This document provides an overview of Mucopolysaccharidosis (MPS). MPS are hereditary progressive diseases caused by mutations in genes coding for lysosomal enzymes needed to break down glycosaminoglycans. Failure to break down GAGs leads to their accumulation in lysosomes, interfering with tissue function. There are several types of MPS classified by the specific enzyme deficiency and GAG accumulation. Features include organomegaly, skeletal abnormalities, joint stiffness, cardiac issues, and neurological involvement depending on the type. Diagnosis involves urine GAG analysis, enzyme testing, and genetic testing. Management options include hematopoietic stem cell transplantation, enzyme replacement therapy, and symptomatic care.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
This document discusses inborn errors of metabolism. It begins by defining metabolism as the breakdown and building up of molecules through catabolic and anabolic pathways, facilitated by enzymes. Inborn errors of metabolism are disorders caused by mutations that block normal metabolic pathways, resulting in toxic metabolites. The document then classifies different types of inborn errors affecting amino acid, carbohydrate, lipid, protein, and pigment metabolism. It outlines patterns of clinical presentation including encephalopathy, liver disease, dysmorphic features, and neurological symptoms. The document stresses the importance of early metabolic investigations for treating inborn errors.
Enzyme replacement therapy in neurological disordersNeurologyKota
This document discusses enzyme replacement therapy (ERT) for lysosomal storage disorders. It provides details on ERT including its development, mechanisms, available products, dosing and costs. Challenges with ERT include limited blood-brain barrier penetration and immunogenicity. Alternative therapies discussed include substrate reduction therapy, pharmacological chaperones, and direct delivery of enzymes into the cerebrospinal fluid. ERT remains the standard treatment but has limitations for treating neurological manifestations of lysosomal storage disorders.
Pompe disease is a rare genetic disease characterized by the abnormal buildup of a sugar molecule called glycogen inside cells. This buildup impairs the working of different organs and tissues, especially the heart, respiratory, and skeletal muscles.
Pompe disease, sometimes referred to as glycogen storage disease type II, is one of nearly 50 diseases classified as lysosomal storage disorders (LSD).Pompe disease is caused by mutations, or abnormalities, in the GAA gene, which encodes for an enzyme called acid alpha-glucosidase
Gaucher disease is an inherited disorder caused by a deficiency of the glucocerebrosidase enzyme, which causes harmful substances to accumulate in organs. There are several types of Gaucher disease. Type 1 is the most common and usually does not affect the nervous system. Types 2 and 3 do affect the nervous system and can cause neurological problems. Symptoms vary depending on type but may include bone and organ enlargement, fatigue, easy bruising, and lung and heart problems. Diagnosis involves blood tests, imaging, and genetic testing. Treatment options include enzyme replacement therapy and bone marrow transplant for severe cases.
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.
Galactosemia is a rare genetic metabolic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is necessary for galactose metabolism. There are three main types depending on the specific enzyme deficiency. It is inherited in an autosomal recessive pattern and causes an inability to properly break down and use the sugar galactose. If left untreated, it can cause serious issues such as liver damage, cataracts, intellectual disabilities and more. Treatment involves a strict lifelong galactose-restricted diet.
This document provides an overview of Mucopolysaccharidosis (MPS). MPS are hereditary progressive diseases caused by mutations in genes coding for lysosomal enzymes needed to break down glycosaminoglycans. Failure to break down GAGs leads to their accumulation in lysosomes, interfering with tissue function. There are several types of MPS classified by the specific enzyme deficiency and GAG accumulation. Features include organomegaly, skeletal abnormalities, joint stiffness, cardiac issues, and neurological involvement depending on the type. Diagnosis involves urine GAG analysis, enzyme testing, and genetic testing. Management options include hematopoietic stem cell transplantation, enzyme replacement therapy, and symptomatic care.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
This document discusses inborn errors of metabolism. It begins by defining metabolism as the breakdown and building up of molecules through catabolic and anabolic pathways, facilitated by enzymes. Inborn errors of metabolism are disorders caused by mutations that block normal metabolic pathways, resulting in toxic metabolites. The document then classifies different types of inborn errors affecting amino acid, carbohydrate, lipid, protein, and pigment metabolism. It outlines patterns of clinical presentation including encephalopathy, liver disease, dysmorphic features, and neurological symptoms. The document stresses the importance of early metabolic investigations for treating inborn errors.
Enzyme replacement therapy in neurological disordersNeurologyKota
This document discusses enzyme replacement therapy (ERT) for lysosomal storage disorders. It provides details on ERT including its development, mechanisms, available products, dosing and costs. Challenges with ERT include limited blood-brain barrier penetration and immunogenicity. Alternative therapies discussed include substrate reduction therapy, pharmacological chaperones, and direct delivery of enzymes into the cerebrospinal fluid. ERT remains the standard treatment but has limitations for treating neurological manifestations of lysosomal storage disorders.
Pompe disease is a rare genetic disease characterized by the abnormal buildup of a sugar molecule called glycogen inside cells. This buildup impairs the working of different organs and tissues, especially the heart, respiratory, and skeletal muscles.
