenic pathway, or the ketogenic pathway. The serotonin pathway produces the neurotransmitter serotonin in the brain and gastrointestinal tract. Disorders of tryptophan metabolism can cause symptoms like depression, skin rashes, and neurological issues due to deficiencies in serotonin and niacin.
Metabolism of Sulfur Containing Amino Acids (Methionine, Cysteine, Cystine)Ashok Katta
Methionine and cysteine are sulfur-containing amino acids involved in important metabolic pathways.
Methionine is an essential amino acid that is converted to S-adenosylmethionine (SAM), which acts as a methyl group donor in transmethylation reactions. SAM is also regenerated back to methionine. Cysteine is synthesized from methionine and serine via cystathionine. It can be catabolized through transamination or direct oxidation pathways.
Genetic disorders of methionine and cysteine metabolism include cystinuria, cystinosis, hypermethioninemia, and different types of homocystinurias caused by defects in enzymes involved in
This document summarizes several disorders associated with amino acid metabolism, including albinism, alkaptonuria, and phenylketonuria. Albinism is caused by a lack of melanin pigment due to defects in the tyrosinase enzyme. Alkaptonuria is caused by a defect in the enzyme homogentisate 1,2-dioxygenase, leading to a buildup of homogentisic acid and the darkening of cartilage and urine. Phenylketonuria results from a defect in the enzyme phenylalanine hydroxylase, causing an accumulation of phenylalanine that can lead to intellectual disabilities if left untreated.
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
Maple syrup urine disease (MSUD) is a rare metabolic disorder caused by a deficiency of the enzyme branched-chain keto acid dehydrogenase (BCKDH), which is required to break down the branched-chain amino acids leucine, valine, and isoleucine. This causes an accumulation of these amino acids in the blood and urine, giving urine a characteristic maple syrup smell. MSUD is treated through a carefully controlled diet low in these amino acids and supplementation to maintain metabolic control. Without treatment, MSUD can cause neurological damage and is often fatal within the first month of life.
This document summarizes four lysosomal storage disorders: Niemann-Pick disease, Gaucher's disease, Krabbe's disease, and Farber's disease. Each disease is caused by a defect in an enzyme involved in sphingolipid metabolism, leading to accumulation of specific sphingolipids in tissues. The diseases are characterized by organomegaly, skeletal abnormalities, dermatological issues, neurological impairment, and early mortality.
This document summarizes the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It describes how they are first transaminated to their corresponding keto acids, then undergo oxidative decarboxylation by alpha-keto acid dehydrogenase to form acyl-CoA thioesters. These are further dehydrogenated and enter different pathways, with valine being converted to propionyl-CoA and being glycogenic, leucine producing acetyl-CoA and acetoacetate and being ketogenic, and isoleucine undergoing both glycogenic and ketogenic fates. Defects in these pathways can cause diseases like maple syrup urine disease.
Amino acid metabolism disorders are hereditary metabolic disorders. Hereditary disorders occur when parents pass the defective genes that cause these disorders on to their children. Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing (metabolism) can result from defects either in the breakdown of amino acids or in the body’s ability to get amino acids into cells.
Inborn errors of metabolism
Definition:- Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.
Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air.
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
Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.
Tyrosinemia is a rare genetic disorder that prevents the body from breaking down the amino acid tyrosine. There are two main types, type 1 and type 2. Type 1 is caused by a defect in the FAH enzyme and can cause liver and kidney damage if left untreated. Treatment involves medication to prevent damage and a low-protein diet that restricts tyrosine and phenylalanine intake. Type 2 is caused by a defect in the TAT enzyme and symptoms include eye and skin lesions as well as developmental delays. Both types require careful dietary management and medical treatment to control symptoms and prevent complications.
This document summarizes the metabolism of branched chain amino acids (BCAAs) - valine, isoleucine, and leucine. It discusses that the initial reactions in BCAA catabolism are common, involving transamination, oxidative decarboxylation, and dehydrogenation to form acyl-CoA derivatives. It then explains that the subsequent catabolism of each BCAA differs and leads to the formation of acetyl-CoA and succinyl-CoA. One key point is that defects in BCAA catabolism can cause metabolic disorders like maple syrup urine disease, where the branch chain keto acid dehydrogenase enzyme is deficient.
This document summarizes various metabolic pathways including glycolysis, fatty acid oxidation, amino acid degradation, the citric acid cycle, oxidative phosphorylation, the hexose monophosphate shunt, gluconeogenesis, and glycogen metabolism. It also describes how these pathways are regulated and integrated in the liver, adipose tissue, skeletal muscle, and brain in both the fed and starved states to meet energy demands and fuel needs of the body.
GLYCOGEN STORAGE DISEASE , GSD , Von Gierke DiseaseRAHUL KATARIA
Detailed presentation about glycogen storage disease.
description about all types of GSDs like .
1. GSD I
2.GSD III
3. GSD IV
4. GSD VI
5. GSD IX
6. GSD 0
The document summarizes the digestion and absorption of proteins in the human body. Dietary and endogenous proteins are broken down through digestion by enzymes in the stomach, pancreas, and intestines. In the stomach, pepsin digests proteins into proteoses and peptones. The pancreas secretes trypsin, chymotrypsin, and other enzymes as zymogens which are activated and further break down proteins. In the intestines, aminopeptidases and dipeptidases break down peptides into amino acids, which are then absorbed into the bloodstream through active transport mechanisms.
Cholesterol is a lipid that plays several important roles in the body. It is synthesized primarily in the liver from acetyl-CoA and can also be obtained through diet. Cholesterol synthesis is a multi-step process regulated by the enzyme HMG-CoA reductase. High levels of cholesterol in the bloodstream, especially LDL cholesterol, increase the risk of cardiovascular disease. The body maintains cholesterol homeostasis through mechanisms like reverse cholesterol transport that move cholesterol from tissues back to the liver.
Cholesterol is one of the most studied molecules in biology. It plays essential roles in animal cell membranes and is a precursor for bile acids, steroid hormones, and vitamin D. Cholesterol is synthesized endogenously through a complex multi-step process and is also obtained through diet. High levels of cholesterol are linked to atherosclerosis and heart disease, while adequate levels are important for various biological functions. Tight regulation of cholesterol homeostasis is necessary for health.
This document summarizes key information about the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It discusses that they are essential amino acids whose metabolism begins in muscle tissue. The first three reactions - transamination, oxidative decarboxylation, and dehydrogenation - are common to all three amino acids. Conditions like maple syrup urine disease and isovaleric acidemia occur due to defects in later steps of this metabolic pathway.
This document discusses several inherited metabolic disorders involving amino acid metabolism. Phenylketonuria is described as the most common disorder, caused by a deficiency of the enzyme phenylalanine hydroxylase, leading to toxic accumulation of phenylalanine. Maple syrup urine disease results from a defect in the enzyme branched-chain keto acid dehydrogenase, causing a buildup of leucine, isoleucine, and valine breakdown products. Homocystinuria is caused by a cystathionine beta-synthase deficiency, preventing the breakdown of homocysteine. These disorders are typically detected via newborn screening and require dietary modifications and supplements to prevent associated complications.
Disorders of protein metabolism were presented. Key points included:
- Protein energy malnutrition (PEM) was discussed, including kwashiorkor caused by insufficient protein intake and marasmus caused by total starvation. Symptoms and treatments were described.
- Amyloidosis is caused by misfolded proteins depositing in tissues. It was classified and systemic, hereditary, and localized forms were outlined. Oral manifestations can include enlarged tongue or palatal nodules. Diagnosis involves biopsy and Congo red staining.
- Gout is caused by uric acid crystal deposition in joints due to diminished renal excretion or increased intake of purines. It commonly affects men and risk increases with age and weight. Sympt
This document discusses intermediary carbohydrate metabolism, specifically glycolysis. It begins with an introduction to glycolysis, noting that it is the degradation of glucose into pyruvate through a series of 10 enzyme-catalyzed reactions. These reactions can occur aerobically, producing pyruvate, or anaerobically, producing lactate. The document then delves into the specific reactions, enzymes, and intermediates involved in both the preparatory and payoff phases of glycolysis. It also discusses the importance of 2,3-bisphosphoglycerate in red blood cells for regulating oxygen release from hemoglobin.
Metabolic Disorders of Phenylalanine and TyrosineAshok Katta
Phenylketonuria is caused by a defect in the enzyme phenylalanine hydroxylase, leading to accumulation of phenylalanine. If untreated, it can cause intellectual disability, seizures, and other issues. Tyrosinemia type II results from a defect in tyrosine transaminase, causing tyrosine and metabolite buildup. Neonatal tyrosinemia is temporary and responds to vitamin C. Alkaptonuria is caused by homogentisate oxidase deficiency, allowing homogentisate to accumulate and be excreted in urine, potentially causing joint and organ problems. Tyrosinemia type I involves fumarylacetoacetate hydroxylase deficiency, which can lead to
This document summarizes the structures, metabolism, and roles of phenylalanine and tyrosine. It discusses how phenylalanine is converted to tyrosine in the liver by the enzyme phenylalanine hydroxylase. Tyrosine can then be used to synthesize important compounds like thyroid hormones, melanin, and catecholamines. The document also outlines several disorders related to phenylalanine and tyrosine metabolism, including phenylketonuria, tyrosinemia, alkaptonuria, and albinism.
This document provides information about lipids. It begins by classifying lipids into simple lipids, conjugated lipids, and derived lipids. The main types of fatty acids and phospholipids are described. Key points include that omega-3 fatty acids have anti-inflammatory properties, and phospholipids like phosphatidylcholine are major components of cell membranes. Disorders associated with abnormalities in sphingolipid metabolism are also listed. The document concludes by explaining the different types of lipoproteins, including their composition, origin, and function in transporting lipids between tissues.
This document discusses nutrition support for various inborn errors of protein metabolism, including amino acid disorders and organic acid disorders. Key points include:
- Treatment involves restricting intake of specific amino acids or proteins to reduce toxic metabolite buildup, while providing adequate nutrition for growth. Formula supplementation provides most protein/nutrients.