Pompe disease, sometimes referred to as glycogen storage disease type II, is one of nearly 50 diseases classified as lysosomal storage disorders (LSD).Pompe disease is caused by mutations, or abnormalities, in the GAA gene, which encodes for an enzyme called acid alpha-glucosidase
Gaucher disease is an inherited disorder caused by a deficiency of the glucocerebrosidase enzyme, which causes harmful substances to accumulate in organs. There are several types of Gaucher disease. Type 1 is the most common and usually does not affect the nervous system. Types 2 and 3 do affect the nervous system and can cause neurological problems. Symptoms vary depending on type but may include bone and organ enlargement, fatigue, easy bruising, and lung and heart problems. Diagnosis involves blood tests, imaging, and genetic testing. Treatment options include enzyme replacement therapy and bone marrow transplant for severe cases.
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.
Galactosemia is a rare genetic metabolic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is necessary for galactose metabolism. There are three main types depending on the specific enzyme deficiency. It is inherited in an autosomal recessive pattern and causes an inability to properly break down and use the sugar galactose. If left untreated, it can cause serious issues such as liver damage, cataracts, intellectual disabilities and more. Treatment involves a strict lifelong galactose-restricted diet.
GSD are inherited disorders of glycogen metabolism caused by defects in glycogen degradation, glycolysis or glycogen synthesis. They can affect the liver, muscle or be generalized. GSD I is the most severe liver GSD affecting glycogen breakdown and gluconeogenesis. It presents in infancy with hypoglycemia, hepatomegaly and growth retardation. Treatment involves preventing hypoglycemia through frequent feeds and nocturnal gastric feeding. GSD III is caused by debranching enzyme deficiency and can present with liver or muscle involvement. Symptoms are similar to GSD I in childhood but improve with age, while myopathy often appears later in life.
The document discusses abnormal hemoglobin metabolism and hemoglobinopathies. It provides information on hemoglobin structure, definitions of thalassemias and hemoglobinopathies, specifics on sickle cell anemia and thalassemia, Bart's hydrops fetalis, and diagnosis of hemoglobinopathies. Sickle cell anemia results from a single amino acid substitution causing hemoglobin S, which polymerizes and makes red blood cells rigid and sickle-shaped. Thalassemias involve absent or reduced alpha or beta globin chains. Diagnosis involves family history, symptoms, lab tests, and analyzing hemoglobin structure.
Macrophage activation syndrome (MAS) is a life-threatening condition that can occur in patients with rheumatological disorders. It is characterized by proliferation and activation of macrophages that leads to cytokine overproduction and hemophagocytosis. The document discusses the pathogenesis, triggers, clinical features, diagnostic guidelines, management, and prognosis of MAS. Treatment involves high-dose corticosteroids as initial therapy, with cyclosporine A and other immunosuppressants used for severe or steroid-resistant cases. Early diagnosis and treatment have improved outcomes for MAS patients.
Galactosemia is a rare genetic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is responsible for breaking down the sugar galactose. This causes galactose and its metabolites to accumulate and can damage the liver, kidneys, and brain if not treated. The only treatment is eliminating all sources of galactose from the diet. If untreated, it can cause complications like cataracts, speech problems, poor bone density, and intellectual disabilities. The document provides details on the causes, types, symptoms, diagnosis, and management of galactosemia.
Type 2 Gaucher disease is a rare genetic disorder caused by a defective gene that inhibits the body's ability to break down a fatty lipid called glucocerebroside. This causes the fatty material to accumulate in organs like the spleen, liver, lungs and bone marrow. Type 2 Gaucher disease specifically affects the central nervous system, with initial signs including neck hyperextension, swallowing issues and eye movement disorders. Affected children usually experience rapid neurological degeneration and die by age 2. The article reviews 15 new cases of Type 2 Gaucher disease and compares them to 104 published cases to better understand the signs, symptoms and progression of this rare condition.
Glycogen storage diseases are caused by defects in glycogen synthesis or breakdown. There are several types affecting the liver or muscle. Type I is caused by glucose-6-phosphatase deficiency leading to liver enlargement and low blood sugar during fasting. Type III involves a debranching enzyme defect causing swollen abdomen and muscle weakness. Type VI deficiency of liver phosphorylase causes hepatomegaly, hypoglycemia, and growth issues. Symptoms, diagnosis, and treatments vary depending on the specific enzyme deficiency and tissues involved.
Mitochondrial diseases are caused by defects in mitochondrial structure or enzymes that result in deficient energy production. They can affect multiple organ systems and occur across all age groups. Mitochondrial DNA mutations can be inherited from the mother and nuclear DNA mutations can affect mitochondrial proteins or DNA maintenance. Common mitochondrial diseases include MELAS, MERRF, and Leigh syndrome. Mitochondrial dysfunction has also been implicated in aging and common diseases like heart disease and Parkinson's.
This document discusses Gaucher disease, which is caused by a deficiency in the glucocerebrosidase enzyme. It classifies Gaucher disease into several types based on symptoms. Type 1 presents in adults and involves bone and organ involvement without neurological symptoms. Type 2 presents in infancy with rapid progression and death by age 2-4. Type 3 also presents in infancy but progresses more slowly into adulthood. The diagnosis involves testing for deficient glucocerebrosidase enzyme activity or identifying mutations in the GBA gene. Treatment involves managing symptoms, and enzyme replacement therapy or substrate reduction therapy to prevent further issues. A multidisciplinary approach is recommended.
Millie, a 3 month old girl, was brought to the pediatrician with issues feeding, irritability, and muscle spasms. Tests found she had no GALC enzyme activity and an MRI showed demyelination. She was diagnosed with Krabbe disease, a rare inherited disorder caused by mutations in the GALC gene resulting in myelin loss and impaired nervous system development. There is currently no approved treatment, but research is exploring inhibitors of enzymes involved in the disease process.
Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase, leading to a buildup of glucocerebroside. There are three main types: type 1 is non-neuropathic and involves the spleen and bones; type 2 is infantile and causes acute neurological involvement; type 3 causes progressive neurological involvement beginning in teenage years. Symptoms include hepatosplenomegaly, bone pain, lung and kidney involvement. Treatment involves enzyme replacement therapy with recombinant enzymes or substrate reduction therapy with drugs like miglustat or eliglustat.
This document summarizes different types of hemoglobinopathies and thalassemias. It describes normal adult hemoglobins and the two major disorders - qualitative hemoglobinopathies caused by structural mutations like sickle cell anemia, and quantitative hemoglobinopathies caused by reduced globin chain synthesis like thalassemias. Sickle cell disease results from a glutamic acid to valine substitution and causes polymerization of deoxygenated hemoglobin. Thalassemias are caused by alpha or beta globin chain deficiency. Beta thalassemia major involves homozygosity for beta thalassemia genes and requires frequent blood transfusions. Alpha thalassemia ranges from silent carrier state to Bart's hydrops
This document discusses neonatal G6PD deficiency, including its epidemiology, pathogenesis, clinical presentation, diagnosis, and management. It notes that G6PD deficiency is one of the most common enzymopathies worldwide and an important cause of neonatal jaundice. The deficiency results in impaired antioxidant defense in red blood cells and can lead to hemolysis when exposed to oxidative stress. Timely diagnosis and avoiding triggering factors are important to prevent severe complications like kernicterus. Newborn screening programs have helped identify at-risk infants.
This document provides an overview of inborn errors of metabolism (IEM). It discusses that IEM have an overall incidence of 1 in 1000 to 1 in 2000 births. The most common presentation is sepsis in 30% of cases. IEM are classified based on the defective metabolic pathway, such as amino acid metabolism defects, carbohydrate metabolism defects, and organic acidemias. Clinical pointers for suspected IEM include deterioration after apparent normalcy, hypoglycemia, metabolic acidosis, abnormal urine odor, and dysmorphic features. Evaluation of neonates involves blood tests, blood gases, glucose and ammonia levels, urine analysis, and plasma amino acid analysis to identify specific disorders. Management involves identifying and limiting the offending substance
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
Lipid storage diseases are a group of inherited metabolic disorders caused by deficiencies of enzymes needed to metabolize lipids. This leads to harmful accumulation of fatty materials in cells and tissues over time, damaging the brain, nerves, liver, spleen, and bone marrow. The document discusses several specific lipid storage diseases - Gaucher disease, Niemann-Pick disease, Fabry disease, Farber's disease, Krabbe disease, metachromatic leukodystrophy, and gangliosidosis - outlining their causes, clinical features, inheritance patterns, treatments, and prognosis.
This document summarizes several glycogen storage diseases and lysosomal storage diseases. For glycogen storage diseases, it lists the enzyme deficiency, symptoms such as hypoglycemia and hepatomegaly, and mnemonics to remember each disease. For lysosomal storage diseases, it provides the deficient enzyme, accumulated substrate, inheritance pattern, and key findings for each condition. It concludes by highlighting some distinguishing features between similar diseases, such as neurological symptoms in Niemann-Pick versus Gaucher's, and differences between Hunter's and Hurler's syndromes.
This document discusses lipid disorders and their causes and treatment. It covers apolipoproteins, dyslipidemia caused by excessive VLDL secretion or impaired lipolysis of triglyceride-rich lipoproteins, and dyslipidemia caused by impaired hepatic uptake of apoB-containing lipoproteins. Specific genetic disorders discussed include familial hypercholesterolemia, familial hypertriglyceridemia, sitosterolemia, and others. Lifestyle modifications and pharmacological treatments are provided for each condition.
This document discusses prion diseases, also known as transmissible spongiform encephalopathies (TSEs). It notes that TSEs have long incubation periods and progressive clinical courses. They can be caused by conventional or unconventional agents and include diseases like Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Prions, the infectious agents responsible for TSEs, are abnormal forms of proteins that can induce normal proteins to also take the abnormal form. They are resistant to heat, chemicals, and radiation. Diagnosis of prion diseases is difficult due to a lack of immune response or signs of infection. Currently, there
Lysosomal storage diseases are caused by a lack of enzymes in lysosomes that normally break down unwanted substances in cells. This causes substances to build up and damage cells over time, leading to progressive physical and mental deterioration. There are over 40 types of lysosomal diseases that vary in severity from mild to fatal. The prognosis depends on the type and severity of the disease, with typical forms causing a full set of symptoms and reduced life expectancy of around 15 years.
Lysosomal storage diseases (LSDs) are a group of over 50 inherited metabolic disorders caused by defects in lysosomal function. The main types are sphingolipidoses, mucopolysaccharidoses, and glycoproteinoses. Symptoms often involve the brain and nervous system. On MRI, the corpus callosum may be not visualized or partially visualized in some LSDs. Histopathology reveals neuronal storage material, spheroids in white matter, and membranous cytoplasmic bodies in neurons. LSDs can also affect dogs and cats, with clinical signs appearing in early life and pathology showing tissue storage.