- Requirements for disorders like PKU, MSUD, and others vary by age but involve restricting intake of certain amino acids while meeting protein and calorie needs. Blood amino acid levels must be carefully monitored.
- Organic acid disorders also involve restricting intake of specific amino acids derived from lysine or tryptophan to control toxic metabolite levels while meeting nutritional needs. Early treatment is
METABOLIC DISORDERS OF PROTEIN AND LIPID( PART-I) /orthodontic courses by Ind...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
This document summarizes the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It describes how they are first transaminated to their corresponding keto acids, then undergo oxidative decarboxylation by alpha-keto acid dehydrogenase to form acyl-CoA thioesters. These are further dehydrogenated and enter different pathways, with valine being converted to propionyl-CoA and being glycogenic, leucine producing acetyl-CoA and acetoacetate and being ketogenic, and isoleucine undergoing both glycogenic and ketogenic fates. Defects in these pathways can cause diseases like maple syrup urine disease.
Amino acid metabolism disorders are hereditary metabolic disorders. Hereditary disorders occur when parents pass the defective genes that cause these disorders on to their children. Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing (metabolism) can result from defects either in the breakdown of amino acids or in the body’s ability to get amino acids into cells.
Inborn errors of metabolism
Definition:- Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally.
These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.
Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air.
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
Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.
Tyrosinemia is a rare genetic disorder that prevents the body from breaking down the amino acid tyrosine. There are two main types, type 1 and type 2. Type 1 is caused by a defect in the FAH enzyme and can cause liver and kidney damage if left untreated. Treatment involves medication to prevent damage and a low-protein diet that restricts tyrosine and phenylalanine intake. Type 2 is caused by a defect in the TAT enzyme and symptoms include eye and skin lesions as well as developmental delays. Both types require careful dietary management and medical treatment to control symptoms and prevent complications.
This document summarizes the metabolism of branched chain amino acids (BCAAs) - valine, isoleucine, and leucine. It discusses that the initial reactions in BCAA catabolism are common, involving transamination, oxidative decarboxylation, and dehydrogenation to form acyl-CoA derivatives. It then explains that the subsequent catabolism of each BCAA differs and leads to the formation of acetyl-CoA and succinyl-CoA. One key point is that defects in BCAA catabolism can cause metabolic disorders like maple syrup urine disease, where the branch chain keto acid dehydrogenase enzyme is deficient.
This document summarizes various metabolic pathways including glycolysis, fatty acid oxidation, amino acid degradation, the citric acid cycle, oxidative phosphorylation, the hexose monophosphate shunt, gluconeogenesis, and glycogen metabolism. It also describes how these pathways are regulated and integrated in the liver, adipose tissue, skeletal muscle, and brain in both the fed and starved states to meet energy demands and fuel needs of the body.
GLYCOGEN STORAGE DISEASE , GSD , Von Gierke DiseaseRAHUL KATARIA
Detailed presentation about glycogen storage disease.
description about all types of GSDs like .
1. GSD I
2.GSD III
3. GSD IV
4. GSD VI
5. GSD IX
6. GSD 0
The document summarizes the digestion and absorption of proteins in the human body. Dietary and endogenous proteins are broken down through digestion by enzymes in the stomach, pancreas, and intestines. In the stomach, pepsin digests proteins into proteoses and peptones. The pancreas secretes trypsin, chymotrypsin, and other enzymes as zymogens which are activated and further break down proteins. In the intestines, aminopeptidases and dipeptidases break down peptides into amino acids, which are then absorbed into the bloodstream through active transport mechanisms.
Cholesterol is a lipid that plays several important roles in the body. It is synthesized primarily in the liver from acetyl-CoA and can also be obtained through diet. Cholesterol synthesis is a multi-step process regulated by the enzyme HMG-CoA reductase. High levels of cholesterol in the bloodstream, especially LDL cholesterol, increase the risk of cardiovascular disease. The body maintains cholesterol homeostasis through mechanisms like reverse cholesterol transport that move cholesterol from tissues back to the liver.
Cholesterol is one of the most studied molecules in biology. It plays essential roles in animal cell membranes and is a precursor for bile acids, steroid hormones, and vitamin D. Cholesterol is synthesized endogenously through a complex multi-step process and is also obtained through diet. High levels of cholesterol are linked to atherosclerosis and heart disease, while adequate levels are important for various biological functions. Tight regulation of cholesterol homeostasis is necessary for health.
This document summarizes key information about the metabolism of the branched chain amino acids valine, leucine, and isoleucine. It discusses that they are essential amino acids whose metabolism begins in muscle tissue. The first three reactions - transamination, oxidative decarboxylation, and dehydrogenation - are common to all three amino acids. Conditions like maple syrup urine disease and isovaleric acidemia occur due to defects in later steps of this metabolic pathway.
This document discusses several inherited metabolic disorders involving amino acid metabolism. Phenylketonuria is described as the most common disorder, caused by a deficiency of the enzyme phenylalanine hydroxylase, leading to toxic accumulation of phenylalanine. Maple syrup urine disease results from a defect in the enzyme branched-chain keto acid dehydrogenase, causing a buildup of leucine, isoleucine, and valine breakdown products. Homocystinuria is caused by a cystathionine beta-synthase deficiency, preventing the breakdown of homocysteine. These disorders are typically detected via newborn screening and require dietary modifications and supplements to prevent associated complications.
Disorders of protein metabolism were presented. Key points included:
- Protein energy malnutrition (PEM) was discussed, including kwashiorkor caused by insufficient protein intake and marasmus caused by total starvation. Symptoms and treatments were described.
- Amyloidosis is caused by misfolded proteins depositing in tissues. It was classified and systemic, hereditary, and localized forms were outlined. Oral manifestations can include enlarged tongue or palatal nodules. Diagnosis involves biopsy and Congo red staining.
- Gout is caused by uric acid crystal deposition in joints due to diminished renal excretion or increased intake of purines. It commonly affects men and risk increases with age and weight. Sympt
This document discusses intermediary carbohydrate metabolism, specifically glycolysis. It begins with an introduction to glycolysis, noting that it is the degradation of glucose into pyruvate through a series of 10 enzyme-catalyzed reactions. These reactions can occur aerobically, producing pyruvate, or anaerobically, producing lactate. The document then delves into the specific reactions, enzymes, and intermediates involved in both the preparatory and payoff phases of glycolysis. It also discusses the importance of 2,3-bisphosphoglycerate in red blood cells for regulating oxygen release from hemoglobin.
Metabolic Disorders of Phenylalanine and TyrosineAshok Katta
Phenylketonuria is caused by a defect in the enzyme phenylalanine hydroxylase, leading to accumulation of phenylalanine. If untreated, it can cause intellectual disability, seizures, and other issues. Tyrosinemia type II results from a defect in tyrosine transaminase, causing tyrosine and metabolite buildup. Neonatal tyrosinemia is temporary and responds to vitamin C. Alkaptonuria is caused by homogentisate oxidase deficiency, allowing homogentisate to accumulate and be excreted in urine, potentially causing joint and organ problems. Tyrosinemia type I involves fumarylacetoacetate hydroxylase deficiency, which can lead to
This document summarizes the structures, metabolism, and roles of phenylalanine and tyrosine. It discusses how phenylalanine is converted to tyrosine in the liver by the enzyme phenylalanine hydroxylase. Tyrosine can then be used to synthesize important compounds like thyroid hormones, melanin, and catecholamines. The document also outlines several disorders related to phenylalanine and tyrosine metabolism, including phenylketonuria, tyrosinemia, alkaptonuria, and albinism.
This document provides information about lipids. It begins by classifying lipids into simple lipids, conjugated lipids, and derived lipids. The main types of fatty acids and phospholipids are described. Key points include that omega-3 fatty acids have anti-inflammatory properties, and phospholipids like phosphatidylcholine are major components of cell membranes. Disorders associated with abnormalities in sphingolipid metabolism are also listed. The document concludes by explaining the different types of lipoproteins, including their composition, origin, and function in transporting lipids between tissues.
This document discusses nutrition support for various inborn errors of protein metabolism, including amino acid disorders and organic acid disorders. Key points include:
- Treatment involves restricting intake of specific amino acids or proteins to reduce toxic metabolite buildup, while providing adequate nutrition for growth. Formula supplementation provides most protein/nutrients.
- Requirements for disorders like PKU, MSUD, and others vary by age but involve restricting intake of certain amino acids while meeting protein and calorie needs. Blood amino acid levels must be carefully monitored.
- Organic acid disorders also involve restricting intake of specific amino acids derived from lysine or tryptophan to control toxic metabolite levels while meeting nutritional needs. Early treatment is
METABOLIC DISORDERS OF PROTEIN AND LIPID( PART-I) /orthodontic courses by Ind...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
METABOLIC DISORDERS OF PROTEIN AND LIPID part 2/endodontic coursesIndian dental academy
This document discusses metabolic disorders of protein and lipid, focusing on amyloidosis and porphyria. It begins by outlining the learning objectives of describing protein and lipid sources and functions, and metabolic disorders associated with them. Amyloidosis is described as the abnormal deposition of amyloid protein between cells. There are different types including primary, secondary to other diseases, familial, and hormone-related amyloidosis. Porphyria refers to overproduction of porphyrins and can be erythropoietic or hepatic in origin. Clinical features, histopathology, treatment and prognosis are discussed for both conditions.
Hello friends ,this presentation is all about ketone bodies .this will help you to understand what are ketone bodies and their functioning .it will benefit specially bpharmacy students.
It is a metabolic disorder characterized by decreased ability or total in ability of the tissues to utilize CHO(glucose). This results in shifts and disturbances in the fat and protein metabolism and in water and electrolyte balance. This disorder is due to absence to insulin, its deficiency or ineffectiveness – the hormone is produced by the beta cells of islet of langerhans in the pancreas. For More health tips visit at http://gisurgery.info/player_presentation.php?id=87
METABOLIC DISORDERS OF PROTEIN AND LIPID-PART III / oral surgery courses Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
DNA chips, also known as microarrays, contain thousands of genes arranged on a small chip. Each gene occupies its own spot on the chip. By introducing genetic samples onto the chip, researchers can determine which genes are most active and gain insights into how genetics affect traits and diseases. Emerging nanotechnologies allow the creation of even smaller DNA chips with higher resolution using techniques like dip pen nanolithography and electrochemical sensing. These nano-scale DNA chips have the potential to revolutionize the study of genomics and functional genomics.