GSD are inherited disorders of glycogen metabolism caused by defects in glycogen degradation, glycolysis or glycogen synthesis. They can affect the liver, muscle or be generalized. GSD I is the most severe liver GSD affecting glycogen breakdown and gluconeogenesis. It presents in infancy with hypoglycemia, hepatomegaly and growth retardation. Treatment involves preventing hypoglycemia through frequent feeds and nocturnal gastric feeding. GSD III is caused by debranching enzyme deficiency and can present with liver or muscle involvement. Symptoms are similar to GSD I in childhood but improve with age, while myopathy often appears later in life.
The document discusses abnormal hemoglobin metabolism and hemoglobinopathies. It provides information on hemoglobin structure, definitions of thalassemias and hemoglobinopathies, specifics on sickle cell anemia and thalassemia, Bart's hydrops fetalis, and diagnosis of hemoglobinopathies. Sickle cell anemia results from a single amino acid substitution causing hemoglobin S, which polymerizes and makes red blood cells rigid and sickle-shaped. Thalassemias involve absent or reduced alpha or beta globin chains. Diagnosis involves family history, symptoms, lab tests, and analyzing hemoglobin structure.
Macrophage activation syndrome (MAS) is a life-threatening condition that can occur in patients with rheumatological disorders. It is characterized by proliferation and activation of macrophages that leads to cytokine overproduction and hemophagocytosis. The document discusses the pathogenesis, triggers, clinical features, diagnostic guidelines, management, and prognosis of MAS. Treatment involves high-dose corticosteroids as initial therapy, with cyclosporine A and other immunosuppressants used for severe or steroid-resistant cases. Early diagnosis and treatment have improved outcomes for MAS patients.
Galactosemia is a rare genetic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is responsible for breaking down the sugar galactose. This causes galactose and its metabolites to accumulate and can damage the liver, kidneys, and brain if not treated. The only treatment is eliminating all sources of galactose from the diet. If untreated, it can cause complications like cataracts, speech problems, poor bone density, and intellectual disabilities. The document provides details on the causes, types, symptoms, diagnosis, and management of galactosemia.
Type 2 Gaucher disease is a rare genetic disorder caused by a defective gene that inhibits the body's ability to break down a fatty lipid called glucocerebroside. This causes the fatty material to accumulate in organs like the spleen, liver, lungs and bone marrow. Type 2 Gaucher disease specifically affects the central nervous system, with initial signs including neck hyperextension, swallowing issues and eye movement disorders. Affected children usually experience rapid neurological degeneration and die by age 2. The article reviews 15 new cases of Type 2 Gaucher disease and compares them to 104 published cases to better understand the signs, symptoms and progression of this rare condition.
Glycogen storage diseases are caused by defects in glycogen synthesis or breakdown. There are several types affecting the liver or muscle. Type I is caused by glucose-6-phosphatase deficiency leading to liver enlargement and low blood sugar during fasting. Type III involves a debranching enzyme defect causing swollen abdomen and muscle weakness. Type VI deficiency of liver phosphorylase causes hepatomegaly, hypoglycemia, and growth issues. Symptoms, diagnosis, and treatments vary depending on the specific enzyme deficiency and tissues involved.
Mitochondrial diseases are caused by defects in mitochondrial structure or enzymes that result in deficient energy production. They can affect multiple organ systems and occur across all age groups. Mitochondrial DNA mutations can be inherited from the mother and nuclear DNA mutations can affect mitochondrial proteins or DNA maintenance. Common mitochondrial diseases include MELAS, MERRF, and Leigh syndrome. Mitochondrial dysfunction has also been implicated in aging and common diseases like heart disease and Parkinson's.
This document discusses Gaucher disease, which is caused by a deficiency in the glucocerebrosidase enzyme. It classifies Gaucher disease into several types based on symptoms. Type 1 presents in adults and involves bone and organ involvement without neurological symptoms. Type 2 presents in infancy with rapid progression and death by age 2-4. Type 3 also presents in infancy but progresses more slowly into adulthood. The diagnosis involves testing for deficient glucocerebrosidase enzyme activity or identifying mutations in the GBA gene. Treatment involves managing symptoms, and enzyme replacement therapy or substrate reduction therapy to prevent further issues. A multidisciplinary approach is recommended.
Millie, a 3 month old girl, was brought to the pediatrician with issues feeding, irritability, and muscle spasms. Tests found she had no GALC enzyme activity and an MRI showed demyelination. She was diagnosed with Krabbe disease, a rare inherited disorder caused by mutations in the GALC gene resulting in myelin loss and impaired nervous system development. There is currently no approved treatment, but research is exploring inhibitors of enzymes involved in the disease process.
Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase, leading to a buildup of glucocerebroside. There are three main types: type 1 is non-neuropathic and involves the spleen and bones; type 2 is infantile and causes acute neurological involvement; type 3 causes progressive neurological involvement beginning in teenage years. Symptoms include hepatosplenomegaly, bone pain, lung and kidney involvement. Treatment involves enzyme replacement therapy with recombinant enzymes or substrate reduction therapy with drugs like miglustat or eliglustat.