A balance disorder is a condition that makes you feel unsteady or dizzy, as if you are moving, spinning, or floating, even though you are standing still or lying down. Balance disorders can be caused by certain health conditions, medications, or a problem in the inner ear or the brain.
Genetic diversity in cheetahs is extremely low due to a population bottleneck that occurred around 10,000 years ago. As a result, cheetahs exhibit only about 1% genetic variation compared to 80% seen in most other mammal species. This low genetic diversity makes cheetahs vulnerable to diseases and reduces reproductive success. Conservation efforts focus on protecting cheetah habitats from loss and educating local communities on coexisting with cheetahs to help increase and preserve wild cheetah populations.
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.
This document provides an overview of DNA microarrays (DNA chips). It discusses that DNA chips allow scientists to simultaneously measure gene expression levels or genotype multiple genomic regions. It describes the principle technologies used in DNA chips, including attaching cDNA or oligonucleotide probes to glass or silicon surfaces. The document also provides background on DNA and microarrays, their history, applications in gene expression analysis and disease research, and principle of hybridization. It discusses alternative bead-based array technologies and how microarrays enabled large-scale genomic experiments.
Genetic diversity is the variation of genes within and between populations of a species. It is important for species survival and adaptability. Loss of genetic diversity reduces a species' ability to adapt to environmental changes and increases risks of inbreeding, which can lead to extinction. Key causes of loss of diversity include habitat loss and degradation, pollution, monocultures in agriculture that replace diverse landraces and varieties, and overexploitation of wild species. Conservation aims to preserve natural patterns of genetic diversity to maintain options for future evolution. Loss of genetic diversity is potentially the most serious environmental problem because it cannot be reversed within just a few generations.
This document provides an overview of DNA microarrays, also known as DNA chips. It discusses the principles and techniques used to prepare DNA microarrays, including photolithography. There are two main types of DNA chips: cDNA-based chips and oligonucleotide-based chips. DNA microarrays have various applications, including gene expression profiling, drug discovery, and diagnostics. They provide the advantage of analyzing thousands of genes simultaneously but also have disadvantages such as high costs and complex data analysis.
This document discusses approach to inborn errors of metabolism. It begins with objectives of understanding normal metabolism, metabolic diseases, frequency and causes of inborn errors of metabolism (IEM). It describes how to recognize IEM in neonates with non-specific signs and symptoms, and how to use simple lab tests in diagnosis. It also covers initial management of life-threatening IEM conditions. The document defines IEM and discusses pathophysiology. It describes clinical presentations of IEM including acute life-threatening illness and pointers to specific IEM based on symptoms. Laboratory evaluation for IEM is also outlined.
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
The document contains a case study of a 29-year-old man presenting with chills and breathing difficulty who is diagnosed with HIV infection based on his history of drug abuse, weight loss, lymphadenopathy, and presence of Kaposi's sarcoma and Pneumocystis pneumonia. It also includes questions about liposomes, collagen, sickle cell anemia, oculo-cutaneous albinism, marasmus, statins, acute intermittent porphyria, megaloblastic anemia, phenylketonuria, and essential amino acids.
Inborn errors of metabolism are a group of genetic disorders caused by defects in metabolic pathways. There are over 300 known types. They are classified into categories based on the systems affected and biochemical basis. Common presentations include metabolic acidosis, hypoglycemia, and developmental delays. Treatment aims to prevent toxic metabolite accumulation and correct abnormalities through dietary management and supportive care. Examples discussed include phenylketonuria, galactosemia, maple syrup urine disease, and lysosomal storage disorders. Newborn screening allows for early detection and intervention.
Maple syrup urine disease (MSUD) is caused by a defect in the branched-chain alpha-ketoacid dehydrogenase complex, leading to a buildup of the branched-chain amino acids leucine, isoleucine, and valine. Left untreated, this can cause neurological issues such as developmental delays. Jakob was diagnosed with MSUD as an infant after presenting with irritability and poor feeding. His family found dietary management stressful and he underwent a successful liver transplant at age 4 to provide an alternative source of the defective enzyme, allowing him to discontinue treatment.
This document provides an overview of inborn errors of metabolism (IEM). It defines IEM as genetic disorders affecting biochemical pathways. The document classifies IEM into 3 main categories: intoxication disorders involving toxic metabolite accumulation, energy metabolism defects, and disorders of complex molecules/organelles. Symptoms of acute and chronic presentation are described. The document outlines diagnostic testing including blood/urine screens and specialized tests. Principles of management are discussed including supportive care. Specific clinical manifestations involving the neurological, hepatic, cardiac and ocular systems are also reviewed.
1. Inborn errors of metabolism are genetic diseases caused by mutations that result in abnormalities in protein, carbohydrate, or fat metabolism.
2. They are usually inherited in an autosomal recessive pattern and can present from birth through adulthood depending on severity.
3. Symptoms vary widely but may include developmental delay, seizures, vomiting, hypoglycemia, liver disease, or other nonspecific findings.
PROTEIN MISFOLDING AND DISEASES ASSOCIATED WITH THEMNaveenKumar654405
This document discusses protein misfolding and diseases associated with misfolded proteins. It begins with an introduction to protein folding and reasons why proteins may misfold. Key points include that protein folding is influenced by mutations and external factors. Diseases caused by misfolded proteins are mentioned, such as Alzheimer's and Parkinson's disease. Therapeutic approaches aim to inhibit aggregation, interfere with post-translational changes, and upregulate molecular chaperones. Issues to resolve include developing tools to predict folding effects and determining the balance between protein elimination and accumulation. The conclusion emphasizes ongoing research to understand protein misfolding mechanisms and develop novel therapies.
Here are the key ways that lysosomes can cause disease:
1. Lysosomal storage disorders: These occur due to defects in lysosomal enzymes or transport proteins that are responsible for breaking down macromolecules. This causes substrates to accumulate within lysosomes, leading to cellular dysfunction. Over 100 lysosomal storage disorders have been identified.
2. Impaired autophagy: Lysosomes play a key role in autophagy, the process by which cells break down and recycle damaged organelles and proteins. Defects in autophagy-lysosomal pathways have been linked to neurodegenerative diseases, myopathies, cancers and other disorders.
3. Sphingolipid storage diseases: These
Metabolic disorders are caused by defects in enzymes involved in metabolic processes. There are several categories of inborn errors of metabolism including disorders of amino acid, carbohydrate, lipid, protein, and organic acid metabolism. Symptoms vary depending on the specific enzyme deficiency but can include developmental delay, organomegaly, neurological symptoms, and in some cases death in infancy if left untreated. Many metabolic disorders are inherited in an autosomal recessive pattern and while individually rare, as a group they have a prevalence of around 1 in 5,000 live births.
Prof. Dr. Vladimir Trajkovski was key note speaker at ReAttach conference in Eindhoven, Holland. He presented this topic: Medical aspects of Autism Spectrum Disorders
The document summarizes cellular adaptation and injury. It states that cells can undergo adaptation to achieve a new steady state and preserve viability when faced with physiological stresses, but severe or persistent stress can lead to reversible or irreversible injury. It describes different types of cellular adaptation like atrophy, hypertrophy, hyperplasia and metaplasia. It also discusses various causes of cellular injury like hypoxia, chemicals, infections and genetic factors. The key mechanisms of injury involve defects in membranes, ATP production and protein/DNA integrity.
The document describes four cases of hyperphenylalaninemia and phenylketonuria (PKU). PKU is caused by a defect in the metabolism of phenylalanine, an essential amino acid. If left untreated, high levels of phenylalanine can lead to intellectual disability, behavioral problems, seizures, and other neurological issues. The cases illustrate both treated and untreated individuals with signs and symptoms of the disorder.
This document provides an overview of biochemical investigation and diagnosis of inborn errors of metabolism (IEM) that present with adult-onset neurological disease. It discusses the types of IEM that can present in adulthood, including lysosomal storage diseases, peroxisomal disorders, mitochondrial disorders, urea cycle disorders, and organic acidurias. It describes appropriate first-line biochemical tests for these disorders, including tests of intermediary metabolism, peroxisomal function, and lysosomal function. It emphasizes the importance of obtaining samples during acute attacks or illnesses when symptoms are present. The document also notes that some IEM diagnosed in childhood may only be recognized as causing neurological problems in adulthood.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
1) The woman is experiencing acute pain in her right upper quadrant, suggesting a problem with her liver or gallbladder.
2) Her obesity puts her at higher risk for gallstones.
3) Gallstones blocking the cystic duct would cause her symptoms of acute pain in the right upper quadrant.
The most likely diagnosis is that she has developed gallstones causing cholecystitis (gallbladder inflammation).
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunctionmitoaction
This document summarizes a presentation by Dr. Richard E. Frye on mitochondrial dysfunction in neurodevelopmental disorders and autism. The presentation covers:
- Evidence that mitochondrial dysfunction is involved in many diseases and now believed to be important in autism based on studies showing abnormalities in electron transport chain complexes in autistic children.
- Further studies demonstrating differences in mitochondrial reserve capacity between autistic children and controls, and associations with environmental exposures like air pollution.
- Research into mechanisms of dysfunction including effects of the gut microbiome, genes, and potential treatments like mitochondrial cocktails.
ENZYMES INHERITED ENZYMOPATHIES. APPLICATION OF ENZYME IN THE TREATMENT OF DI...Dr. Hament Sharma
This document discusses enzymopathies, which are hereditary diseases caused by errors in metabolism resulting from enzyme disorders. Specific examples of enzymopathies are provided, such as those affecting the metabolism of carbohydrates, fats, and amino acids. Inborn errors of metabolism are genetic disorders caused by defects in enzymes involved in biochemical pathways that break down food. Metabolic diseases can present in neonates as acute life-threatening illnesses or cause neurological deterioration if left untreated. Treatment options discussed include dietary restrictions, enzyme replacement therapy, and gene therapy.
This document discusses several types of metabolic diseases including diabetes mellitus, Gaucher's disease, mitochondrial disease, Niemann-Pick disease, hemochromatosis, phenylketonuria, and their pathogenesis, clinical manifestations, and treatment modalities. It provides details on the different types of each disease, how they develop at the genetic and cellular levels, their signs and symptoms, methods of diagnosis, and approaches to management. The document aims to comprehensively cover the key aspects of these inherited metabolic disorders through contributions from expert medical students.
The document discusses the urea cycle and its role in removing toxic ammonia from the body. The urea cycle occurs primarily in the liver and involves several steps to convert ammonia and carbon dioxide into urea, which is excreted in urine. First, carbamoyl phosphate is formed in the mitochondria using ammonia, bicarbonate, and ATP. Carbamoyl phosphate then reacts with ornithine to form citrulline. Further reactions involving aspartate, ATP hydrolysis, and other enzymes ultimately yield arginine and then urea, which is excreted, along with regenerated ornithine to continue the cycle. Defects in this cycle can cause toxic hyperammonemia in
Enzyme-Linked ImmunoSorbent Assay, or ELISA, is a biochemical technique used mainly in immunology to detect the presence of an antibody or an antigen in a sample. The ELISA has been used as a diagnostic tool in medicine and plant pathology, as well as a quality control check in various industries. In simple terms, in ELISA an unknown amount of antigen is affixed to a surface, and then a specific antibody is washed over the surface so that it can bind the antigen. This antibody is linked to an enzyme, and in the final step a substance is added that the enzyme can convert to some detectable signal.
The document discusses the biological functions of zinc. It begins with an introduction to zinc, including its history of use in ancient India and its discovery in 1746. The document then outlines topics to be covered, including sources of zinc, requirements and homeostasis, deficiency and toxicity, biochemical and molecular functions, and immunological and endocrinological roles. It proceeds to cover these topics in depth over several slides, focusing on zinc absorption, transport, regulation, storage, and distribution within the body and cells.
The document discusses cadmium metabolism and pathogenesis effects. It provides an overview of cadmium, including its discovery, properties, sources of exposure, and industrial applications. Regarding pharmacokinetics, it notes that cadmium is absorbed through inhalation from sources like smoking or smelters (15-50% absorption) and ingestion mainly through foods like meats (6% absorption). Once absorbed, cadmium binds to proteins like albumin and metallothionein and is transported primarily to the liver and kidneys, where 50-75% of the total body burden accumulates over time.
The effects of a deficiency of one vitamin would not ordinarily be expected to be highly dependent on the presence or absence of another vitamin in the diet, since the symptoms of deficiency of each vitamin are usually quite distinct. Nevertheless, antagonistic or synergistic interactions between vitamins may occur to a greater or less extent. While several mechanisms can be proposed whereby vitamins can be synergistic, it is more difficult to conceive of one which could explain vitamin antagonism.
Vitamins and Anemia:
Your body needs vitamins ( nutrients found in most foods) for many reasons, including producing healthy red blood cells. If your body is deficient in certain key vitamins, you can develop a type of anemia ( a condition in which your blood is low on healthy red blood cells ) called vitamin deficiency anemia.
Red blood cells carry oxygen from your lungs to all parts of your body. Without enough healthy red blood cells, your body can't get the oxygen it needs to feel energized. To produce red blood cells, your body needs iron and certain vitamins along with adequate protein and calorie intake.
Vitamin deficiency anemia can also lead to other health problems. Fortunately, you can usually correct vitamin deficiency anemia with supplements and dietary changes.
DNA microarray:
A DNA microarray (also commonly known as gene or genome chip, DNA chip, or gene array) is a collection of microscopic DNA spots, commonly representing single genes, arrayed on a solid surface by covalent attachment to a chemical matrix. DNA arrays are different from other types of microarray only in that they either measure DNA or use DNA as part of its detection system. Qualitative or quantitative measurements with DNA microarrays utilize the selective nature of DNA-DNA or DNA-RNA hybridization under high-stringency conditions and fluorophore-based detection. DNA arrays are commonly used for expression profiling, i.e., monitoring expression levels of thousands of genes simultaneously.
Amniotic fluid surrounds the fetus during intrauterine development.
This fluid cushions the fetus against trauma, has antibacterial properties to lessen infections, and functions as a reservoir that may provide a short-term source of fluid and nutrients to the fetus.
Amniotic fluid are required for the fetal musculoskeletal system to develop normally, for gastrointestinal system development, and for the fetal lungs to develop.
This document provides an overview of RNA interference (RNAi) including its mechanism, applications, and methods for delivering small interfering RNA (siRNA). It discusses how dsRNA is processed by the enzyme Dicer into siRNAs which are incorporated into the RISC complex to degrade complementary mRNA. Viral vectors, liposomes, nanoparticles, and chemical modifications are described as methods used to deliver exogenous siRNAs. The document outlines both the therapeutic potential of RNAi and challenges associated with effective siRNA delivery.
Adipose tissue as an endocrine organ:
Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.
How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
Chapter wise All Notes of First year Basic Civil Engineering.pptxDenish Jangid
Chapter wise All Notes of First year Basic Civil Engineering
Syllabus
Chapter-1
Introduction to objective, scope and outcome the subject
Chapter 2
Introduction: Scope and Specialization of Civil Engineering, Role of civil Engineer in Society, Impact of infrastructural development on economy of country.
Chapter 3
Surveying: Object Principles & Types of Surveying; Site Plans, Plans & Maps; Scales & Unit of different Measurements.
Linear Measurements: Instruments used. Linear Measurement by Tape, Ranging out Survey Lines and overcoming Obstructions; Measurements on sloping ground; Tape corrections, conventional symbols. Angular Measurements: Instruments used; Introduction to Compass Surveying, Bearings and Longitude & Latitude of a Line, Introduction to total station.
Levelling: Instrument used Object of levelling, Methods of levelling in brief, and Contour maps.
Chapter 4
Buildings: Selection of site for Buildings, Layout of Building Plan, Types of buildings, Plinth area, carpet area, floor space index, Introduction to building byelaws, concept of sun light & ventilation. Components of Buildings & their functions, Basic concept of R.C.C., Introduction to types of foundation
Chapter 5
Transportation: Introduction to Transportation Engineering; Traffic and Road Safety: Types and Characteristics of Various Modes of Transportation; Various Road Traffic Signs, Causes of Accidents and Road Safety Measures.
Chapter 6
Environmental Engineering: Environmental Pollution, Environmental Acts and Regulations, Functional Concepts of Ecology, Basics of Species, Biodiversity, Ecosystem, Hydrological Cycle; Chemical Cycles: Carbon, Nitrogen & Phosphorus; Energy Flow in Ecosystems.
Water Pollution: Water Quality standards, Introduction to Treatment & Disposal of Waste Water. Reuse and Saving of Water, Rain Water Harvesting. Solid Waste Management: Classification of Solid Waste, Collection, Transportation and Disposal of Solid. Recycling of Solid Waste: Energy Recovery, Sanitary Landfill, On-Site Sanitation. Air & Noise Pollution: Primary and Secondary air pollutants, Harmful effects of Air Pollution, Control of Air Pollution. . Noise Pollution Harmful Effects of noise pollution, control of noise pollution, Global warming & Climate Change, Ozone depletion, Greenhouse effect
Text Books:
1. Palancharmy, Basic Civil Engineering, McGraw Hill publishers.
2. Satheesh Gopi, Basic Civil Engineering, Pearson Publishers.
3. Ketki Rangwala Dalal, Essentials of Civil Engineering, Charotar Publishing House.
4. BCP, Surveying volume 1
How to Fix the Import Error in the Odoo 17Celine George
An import error occurs when a program fails to import a module or library, disrupting its execution. In languages like Python, this issue arises when the specified module cannot be found or accessed, hindering the program's functionality. Resolving import errors is crucial for maintaining smooth software operation and uninterrupted development processes.
2. Clinical Biochemistry Metabolic Disorders of Proteins
What is a metabolic disease?
“Inborn errors of metabolism”
inborn error : an inherited (i.e. genetic)
disorder
metabolism : chemical or physical changes
in a biological system
June 26, 2012 Total slide. 132 2
3. Clinical Biochemistry Metabolic Disorders of Proteins
What is a metabolic disease?
Garrod’s hypothesis
A B Cproduct deficiency
substrate excess
D toxic metabolite
June 26, 2012 Total slide. 132 3
4. Clinical Biochemistry Metabolic Disorders of Proteins
What is a metabolic disease?
Small molecule disease Organelle disease
Carbohydrate Lysosomes
Protein Mitochondria
Lipid Peroxisomes
Nucleic Acids Cytoplasm
June 26, 2012 Total slide. 132 4
5. Clinical Biochemistry Metabolic Disorders of Proteins
How do metabolic diseases present
in the neonate ??
Acute life threatening illness
encephalopathy - lethargy, irritability, coma
vomiting
respiratory distress
Seizures, Hypertonia
Hepatomegaly (enlarged liver)
Hepatic dysfunction / jaundice
Odour, Dysmorphism, FTT (failure to thrive),
Hiccoughs
June 26, 2012 Total slide. 132 5
6. Clinical Biochemistry Metabolic Disorders of Proteins
How do you recognize a metabolic
disorder ??
Index of suspicion
eg “with any full-term infant who has no antecedent
maternal fever or PROM (premature rupture of the
membranes) and who is sick enough to warrant a blood
culture, one should proceed with a few simple lab tests.