This document summarizes different types of hemoglobinopathies and thalassemias. It describes normal adult hemoglobins and the two major disorders - qualitative hemoglobinopathies caused by structural mutations like sickle cell anemia, and quantitative hemoglobinopathies caused by reduced globin chain synthesis like thalassemias. Sickle cell disease results from a glutamic acid to valine substitution and causes polymerization of deoxygenated hemoglobin. Thalassemias are caused by alpha or beta globin chain deficiency. Beta thalassemia major involves homozygosity for beta thalassemia genes and requires frequent blood transfusions. Alpha thalassemia ranges from silent carrier state to Bart's hydrops
This document discusses neonatal G6PD deficiency, including its epidemiology, pathogenesis, clinical presentation, diagnosis, and management. It notes that G6PD deficiency is one of the most common enzymopathies worldwide and an important cause of neonatal jaundice. The deficiency results in impaired antioxidant defense in red blood cells and can lead to hemolysis when exposed to oxidative stress. Timely diagnosis and avoiding triggering factors are important to prevent severe complications like kernicterus. Newborn screening programs have helped identify at-risk infants.
This document provides an overview of inborn errors of metabolism (IEM). It discusses that IEM have an overall incidence of 1 in 1000 to 1 in 2000 births. The most common presentation is sepsis in 30% of cases. IEM are classified based on the defective metabolic pathway, such as amino acid metabolism defects, carbohydrate metabolism defects, and organic acidemias. Clinical pointers for suspected IEM include deterioration after apparent normalcy, hypoglycemia, metabolic acidosis, abnormal urine odor, and dysmorphic features. Evaluation of neonates involves blood tests, blood gases, glucose and ammonia levels, urine analysis, and plasma amino acid analysis to identify specific disorders. Management involves identifying and limiting the offending substance
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
Lipid storage diseases are a group of inherited metabolic disorders caused by deficiencies of enzymes needed to metabolize lipids. This leads to harmful accumulation of fatty materials in cells and tissues over time, damaging the brain, nerves, liver, spleen, and bone marrow. The document discusses several specific lipid storage diseases - Gaucher disease, Niemann-Pick disease, Fabry disease, Farber's disease, Krabbe disease, metachromatic leukodystrophy, and gangliosidosis - outlining their causes, clinical features, inheritance patterns, treatments, and prognosis.
This document summarizes several glycogen storage diseases and lysosomal storage diseases. For glycogen storage diseases, it lists the enzyme deficiency, symptoms such as hypoglycemia and hepatomegaly, and mnemonics to remember each disease. For lysosomal storage diseases, it provides the deficient enzyme, accumulated substrate, inheritance pattern, and key findings for each condition. It concludes by highlighting some distinguishing features between similar diseases, such as neurological symptoms in Niemann-Pick versus Gaucher's, and differences between Hunter's and Hurler's syndromes.
This document discusses lipid disorders and their causes and treatment. It covers apolipoproteins, dyslipidemia caused by excessive VLDL secretion or impaired lipolysis of triglyceride-rich lipoproteins, and dyslipidemia caused by impaired hepatic uptake of apoB-containing lipoproteins. Specific genetic disorders discussed include familial hypercholesterolemia, familial hypertriglyceridemia, sitosterolemia, and others. Lifestyle modifications and pharmacological treatments are provided for each condition.
This document discusses prion diseases, also known as transmissible spongiform encephalopathies (TSEs). It notes that TSEs have long incubation periods and progressive clinical courses. They can be caused by conventional or unconventional agents and include diseases like Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Prions, the infectious agents responsible for TSEs, are abnormal forms of proteins that can induce normal proteins to also take the abnormal form. They are resistant to heat, chemicals, and radiation. Diagnosis of prion diseases is difficult due to a lack of immune response or signs of infection. Currently, there
Lysosomal storage diseases are caused by a lack of enzymes in lysosomes that normally break down unwanted substances in cells. This causes substances to build up and damage cells over time, leading to progressive physical and mental deterioration. There are over 40 types of lysosomal diseases that vary in severity from mild to fatal. The prognosis depends on the type and severity of the disease, with typical forms causing a full set of symptoms and reduced life expectancy of around 15 years.
Lysosomal storage diseases (LSDs) are a group of over 50 inherited metabolic disorders caused by defects in lysosomal function. The main types are sphingolipidoses, mucopolysaccharidoses, and glycoproteinoses. Symptoms often involve the brain and nervous system. On MRI, the corpus callosum may be not visualized or partially visualized in some LSDs. Histopathology reveals neuronal storage material, spheroids in white matter, and membranous cytoplasmic bodies in neurons. LSDs can also affect dogs and cats, with clinical signs appearing in early life and pathology showing tissue storage.
This document discusses the importance and therapeutic benefits of enzymes. It explains that enzymes are proteins that act as catalysts for biochemical reactions in living things. The document discusses theories that sufficient enzymes may help break down cancer cells and support the immune system in fighting cancer. It also outlines the history of enzyme therapy for cancer treatment dating back to the 1940s and reviews current research on how enzymes may help inhibit cancer progression and metastasis.
This document provides an update on research into Fabry disease. Some key points:
- Fabry disease is an X-linked lysosomal storage disease caused by a deficiency in the enzyme alpha-galactosidase A. Symptoms typically appear in childhood and include pain, fatigue, and kidney, heart, and neurological problems.
- Current treatments include enzyme replacement therapies which require intravenous infusions. Research is exploring oral treatments, biomarkers to monitor treatment effectiveness, and ways to target tissues not reached by current therapies.
- Studies show symptoms often appear earlier than previously thought, and early initiation of treatment may help prevent organ damage. However, most patients still start treatment after significant disease progression.