Simple laboratory tests
Glucose, Electrolytes, Gas, Ketones, BUN (blood urea
nitrogen), Creatinine
Lactate, Ammonia, Bilirubin
Amino acids, Organic acids
June 26, 2012 Total slide. 132 6
7. Clinical Biochemistry Metabolic Disorders of Proteins
Inborn Errors of Metabolism
An inherited enzyme deficiency leading to the
disruption of normal bodily metabolism
Accumulation of a toxic substrate
(compound acted upon by an enzyme in a
chemical reaction)
Impaired formation of a product normally
produced by the deficient enzyme
June 26, 2012 Total slide. 132 7
8. Clinical Biochemistry Metabolic Disorders of Proteins
Three Types
Type 1: Silent Disorders
Type 2: Acute Metabolic Crises
Type 3: Neurological Deterioration
June 26, 2012 Total slide. 132 8
9. Clinical Biochemistry Metabolic Disorders of Proteins
Type 1: Silent Disorders
Do not manifest life-threatening crises
Untreated could lead to brain damage and
developmental disabilities
Example: PKU (Phenylketonuria)
June 26, 2012 Total slide. 132 9
10. Clinical Biochemistry Metabolic Disorders of Proteins
Type 2: Acute Metabolic Crisis
Life threatening in infancy
Children are protected in utero by maternal
circulation which provide missing product
or remove toxic substance
Example OTC (Urea Cycle Disorders)
June 26, 2012 Total slide. 132 10
11. Clinical Biochemistry Metabolic Disorders of Proteins
Type 3: Progressive Neurological
Deterioration
Examples: Tay Sachs disease
Gaucher disease
Metachromatic leukodystrophy
DNA analysis show: mutations
June 26, 2012 Total slide. 132 11
12. Clinical Biochemistry Metabolic Disorders of Proteins
Genetic Basis
of
Inherited Disorders
Point mutations,
Insertions, Deletions,
Missense Mutations
and Rearrangements
June 26, 2012 Total slide. 132 12
13. Clinical Biochemistry Metabolic Disorders of Proteins
Generalities of Inherited Disorders
Although each
individual IEM is rare,
cumulatively they occur
~ 1:5000 live births
Majority of IEM follow
an autosomal recessive
mode of inheritance
June 26, 2012 Total slide. 132 13
14. Clinical Biochemistry Metabolic Disorders of Proteins
Inborn Errors of Metabolism
Uneventful delivery
Normal birth weight
Non-dysmorphic (no physical findings)
Uneventful days /weeks
June 26, 2012 Total slide. 132 14
15. Clinical Biochemistry Metabolic Disorders of Proteins
Defective Proteins and Disease
Defects in Carbohydrate Metabolism
Defects in Cholesterol and Lipoprotein
Metabolism
Mucopolysaccharide and Glycolipid Disorders
Defects in Amino and Organic Acid Metabolism
Porphyrias and Bilirubinemias
Errors in Fatty Acid Metabolism
Defects in Nucleotide Metabolism
Disorders in Metal Metabolism and Transport
Defects in Peroxisomes
Diseases Associated with Defective DNA Repair
16. Clinical Biochemistry Metabolic Disorders of Proteins
Defective Proteins and Disease
Oxygen carrying proteins
Connective tisue proteins
Clotting factors
June 26, 2012 Total slide. 132 16
17. Clinical Biochemistry Metabolic Disorders of Proteins
Diseases Associated with
Oxygen Carrying Proteins
Sikle-Cell Anemia
B-Talassemia
A-Talassemia
June 26, 2012 Total slide. 132 17
18. Clinical Biochemistry Metabolic Disorders of Proteins
Diseases Associated with
Connective Tissue Proteins
Ehlers-Danlos Type I- Type VIII
Ehlers-Danlos with Platelet Dysfunction
Marfan's Syndrome
Cutis Laxa
Occipital Horn Syndrome Cutis Laxa, X-linked
Osteogenesis Imperfecta Type I
Osteogenesis Imperfecta Type I-C
Osteogenesis Imperfecta Silent Type II/III
Osteogenesis Imperfecta Type IV
Osteogenesis Imperfecta Neonatal Lethal form
Osteogenesis ImperfectaTotal slide. 132
June 26, 2012 progressively deforming 18
19. Clinical Biochemistry Metabolic Disorders of Proteins
Diseases Associated with
Clotting Factor Dysfunction
Afibrinogenemia complete loss of fibrinogen, Factor I
Dysfibrinogenemia dysfunctional fibrinogen, Factor I
Factor II Disorders
Factor III (tissue factor) is the only coagulation factor for which a congenital defect has not been
identified
Factor V Deficiency Labile Factor deficiency
Factor VII Deficiency
Hemophilia A Factor VIII deficiency
Hemophilia B Factor IX deficiency
Factor X Deficiency
Factor XI Deficiency Rosenthal Syndrome, Plasma Thromboplastin Antecedent (PTA) deficiency
Factor XII Deficiency Hageman factor deficiency
Factor XIII Deficiency
Factor V & VIII Combined Deficiency
Factor VIII & IX combined Deficiency
Factor IX & XI Combined Deficiency
Protein C Deficiency
Protein S Deficiency
Thrombophilia Antithrombin III deficiency
Giant Platelet Syndrome platelet glycoprotein Ib deficiency
von Willebrand Disease
June 26, 2012 Total slide. 132 19
Fletcher Factor Deficiency Prekallikrein deficiency
20. Clinical Biochemistry Metabolic Disorders of Proteins
Defects in Amino Acid Metabolism
Phenylketonuria
Type I Tyrosinemia - Tyrosinosis
Type II Tyrosinnemia - Richner-Hanhart Syndrome
Type III Tyrosinemia
Alcaptonuria
Homocystinuria
Histidinemia
Maple Syrup Urine Disease, MSUD
MSUD Type Ib
MSUD Type II
Methylmalonic Aciduria
Non-ketonic Hyperglycinemia Type I (NKHI)
Hyperlysinemia
June 26, 2012 Total slide. 132 20
21. Clinical Biochemistry Metabolic Disorders of Proteins
Syndrome 1
June 26, 2012 Total slide. 132 21
22. Clinical Biochemistry Metabolic Disorders of Proteins
Case 1
Patrick
Birth History: Full Term, 3,620 gm
Uncomplicated Pregnancy, Labor & Delivery
Mother 24 yr old, healthy
No Prenatal exposure to alcohol, drugs,
infection, known teratogens
Discharged home on day of life 2
June 26, 2012 Total slide. 132 22
23. Clinical Biochemistry Metabolic Disorders of Proteins
Case 1 (CONTINUED)
Developmental Hx Seizure History
Rolled over – 3 months First – 11 m
Social smile - 4 m Generalized, tonic/clonic
Stand alone – 14 m Total – 4 seizures
First word – 18 m MRI – decreased
grey/white differentiation
Phrases – not yet and cortical atrophy
Walk alone – 2 yr
June 26, 2012 Total slide. 132 23
24. Clinical Biochemistry Metabolic Disorders of Proteins
Case 1 (Cont)
Physical Exam
Growth
Blond hair, blue eyes
Non-dysmorphic child
Neurological exam:
Decreased tone, brisk reflexes
June 26, 2012 Total slide. 132 24
25. Clinical Biochemistry Metabolic Disorders of Proteins
Normal Patrick
• Abnormal high intensity signal in deep white matter
• Leucodystrophy and Cortical atrophy
June 26, 2012 Total slide. 132 25
26. Clinical Biochemistry Metabolic Disorders of Proteins
Case 2
Jeremy newborn male Mother - 19 yr old
Full Term: 3,100 gm First Pregnancy
Uncomplicated P,L & D Father -18 yr old
No perinatal infection, Healthy
no alcohol, no drugs, no
known teratogens
June 26, 2012 Total slide. 132 26
27. Clinical Biochemistry Metabolic Disorders of Proteins
Case 2
Physical Exam and Labs
Ht & Wt = 70% General exam normal
HC< 5% Neurological exam - normal
Urine Ferric Chloride (FeCl3) is positive
June 26, 2012 Total slide. 132 27
28. Clinical Biochemistry Metabolic Disorders of Proteins
Case 2
Jeremy is now 13
years old and exhibits
Persistent
microcephaly
Spasticity
Mental retardation
Coarctation of Aorta
June 26, 2012 Total slide. 132 28
29. Clinical Biochemistry Metabolic Disorders of Proteins
Case 3
Luis (8yo) referred to
Developmental
Pediatrics clinic
Chief Complaint:
Hyperactivity and
Learning Disabilities
Patient and his Brother
•Self selects diet
•low in meat, eggs, cheese
•enriched in fruits / vegetables
June 26, 2012 •Similar
Total slide. 132 pigmentation to his brother
29
30. Clinical Biochemistry Metabolic Disorders of Proteins
Case 4
Hannah: 6 month old female
Diagnosed with metabolic
disorder on abnormal newborn
metabolic screen
Normal growth / development
Normal physical exam
On treatment with metabolic
formula
June 26, 2012 Total slide. 132 30
31. Clinical Biochemistry Metabolic Disorders of Proteins
All four cases
Examples of hyperphenylalanemia
Defects in metabolism of phenylalanine
Prototype – PKU
Elevation of PHE > 20 mg/dl
Normal < 2 mg/dl
June 26, 2012 Total slide. 132 31
32. Clinical Biochemistry Metabolic Disorders of Proteins
PKU
Clinical Findings
Mousy or musty odor
Exzema
Fair coloring (decreased hair and skin
pigmentation)
Behavior Problems
Mental Retardation
Lose ~ 1 IQ point per week of non-treatment
June 26, 2012 Total slide. 132 32
33. Clinical Biochemistry Metabolic Disorders of Proteins
Phenylalanine Metabolism
Food Catabolism
Phenylalanine
PHE Essential AA
50% Body Protein
Major
TYR
interconversions
Melanin through tyrosine
DOPA
NE / EPI
June 26, 2012 Total slide. 132 33
34. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 34
35. Clinical Biochemistry Metabolic Disorders of Proteins
Conditionally
Essential AA
June 26, 2012 Total slide. 132 35
36. Clinical Biochemistry Metabolic Disorders of Proteins
Essential Amino Acids
Histidine
Isoleucine
Leucine
Lysine
Methionine (and/or cysteine)
Phenylalanine (and/or tyrosine)
Threonine
Tryptophan
Valine
June 26, 2012 Total slide. 132 36
37. Clinical Biochemistry Metabolic Disorders of Proteins
Urine
Alternate Disposal
Phenyl lactate
Phenylacetate
Phenylethylamine
Phenylacetyl glutamine
Mousy or musty
odor
June 26, 2012 Total slide. 132 37
38. Clinical Biochemistry Metabolic Disorders of Proteins
PKU
Autosomal Recessive disorder caused by
mutation in PAH gene
Newborn screening started in 1963
Incidence: 1 in 15,000
Subtypes and heterogeneity
Classic
Moderate and mild
Non-classical or non-PKU hyperphenylalaninemia
June 26, 2012 Total slide. 132 38
39. Clinical Biochemistry Metabolic Disorders of Proteins
PKU
Autosomal Recessive disorder caused by
mutation in PAH gene
Newborn screening started in 1963
Incidence: 1 in 15,000
Subtypes and heterogeneity
Classic
Moderate and mild
Non-classical or non-PKU hyperphenylalaninemia
% enzyme activity determines clinical severity
June 26, 2012 Total slide. 132 39
40. Clinical Biochemistry Metabolic Disorders of Proteins
PKU
Autosomal Recessive disorder caused by
mutation in PAH gene
Newborn screening started in 1963
Incidence: 1 in 15,000
Subtypes and heterogeneity
Classic (tolerate < 250mg phe/day)
Mild (tolerate 400-600mg phe/day)
Hyperphenylalaninemia (normal diet)
% enzyme activity determines clinical severity
June 26, 2012 Total slide. 132 40
41. Clinical Biochemistry Metabolic Disorders of Proteins
PKU
Autosomal Recessive disorder caused by
mutation in PAH gene
Newborn screening started in 1963
Incidence: 1 in 15,000
Subtypes and heterogeneity
Classic
Moderate Tetrahydrobiopterin (BH4) responsive
Mild Hyperphenylalaninemia
Hyperphe • Urine pterins
June 26, 2012 • blood dihydropteridine reductase 41
Total slide. 132
42. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 42
43. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 43
44. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 44
45. Clinical Biochemistry Metabolic Disorders of Proteins
BH4 Responders
PAH mutation
62% catalytic
21% regulatory
Allelic pattern
1 mild + 1 severe
2 mild
2 severe (rare)
Diet – BH4
without protein
restriction
June 26, 2012 Total slide. 132 45
46. Clinical Biochemistry Metabolic Disorders of Proteins
Biological Effects
HyperPhe inhibits transport of large, neutral AA
into the brain (as does Leucine)
Inhibition of protein and neurotransmitters
Deficiencies of dopamine, serotonin
June 26, 2012 Total slide. 132 46
47. Clinical Biochemistry Metabolic Disorders of Proteins
Major Neuropathologic changes
Hypomyelination (Phe-sensitive oligodendrocytes)
White matter degeneration (leucodystrophy)
Developmental delay/arrest cerebral cortex
Microcephaly
Mental retardation
Seizures
June 26, 2012 Total slide. 132 47
48. Clinical Biochemistry Metabolic Disorders of Proteins
Non-Neuro pathology
Hypomelanosis – Why ?
June 26, 2012 Total slide. 132 48
49. Clinical Biochemistry Metabolic Disorders of Proteins
Non-Neuro pathology
Hypomelanosis
Blond hair, blue eyes, pale
Deficient Tyrosine production (precursor of
Melanin)
Cardiac
Coarctation of the Aorta
June 26, 2012 Total slide. 132 49
50. Clinical Biochemistry Metabolic Disorders of Proteins
Maternal PKU syndrome
First mentioned in literature in 1937
First mentioned as a complication of PKU
in 1956
Women with MR and PKU has 3 children, all
retarded despite not having PKU
Microcephaly and cardiac defects reported
in 1960’s
1983 – MPKUCS begun
June 26, 2012 Total slide. 132 50
51. Clinical Biochemistry Metabolic Disorders of Proteins
Maternal PKU Collaborative Study
Untreated women
92% risk of mental retardation
73% risk of microcephaly
40% risk of low birth weight
12% risk of congenital heart disease
Reduced risk if maternal plasma phe levels are
normalized pre-conceptually
June 26, 2012 Total slide. 132 51
52. Clinical Biochemistry Metabolic Disorders of Proteins
Maternal PKU syndrome
Dose-Response Relationship
Goal: Phe level between 2-6 mg/dl by 8 weeks
June 26, 2012 Total slide. 132 52
53. Clinical Biochemistry Metabolic Disorders of Proteins
The longer it
takes to get Phe
level < 8 mg/dl
the lower the IQ
of the baby
June 26, 2012 Total slide. 132 53
54. Clinical Biochemistry Metabolic Disorders of Proteins
Balancing Metabolic Control
Exposure to Elimination
normal of PHE
PHE intake from the diet
June 26, 2012 Total slide. 132 54
55. Clinical Biochemistry Metabolic Disorders of Proteins
Balancing Metabolic Control
Exposure to normal PHE
intake:
Elevations of PHE
Elevations of PHE-ketones
Deficient TYR, DOPA,
NE, EPI
Mental retardation /
seizures
June 26, 2012 Total slide. 132 55
56. Clinical Biochemistry Metabolic Disorders of Proteins
Balancing Metabolic Control
Exposure to normal PHE
intake:
Elevations of PHE
Elevations of PHE-ketones
Deficient TYR, DOPA,
= Bad
NE, EPI
Mental retardation /
seizures
June 26, 2012 Total slide. 132 56
57. Clinical Biochemistry Metabolic Disorders of Proteins
Balancing Metabolic Control
Elimination of PHE
from the diet:
Decreases PHE
Decreases PHE-ketones
Deficient TYR, DOPA,
NE, EPI
DEATH from essential
AA deficiency
June 26, 2012 Total slide. 132 57
58. Clinical Biochemistry Metabolic Disorders of Proteins
Balancing Metabolic Control
Elimination of PHE
from the diet:
Decreases PHE
Decreases PHE-ketones
Bad =
Deficient TYR, DOPA,
NE, EPI
DEATH from essential
AA deficiency
June 26, 2012 Total slide. 132 58
59. Clinical Biochemistry Metabolic Disorders of Proteins
Optimal Therapy of PKU
Initiate treatment by 7 days of life
Phenylalanine levels
Age Level Freq of Testing
0-12 months 2-6 mg/dl 1x/week
1-12 years Same 2x/month
> 12 years 2-15 mg/dl 1x/month
Pregnancy 2-6 mg/dl* 2x/week
June 26, 2012 * 3m before conception
Total slide. 132 59
60. Clinical Biochemistry Metabolic Disorders of Proteins
summery
Hyperphenylalanemia Treatment is
An abnormal lab Effective if begun
finding early and continued
Several defects may for life
result in hyperphe
Aggressive
Specific Dx is critical management
PHE restriction in during growth and
BH4 deficiency is lethal during illness
June 26, 2012 Total slide. 132 60
61. Clinical Biochemistry Metabolic Disorders of Proteins
What about our cases??
Patrick – case 1 Jeremy – case 2
Dx ? Dx ?
3 yr old with Newborn with
developmental delay microcephaly and + FeCl3
and seizures…..
Now mentally retarded
Choices
2. Classic PKU – treated or untreated
3. Maternal PKU
4. Hyperphe
June 26, 2012 Total slide. 132 61
62. Clinical Biochemistry Metabolic Disorders of Proteins
What about our cases??
Patrick – case 1 Jeremy – case 2
Classic PKU (mod) Maternal PKU syndrome
Newborn with
3 yr old with microcephaly and + FeCl3
developmental delay Now mentally retarded
and seizures….. He is metabolically
Patrick has permanent normal… but his mother
disabilities had PKU
His mother wants more
children but is not on diet
June 26, 2012 Total slide. 132 62
63. Clinical Biochemistry Metabolic Disorders of Proteins
Our Cases
Luis - Case 3 Hannah - Case 4
Dx ? Dx ?
8yo with learning 6 month old
disability and Normal growth and
hyperactivity development
Choices
2. Classic PKU – treated or untreated
3. Maternal PKU
4. Hyperphe
June 26, 2012 Total slide. 132 63
64. Clinical Biochemistry Metabolic Disorders of Proteins
Our Cases
Luis - Case 3 Hannah - Case 4
Classic PKU (Mexico) Classic PKU, treated
On treatment Continues to do well
His hyperactivity has on therapy
improved Growth, development
He will not regain and intellectual
normal intellect situation are normal
June 26, 2012 Total slide. 132 64
65. Clinical Biochemistry Metabolic Disorders of Proteins
Syndrome 2
June 26, 2012 Total slide. 132 65
66. Clinical Biochemistry Metabolic Disorders of Proteins
Jakob
Jakob was the product of a full term
pregnancy
Appeared healthy until day of life nine
Hospitalized in ICU
At 9 months Jakob is developmentally
normal and growing well
However, some times his amino acid
levels are dramatically elevated.
June 26, 2012 Total slide. 132 66
67. Clinical Biochemistry Metabolic Disorders of Proteins
MSUD
What is MSUD ?
What odor was the physician asking mom about ?
Where else can you smell it ?
Is odor a reliable physical finding ?
What causes neurotoxicity ?
What is the long-term treatment and outcome ?