- Research is
This document summarizes advances in understanding and treating Gaucher disease from the past to present and future prospects. It describes key findings such as the identification of the metabolic defect, development of diagnostic tests, characterization of the Gaucher cell, and establishment of enzyme replacement therapy as an effective treatment that improves outcomes. The summary also notes areas of ongoing research including potential new treatments like chaperone therapy, gene therapy and small molecule approaches, as well as emerging links between Gaucher disease and Parkinson's disease.
Fabry disease runs in families. It can have lots of different symptoms, including pain in the hands and feet and a specific kind of rash.When you have Fabry disease, a certain type of fatty substance builds up in your body. It narrows your blood vessels, which can hurt your skin, kidneys, heart, brain, and nervous system.
Gaucher disease is a multisystemic lipidosis characterized by hematologic abnormalities, organomegaly, and skeletal involvement. There are three clinical subtypes delineated by the absence or presence and progression of neurologic manifestations. Treatment of type 1 includes enzyme replacement therapy to reverse symptoms. Types 2 and 3 also involve neurologic deterioration and have a poorer prognosis, though enzyme replacement may help with visceral symptoms in type 3.
Mucopolysaccharidoses are hereditary lysosomal storage disorders caused by deficiencies in enzymes that break down glycosaminoglycans. This results in glycosaminoglycan accumulation in tissues and organs, leading to symptoms like facial abnormalities, short stature, corneal clouding, developmental delays, bone deformities, organ enlargement, and neurological issues. Diagnosis involves testing urine for glycosaminoglycan levels and measuring enzyme activity levels. Treatment focuses on managing symptoms through supportive care, physical therapy, surgeries, and enzyme replacement therapy or hematopoietic stem cell transplantation to reduce clinical effects.
This document discusses different types of biochemical disorders caused by enzyme deficiencies. It covers several key areas:
- Metabolic disorders are often inherited and can affect enzyme activity levels. Disorders like Parkinson's disease and schizophrenia may involve alterations in the enzyme tyrosine hydroxylase.
- Enzyme deficiencies can occur in various metabolic pathways like phenylalanine, urea cycle, carbohydrate, steroid, lipid, lysosomal, purine, copper, and peroxisome metabolism.
- Specific disorders touched on include homocystinuria, urea cycle disorders, glycogen storage diseases, congenital adrenal hyperplasia, familial hypercholesterolemia, Wilson's disease, Zellwe
Fabry disease is a rare genetic disorder caused by deficient activity of the enzyme alpha-galactosidase A. This enzyme breakdown lipids in the body. Its deficiency leads to a buildup of lipids in blood vessels, kidneys, and other organs. Symptoms include skin lesions, pain, kidney failure, and increased risk of heart disease. Treatment involves enzyme replacement therapy via intravenous infusion to help break down the buildup of lipids. However, this treatment does not cure the condition but only manages symptoms.
This document discusses various approaches for therapy of genetic diseases, including conventional and gene therapy approaches. Conventional approaches include dietary therapy, protein/enzyme replacement, pharmacal therapy, and surgery. Gene therapy involves the deliberate introduction of genetic material into human cells for therapeutic purposes, and can be done through somatic or germline cell gene therapy, as well as ex vivo or in vivo approaches. Viral vectors are commonly used to deliver the therapeutic gene to target cells.
18 June 2015 Rare Disease Site & Patient Recruitment KJAKevin J. Anderson
This document discusses challenges and approaches for site and patient recruitment in rare disease clinical studies. Key challenges include the rarity of diseases, difficulty finding patients and physicians, complex logistics, and vulnerable patient populations. Effective approaches involve casting a wide net globally, leveraging registries and advocacy groups, using medical informatics to identify sites, and hiring specialists to assist with outreach and education. Lessons learned emphasize starting recruitment efforts early, challenging site estimates, and ensuring multiple potential enrollment sites are identified for each patient.
Slides presentate dalla dr.ssa Andrea Dardis, responsabile del Laboratorio del Centro Malattie Rare di Udine, al corso "La malattia di Fabry: conoscere per riconoscere", Udine, 17 giugno 2015.
This document discusses the importance and therapeutic benefits of enzymes. It explains that enzymes are proteins that act as catalysts for biochemical reactions in living things. The document discusses theories that sufficient enzymes may help break down cancer cells and support the immune system in fighting cancer. It also outlines the history of enzyme therapy for cancer treatment dating back to the 1940s and reviews current research on how enzymes may help inhibit cancer progression and metastasis.
The patient presents with abdominal pain, foamy urine, and diarrhea after eating. Examination reveals tiny reddish-blue papules on the buttocks and groin, and a whorl-type pattern in both corneas. These symptoms suggest Fabry disease, an X-linked recessive lysosomal storage disease caused by alpha-galactosidase deficiency leading to lipid accumulation. This results in organ involvement like the kidneys, heart, and gastrointestinal system, as well as peripheral neuropathy. Diagnosis is confirmed through enzyme testing and treatment involves enzyme replacement therapy.
The document summarizes a business plan presentation for a proposed reference laboratory for pharmacogenomics. The founders, Sandeep Saxena and Sunil Kumar, have experience in life sciences and business. They propose to establish a laboratory that performs genetic tests to predict patients' responses to drugs, with an initial focus on cancer therapies. This could help identify patients likely to benefit from drugs, experience side effects, or be at high risk, in order to optimize treatment outcomes. The business plan outlines market opportunities, examples of genetic tests, the team, advisors, competition, risks, finances, investments required, and next steps.