June 26, 2012 Total slide. 132 67
68. Clinical Biochemistry Metabolic Disorders of Proteins
MSUD
Autosomal Recessive
Mutations in branched chain α-ketoacid
dehydrogenase (BCKDH)
Mitochondrial enzyme complex
3 subunits (E1, E2, and E3) encoded by 4
unlinked genes
E1 decarboxylase – heterotetramer (α and β
subunits)
E2 transacylase
E3 dehydrogenase
E1 is thiamine dependent
June 26, 2012 Total slide. 132 68
69. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 69
70. Clinical Biochemistry Metabolic Disorders of Proteins
Maple Syrup Urine Disease
Classical
Normal newborn, hours to days
Poor feeding and drowsiness
metabolic acidosis, hypoglycemia, cerebral
edema, respiratory distress, hiccups, apnea,
bradycardia, hypothermia, coma
June 26, 2012 Total slide. 132 70
71. Clinical Biochemistry Metabolic Disorders of Proteins
Clinical Manifestations
Time Symptom/Sign
12-24 hours Maple syrup odor to cerumen
Elevated BCAA
2-3 days Irritability, poor feeding
Ketonuria
4-5 days Encephalopathy (lethargy,
apnea, atypical movements
7-10 days Coma and respiratory failure
June 26, 2012 Total slide. 132 71
72. Clinical Biochemistry Metabolic Disorders of Proteins
Metabolic Defect
BCAA amino-
transferases
BCKDH
- Rate limiting
June 26, 2012 Total slide. 132 72
73. Clinical Biochemistry Metabolic Disorders of Proteins
Branch Chain Amino Acids
Leucine, Isoleucine and Valine
Comprise ~40% of essential AA
During fasting, ~ 80% of AA released is
recycled back into protein synthesis
June 26, 2012 Total slide. 132 73
74. Clinical Biochemistry Metabolic Disorders of Proteins
Branch Chain Amino Acids
Transamination and oxidative disposal of leucine
occurs in skeletal muscle (50%), kidney (25%) and
gut/liver (25%)
Nitrogen released is used to form glutamate -> alanine -
> glucose (alanine aminotransferase reaction)
Leucine + α-Ketoglutarate -> α-Ketoisocaproate and Glutamate
Glutamate and Pyruvate -> α-Ketoglutarate and Alanine
Alanine -> -> -> Glucose
June 26, 2012 Total slide. 132 74
75. Clinical Biochemistry Metabolic Disorders of Proteins
Branch Chain Amino Acids
Increase in supply from diet or proteolysis
must be met with appropriate increase in
anabolic pathway (blocked in disorder)
Most severe biochemical intoxication caused by
catabolism of endogenous protein
June 26, 2012 Total slide. 132 75
76. Clinical Biochemistry Metabolic Disorders of Proteins
Branch Chain Amino Acids
Defect leads to elevated levels, more
pronounced in infants and children due to
enhanced rates of growth
Leucine accumulation is most toxic
June 26, 2012 Total slide. 132 76
77. Clinical Biochemistry Metabolic Disorders of Proteins
Signs/Symptoms of Acute Toxicity
Ataxia (unsteady, clumsy movements)
Acute dystonia (involuntary muscle contractions)
Mood swings
Nausea, Vomiting, and Anorexia
Hallucinations
Altered level of consciousness
Stroke, coma, and death
June 26, 2012 Total slide. 132 77
78. Clinical Biochemistry Metabolic Disorders of Proteins
Signs/Symptoms of Chronic Toxicity
Mood Disorders – anxiety and depression
Mental retardation
Neurologic deficits (stroke)
June 26, 2012 Total slide. 132 78
79. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
• Leucine and KIC intracellular
accumulation results in cellular edema
June 26, 2012 Total slide. 132 79
80. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Leucine and KIC intracellular accumulation
results in cellular edema
Leucine accumulation inhibits entry of other
large neutral amino acids
June 26, 2012 Total slide. 132 80
81. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
• Leucine and KIC
intracellular accumulation
results in cellular edema
• Leucine accumulation
inhibits entry of other large
neutral amino acids
Disrupted monoamine
transmitter production
Decreased ‘fast’ neurotransmitter pools – glutamate,
GABA, aspartate
June 26, 2012 Total slide. 132 81
82. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Leucine and KIC intracellular accumulation
results in cellular edema
Leucine accumulation inhibits entry of other
large neutral amino acids
Metabolites (KIC) induce oxidative injury
Melatonin, Vitamins C and E may be protective
June 26, 2012 Total slide. 132 82
83. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
1. Excess KIC results in consumption of substrates needed
for malate-aspartate shuttle resulting in increased brain
lactate and energy failure
June 26, 2012 Total slide. 132 83
84. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
KIC + glutamate Leucine + α-Ketoglutarate
Increased Aspartate utilization
Decreased functioning of malate-aspartate shuttle
Decreased transfer of reducing equivalent
Energy failure And lactic acidosis
June 26, 2012 Total slide. 132 84
85. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Glutamic Acid is a critical excitatory
neurotransmitter
Leucine is trafficked to the brain as a source
of –NH2 groups (Leucine-Glutamate cycle)
June 26, 2012 Total slide. 132 85
86. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Elevated Leucine
Accumulation of KIC
drives leucine-glutamate cycle in reverse direction
LEU decreased brain glutamate
2-ketoisocaproate
Isovaleryl-CoA
June 26, 2012 Total slide. 132 86
87. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Elevated Leucine
Altered brain water homeostasis
cell edema
June 26, 2012 Total slide. 132 87
88. Clinical Biochemistry Metabolic Disorders of Proteins
Neurotoxicity of Leucine
Elevated Leucine
Inhibits entry into the brain of other large,
neutral AA (as in PKU) phenylalanine, tryptophane, methionine,
tyrosine,histidine, threonine, and BCAA (L1-NAA-t)
Dystonia and ataxia may arise from acute deficiency of
tyrosine and dopamine
Decreased dendritic branching, hypomyelination
June 26, 2012 Total slide. 132 88
89. Clinical Biochemistry Metabolic Disorders of Proteins
MSUD
Goals of Treatment
Restriction of Leucine, Isoleucine, and Valine to
maintain post-prandial plasma BCAA near
normal level
Supplement free valine and isoleucine
Give glutamine and alanine
Hemodialysis
June 26, 2012 Total slide. 132 89
90. Clinical Biochemistry Metabolic Disorders of Proteins
MSUD
Goals of Treatment
Excessive restriction
Growth failure
Anemia
Breakdown of mucosa
Immunodeficiency
Dysmyelination, abnormal dendritic branching,
microcephaly and mental retardation
June 26, 2012 Total slide. 132 90
91. Clinical Biochemistry Metabolic Disorders of Proteins
Follow-Up Jacob – Age 4 yr
Family unwilling to tolerate
Continual stress of life threatening disorder
dietary management, forcing feeds by G-tube when
not interested in eating)
Severe limitations on their lives
June 26, 2012 Total slide. 132 91
92. Clinical Biochemistry Metabolic Disorders of Proteins
Liver Transplantation
Liver transplantation results in increase in
whole body BCKD activity
Muscle = 50%
Kidney = 25%
Liver and gut = 25%
Placed on liver transplant list at Pittsburgh
and underwent successful liver transplant 3
years ago
Now on unrestricted diet
June 26, 2012 Total slide. 132 92
93. Clinical Biochemistry Metabolic Disorders of Proteins
Jacop after liver transplantation
June 26, 2012 Total slide. 132 93
94. Clinical Biochemistry Metabolic Disorders of Proteins
Liver Transplant:
Outcomes
Normalization of
BCAA within 6-12
hours
Sustained
normalization of
BCAA on
unrestricted diet
(4-18 months f/u)
June 26, 2012 Total slide. 132 94
Strauss KA. Am J Transpl; 2006
95. Clinical Biochemistry Metabolic Disorders of Proteins
Alkaptonuria
Alkaptonuria: a.k.a. Black Urine Disease
First recognized “Inborn Error of Metabolism”
by Archibald Garrod in 1902
Symptoms: Homogentisate in the urine oxidizes to a
black color
Also, black deposits in the sclera
In adults, accumulation of deposits
in connective tissue leads to arthritis
No effective treatment
June 26, 2012 Total slide. 132 95
96. Clinical Biochemistry Metabolic Disorders of Proteins
Symptoms of alkaptonuria
Urine from patients
Normal urine with alkaptonuria
June 26, 2012 Total slide. 132 96
97. Clinical Biochemistry Metabolic Disorders of Proteins
Patients may display painless bluish darkening of the outer ears,
nose and whites of the eyes. Longer term arthritis often occurs.
June 26, 2012 Total slide. 132 97
98. Clinical Biochemistry Metabolic Disorders of Proteins
Homogentisic acid is an intermediate in the degradation pathway of
phenylalanine. The reaction is catalysed by homogentisate dioxygenase
(HGO).
homogentisic acid
OH
O O
HOOC C C
CH CH CH2 CH2 COOH
OH
HGO maleylacetoacetic acid
CH2
COOH
A deficiency of HGO causes
alkaptonuria.
June 26, 2012 Total slide. 132 98
99. Clinical Biochemistry Metabolic Disorders of Proteins
Catabolic pathway for phenylalanine and
tyrosine
Defect here causes Homogentisate
dioxygenase
alkaptonuria
Defect here causes Fumarylacetoacetate
Type I Tyrosinemia hydrolase
June 26, 2012 Total slide. 132 99
100. Clinical Biochemistry Metabolic Disorders of Proteins
Tyrosinemia
Tyrosinemia is diagnosed by a blood and urine test.
Tyrosinemia is treated by a low protein diet (low in
phenylalanine, methionine and tyrosine) and a drug
called NTCB.
June 26, 2012 Total slide. 132 100
101. Clinical Biochemistry Metabolic Disorders of Proteins
homogentisic acid FAAH catalyses the last step in the
degradation path of phenylalanine and
tyrosine.
O O
Tyrosinemia
HOOC C C O O
=
=
CH CH CH2 CH2 COOH
HOOC - CH2 - CH2 - C - CH2 - C - CH2 - COOH
maleylacetoacetic acid
succinylacetoacetic acid
spontaneous
HOOC
CH CH CH2 CH2 COOH COOH
C C
O O O O
=
=
fumarylacetoacetate HOOC - CH2 - CH2 - C - CH2 - C - CH3
Succinylacetone
FAAH toxic and mutagenic
Fumarate + acetoacetate
Deficiency of the enzyme FAAH results in Type I tyrosinemia
June 26, 2012 Total slide. 132 101
102. Clinical Biochemistry Metabolic Disorders of Proteins
WHAT ARE THE SYMPTOMS
OF
TYROSINEMIA?