- Glycosaminoglycans (GAGs) are long, negatively charged, unbranched heteropolysaccharide chains composed of repeating disaccharide units. The major GAGs include hyaluronic acid, chondroitin sulfate, keratin sulfate, dermatan sulfate, heparin, and heparan sulfate.
- GAGs are important structural components of connective tissues and play roles in cell signaling and adhesion. They bind large amounts of water and lubricate joints.
- Mucopolysaccharidoses are a group of inherited disorders caused by deficiencies of lysosomal enzymes that degrade GAGs, leading to their accumulation in tissues and symptoms like skeletal abnormalities and developmental delays.
Lysosomal storage diseases are a group of disorders caused by deficiencies in lysosomal enzymes, leading to an accumulation of substrates. Some key lysosomal storage diseases discussed include Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, Krabbe disease, and Batten disease. Gaucher disease results from glucocerebrosidase deficiency and causes liver and spleen enlargement. Tay-Sachs disease is fatal in most cases due to hexosaminidase A deficiency, causing mental retardation and cherry red spots. Niemann-Pick disease involves sphingomyelinase deficiency and causes liver/spleen enlargement and neurological symptoms.
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
Metabolic bone disease with focus on hypophosphatasiaAbdulmoein AlAgha
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Lesson 7.1 inborn errors of metabolism princesa2000
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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.
Pomps disease | genetic disorder |neuromuscular disease |GAA disorderNEHA MALIK
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Definition:
Many childhood conditions are caused by gene mutations that encode specific proteins. These mutations can result in the alteration of primary protein structure or the amount of protein synthesized.
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These hereditary biochemical disorders are collectively termed as ‘’Inborn errors of metabolism’’
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A branch of medicine dealing with diseases and metabolic disorders that affect mitochondria. Focusing on diagnosing and treatment of wide range of these diseases. The symptom of these diseases varies from metabolic-induced developmental delay to complex problems that involve many body systems.
1. Researchers generated a knockout mouse model of Pompe disease by disrupting the murine acid α-glucosidase gene (Gaa). Mice with this gene knockout (Gaa-/-) represented both the infantile and adult phenotypes of the human lysosomal storage disorder.
2. Comparison of different mouse models found that mice with a disruption of exon 13 remained healthy while mice with disruptions of exon 6 and 14 showed weakness and increased glycogen accumulation, particularly in the heart muscle.
3. Emerging treatments for Pompe disease in mouse models include recombinant human acid α-glucosidase enzyme with optimized carbohydrate structures to enhance uptake in muscles and a "double knockout" mouse model suppressing both
Knockout mouse model of Pompe Disease(Group 8)Sindu09
1. Researchers generated a knockout mouse model of Pompe disease by disrupting the murine acid α-glucosidase gene (Gaa). Mice with this gene knockout (Gaa-/-) lacked acid α-glucosidase and accumulated glycogen in their lysosomes, mimicking the disease.
2. Comparison of different mouse models found that disruption of exon 13 represented the infantile form, while disruption of exon 6 represented both infantile and adult forms, showing varying degrees of weakness and glycogen storage.
3. Future research includes developing new recombinant enzymes and investigating alternative treatment approaches, such as suppressing the starch binding domain-containing protein 1 gene along with acid α-glucosidase.
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Enzyme Replacement Therapy for Lysosomal Storage Diseases
1. Enzyme Replacement Therapy for
Lysosomal Storage Diseases
PHS Lecture Series
Roy Maynard, MD
March 18, 2010
2. Objectives
1. Understand the pathophysiology of
lysosomal storage diseases
2. Identify lysosomal storage diseases
amenable to enzyme replacement therapy
3. Understand the limitations of enzyme
replacement therapy
4. Recognize side effects of IV enzyme
replacement therapy
2
3. What is a Lysosome?
• Spherical organelles, discovered 1949
• Contain enzymes (acid hydrolases)
• Role in digestion “suicide sacs”
• Low pH
• Cells’ garbage disposal system
3
7. Pompe’s Disease
• Genetics
– Autosomal recessive
– Pan-ethnic 1/40,000 – 1/146,000
– Infantile and late onset forms
– Glycogen storage disease type II
– Acid alpha-glucosidase deficiency
– Over 200 different mutations account for
clinical heterogeneity
7
8. Pompe’s Disease
Autosomal Recessive
http://www.pompe.com/en/healthcare-professionals/genetics-epidemiology.aspx. Accessed on March 16, 2010.
8
9. Pompe’s Disease
• Clinical features infantile form
– Normal birth history
– Age at presentation 2–4 months
– Muscle weakness, hypotonia
– Macroglossia
– Hypertrophic cardiomyopathy
– Respiratory failure
– Early death
9
10. Infantile Pompe’s Disease Survival
http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition. Accessed on March 16, 2010.
10
11. Pompe’s Disease
Head lag caused by muscle weakness
http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010.
11
12. Pompe’s Disease
Cardiomegaly in infant
http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010.
12
13. Pompe’s Disease
• Clinical features late onset form
– Normal birth history
– Heterogeneous (childhood, juvenile, adult)
– Adult onset 2nd to 6th decade
– Typically no severe cardiomyopathy
– Progressive skeletal myopathy
13
15. Pompe’s Disease
• Pathophysiology
– Accumulation glycogen in liver, heart, skeletal
muscle, smooth muscle in GI tract, ear
– Large glycogen deposits in muscle cells
(cardiac, skeletal, smooth) impair muscle fiber
contraction
– Ultimately there is gross muscle hypertrophy
due to increased glycogen storage at the
expense of muscle atrophy and destruction
15
16. Glycogen Buildup in Pompe Disease
http://www.mda.org/publications/quest/q161RescuedLives.html. Accessed on March 15, 2010.