The clinical features of the disease fall
into two categories:
Acute
Chronic
June 26, 2012 Total slide. 132 102
103. Clinical Biochemistry Metabolic Disorders of Proteins
Acute tyrosinemia
• abnormalities appear in the
first month of life
• poor weight gain
• enlarged liver and spleen
• distended abdomen
• swelling of the legs
• increased tendency to
bleeding, particularly nose bleeds
• Jaundice
• death from hepatic failure
frequently occurs between three
and nine months of age unless a
liver transplantation is
performed.
June 26, 2012 Total slide. 132 103
104. Clinical Biochemistry Metabolic Disorders of Proteins
Homocystinuria
Defective activity of cystathionine synthase
June 26, 2012 Total slide. 132 104
105. Clinical Biochemistry Metabolic Disorders of Proteins
Major phenotypic expression
Ectopia lentis
Vascular occlusive disease
Malar flash
Osteoporosis
Accumulation of homocysteine and methionine
June 26, 2012 Total slide. 132 105
106. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 106
107. Clinical Biochemistry Metabolic Disorders of Proteins
June 26, 2012 Total slide. 132 107
108. Clinical Biochemistry Metabolic Disorders of Proteins
A family of homocystinuria
June 26, 2012 Total slide. 132 108
110. Clinical Biochemistry Metabolic Disorders of Proteins
What is Albinism?
A lack of pigment in skin, hair, and eyes.
Albinism is an inherited condition that
results from a gene mutation.
Altered genes are unable to exhibit natural
pigments that normally occur.
Albinism can occur in nearly all species:
animals, plants, or humans.
June 26, 2012 Total slide. 132 110
111. Clinical Biochemistry Metabolic Disorders of Proteins
Albinism in all forms…
June 26, 2012 Total slide. 132 111
112. Clinical Biochemistry Metabolic Disorders of Proteins
Lets take a closer look…
What causes Albinism?
Albinism is genetic and is
passed on through heredity via
the genes.
Genes involved are supposed to
communicate the pigmentation (Retina of albino)
of eyes, skin, and hair.
Albino Individuals have
received a recessive gene (aa)
from both parents resulting in
an incorrect genetic blueprint
for pigment.
June 26, 2012 Total slide. 132 112
113. Clinical Biochemistry Metabolic Disorders of Proteins
Albinism
June 26, 2012 Total slide. 132 113
114. Clinical Biochemistry Metabolic Disorders of Proteins
Albinism
June 26, 2012 Total slide. 132 114
115. Clinical Biochemistry Metabolic Disorders of Proteins
Characteristics of albinism:
Low Vision (20/50 to 20/800)
Sensitivity to bright light and
glare
Rhythmic, involuntary eye
movements
Absent or decreased pigment in
the skin and eye and sensitivity
to sunburn that could lead to
skin cancers or cataracts in
later life
"Slowness to see" in infancy
June 26, 2012 Total slide. 132 115
116. Clinical Biochemistry Metabolic Disorders of Proteins
Characteristics of albinism:
Farsighted, nearsighted,
often with astigmatism
Underdevelopment of the
central retina
Decreased pigment in the
retina
Inability of the eyes to
work together
Light colored eyes ranging
from lavender to hazel,
with the majority being
blue
June 26, 2012 Total slide. 132 116
117. Clinical Biochemistry Metabolic Disorders of Proteins
Problems associated with Albinism…
Impaired vision due to
the lack of melanin
pigment
Skin damage due to
Sun
Mild problems with
blood clotting
Hearing impairment
June 26, 2012 Total slide. 132 117
118. Clinical Biochemistry Metabolic Disorders of Proteins
Classification & Types of Albinism
Oculocutaneous albinism (OCA): melanin
pigment is missing in skin, hair, and eyes.
Ocular albinism (OA): melanin pigment is
primarily missing in the eyes and the skin
and the hair appear normal.
OCA is more common than OA.
June 26, 2012 Total slide. 132 118
119. Clinical Biochemistry Metabolic Disorders of Proteins
Oculocutaneous
Albinism
June 26, 2012 Total slide. 132 119
120. Clinical Biochemistry Metabolic Disorders of Proteins
Genes Associated with Albinism
& Pigmentation:
Tyrosinase: major enzyme involved
in melanin formation
Location: Chromosome 11
DHICA-oxidase: loose of function
of this enzyme leads to albinism
Location: Chromosome 9
Ocular Albinism Gene: role
unknown
Location: Chromosome X (primarily
Sammy’s fault not Jeff’s)
June 26, 2012 Total slide. 132 120
121. Clinical Biochemistry Metabolic Disorders of Proteins
Tyrosin hydroxylase
dopa
Tyrosin hydroxylase
dopaquinone
Eumelanins
Indole 5,6 quinone
Quinoleimine
intermediate
Mixed-type
melanins
Pheomelanins
trichochroms
June 26, 2012 Total slide. 132 121
122. Clinical Biochemistry Metabolic Disorders of Proteins
Facts you may not know…
1 in 70 humans carries a Hey want to
know
recessive gene linked to something…
albinism.
If both parents carry an albino
gene the chances are 1 in 4 (½ x
½) that offspring will display
albinism. Not really,
but I
If one parent displays albinism, suppose
and one does not but carries a you are
recessive gene, the chances of going to
tell me
the offspring displaying anyway…
albinism is 1 in 2 (1 x ½). 132
June 26, 2012 Total slide. 122
123. Clinical Biochemistry Metabolic Disorders of Proteins
Common Myths & Misconceptions
Persons with albinism always have red eyes.
Persons with albinism are totally blind.
Albinism is contagious.
Persons with albinism are the result of evil spirits
or wrongdoing.
Persons with albinism are retarded or deaf.
Albinism results from inbreeding or the mixture
of two races.
Persons with albinism have magical powers.
June 26, 2012 Total slide. 132 123
124. Clinical Biochemistry Metabolic Disorders of Proteins
In summary…
Albinism is a rather
rare recessive
mutation that can be
witnessed in many
multiple species;
plant, animal, and
human, all with
phenotypic
similarities.
June 26, 2012 Total slide. 132 124
125. Clinical Biochemistry Metabolic Disorders of Proteins
Albinism in animals
June 26, 2012 Total slide. 132 125
126. Clinical Biochemistry Metabolic Disorders of Proteins
Albinism in films
June 26, 2012 Total slide. 132 126
127. Clinical Biochemistry Metabolic Disorders of Proteins
A family of albinism
June 26, 2012 Total slide. 132 127
128. Clinical Biochemistry Metabolic Disorders of Proteins
Newborn
screening
June 26, 2012 Total slide. 132 128
129. Clinical Biochemistry Metabolic Disorders of Proteins
Newborn screening
The goal of newborn screening is to eliminate,
through early identification and treatment, and
improve the quality of life for affected
individuals.
June 26, 2012 Total slide. 132 129
130. Clinical Biochemistry Metabolic Disorders of Proteins
Newborn screening
Newborn screening is not just a laboratory
service; it is a system of care including, not
only testing, but also follow up, definitive
diagnosis, treatment, long term management,
education and evaluation----
June 26, 2012 Total slide. 132 130
131. Clinical Biochemistry Metabolic Disorders of Proteins
Newborn screening
The goal of newborn screening follow up is to
ensure that each affected infant receives the
full benefit of early detection and optimal
long term treatment and management.
June 26, 2012 Total slide. 132 131
132. Clinical Biochemistry Metabolic Disorders of Proteins
Follow Up
short term follow up- assure that a definitive
diagnostic work-up is done, that the infant really
has the disorder and that the infant is started on
appropriate treatment
long term follow up- assure that the infant
continues to receive appropriate treatment and
monitors the long term outcome
June 26, 2012 Total slide. 132 132
133. Clinical Biochemistry Metabolic Disorders of Proteins
THE END
June 26, 2012 Total slide. 132 133
Editor's Notes
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
06/26/12
The urine of normal patients (left) and those with alkaptonuria (right). The accumulation of homogentisic acid – an intermediate in the catabolic pathway of the aromatic amino acids phenylalanine and tyrosine - in the urine of alkaptonuria patients is observed on standing (or under alkaline conditions) when its oxidation leads to a brownish black pigment characteristic of the disease. Discolouration of urine on standing is diagnostic of the disorder along with noticing persistent, painless bluish darkening of the outer ears, nose, and whites of the eyes. Longer term, arthritis and premature degeneration of joints occurs in many patients.
. We now know from studying the pathways in the fungus Aspergillus that the deficiency of this enzyme HGO is responsible for the disease alkaptonuria which results in an accumulation of the enzyme substrate homogentisic acid.
Pathway of catabolism of phenylalanine and tyrosine showing the enzymes responsible for each stage.
Tyrosinemia is treated by a low protein diet (low in phenylalanine, methionine and tyrosine) and a drug called NTCB. This drug is an inhibitor which blocks the metabolism of phenylalanine and tyrosine. Although the drug is not a cure, it manages the disease. The only cure for Tyrosinemia is a liver transplant. WHAT ARE THE SYMPTOMS OF TYROSINEMIA? The clinical features of the disease ten to fall into two categories, acute and chronic. In the so-called acute form of the disease, abnormalities appear in the first month of life. Babies may show poor weight gain, an enlarged liver and spleen, a distended abdomen, swelling of the legs, and an increased tendency to bleeding, particularly nose bleeds. Jaundice may or may not be prominent. Despite vigorous therapy, death from hepatic failure frequently occurs between three and nine months of age unless a liver transplantation is performed. Some children have a more chronic form of tyrosinemia with a gradual onset and less severe clinical features. In these children, enlargement of the liver and spleen are prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting and diarrhoea occur frequently. Affected patients usually develop cirrhosis and its complications. These children also require liver transplantation.
The accumulation of Succinylacetone (SA) is exclusively found in the serum and urine of FAAH deficient patients and is a diagnostic compound for type I tyrosinemia . Fumarylacetoacetate accumulates as a consequence of the blockage and its spontaneous degradation products (SA) are toxic and mutagenic . Deficiency of the enzyme responsible -fumarylacetate hydrolase (FAAH) results in a devastating condition known as type I hereditary tyrosinemia – affected children die shortly after birth or develop hepatic carcinomas in early childhood.