16
17. Electron Micrograph of Pompe
Affected Muscle Cell
http://www.pompe.com/en/healthcare-professionals/overview/pathology.aspx. Accessed on March 15, 2010.
17
19. Pompe’s Disease
• Enzyme replacement therapy
– Alpha-glucosidase (GAA)
– 1960’s enzyme replacement attempted
– 2006 recombinant GAA available
– IV dosing every 2 weeks
– Early treatment – better outcome
– Cell-surface receptors (mannose) plays a role in
endocytosis
• Mannose-6-phosphate (M6P) tag on enzymes
19
20. Myozyme Production
Production of acid a-glucosidase in Chinese hamster ovary (CHO-)
cells and in the milk of transgenic rabbits.
http://www.pompecenter.nl/en/?History. Accessed on March 16, 2010.
20
21. Pompe’s Disease
with Mannose 6-phosphate Tags
http://www.mda.org/publications/quest/q76resup.html. Accessed on March 15, 2010.
21
23. Pompe’s Disease
• Outcome after ERT
– Decrease glycogen in tissues
– Improved quality and quantity of life
– Decreased ventilator days
– Study n=18, enrolled <7 mths/age
• 3 needed vent within 12 mths, 4 more needed vent beyond 12
mths treatment and 2/4 died
• 2/9 that had increased motor gains lost ground
– Decrease in LV size (no correlation to clinical
outcome)
Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009 Sep;66(3):329-35.
23
24. Pompe’s Disease Outcomes
• French study
– N=21, 3–43 months age (median 13 mths)
– Treated median 120 weeks
– 71% alive study end
– 44% of vent free patients at time of enrollment
remained vent free
– Death reduced 79%
– Vent risk reduced 58%
– 86% functional independence skills (5 walking)
– 52% infusion-associated reactions
– 95% IgG antibodies
Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009 Mar;11(3):210-9.
24
25. Complications of Enzyme
Replacement Therapy (Pompe’s)
• Life-threatening anaphylaxis/cardiac arrest – 1%
• Allergic reaction – 14 %
• Infusion reaction – 51%
• 89% anti-IgG against GAA (higher incidence of
reactions in these patients and less efficacy
of GAA)
• Serum sickness in IgG positive patients
• Reactions can occur any time up to 2 hours after
infusion
25
52. Maroteaux-Lamy Syndrome
Normal Storage Disorder
Left: In a healthy cell
with sufficient ASB
activity, lysosomes
constitute a negligible
portion of cellular
volume (about 1%).15
Right: In an MPS cell,
lysosomes, replete with
excess GAG, increase in
both size and number,
crowding the nucleus and
other critical organelles,
engorging the cell.
http://www.naglazyme.com/en/Images/Patients/StorageDisorderCells.JPG. Accessed on March 15, 2010.
52
53. Maroteaux-Lamy Syndrome
• Treatment
– Palliative
– Bone marrow transplant
– Enzyme replacement therapy
• Naglazyme®
• Approved in 2005
• IV administration once/week
53
54. Maroteaux-Lamy Syndrome
• Initial reactions occurred as late as week 55
• The most frequent serious adverse events
related to Naglazyme® occurring during
infusions included urticaria of the face and
neck, bronchospasm, respiratory distress,
and apnea.
• Almost all patients develop IgG antibodies
54
55. Maroteaux-Lamy Syndrome
• Outcome
– Improved walking and stair climbing ability
– Decreased joint pain
– No change in facial features or skeletal
deformities
55
56. Treatment of Adverse Events
• Stop infusion or slow down infusion
• Steroids
• Antihistamines
• Epinephrine
• B-agonist nebulizer
• Antipyretics
56
57. Lysosomal Storage Diseases
Conclusions
• Orphan disease for many, not funded
• Enzyme replacement therapy very expensive
• Long-term outcomes largely unknown
• Limited results with CNS disease
• Not curative
• Difficult to target specific tissue (e.g. skeletal
muscle in Pompe’s Disease)
• Tissues involved may not sufficiently remodel,
need to diagnose early for best results
57
58. Future Considerations
• CNS penetration
• Improved tissue-specific penetration
• Stem cell transplant
• Endogenous enzyme modulation
• Gene therapy
• In the future, more genetic diseases
amendable to enzyme replacement therapy
will be discovered.
58
59. Essentials of Successful Home
Treatment Program
• Careful patient selection
• Experienced home infusion team
• Detailed management plan for potential
anaphylaxis and infusion-associated
reactions
59
60. Journal References
• Burton BK, Wiesman C, Paras A, Kim K, Katz R. Mol Genet
Metab. 2009 Jul;97(3):234-6. Epub 2009 Apr 21.
• Desnick RJ, Schuchman EH. Nat Rev Genet. 2002
Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157.
• Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009
Sep;66(3):329-35.
• Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009
Mar;11(3):210-9.
• Roscoe O Brady. Annual Review of Medicine. 2006;57: 283-96.
60
60
61. Suggested Reading
• Kishnani PS, Steiner RD, Bali D, Berger K, et al:
Pompe disease diagnosis and management guideline.
Genet Med. 2006 May;8(5):267-88. No abstract
available. Erratum in: Genet Med. 2006 Jun;8(6):382.
• Muenzer J, Wraith JE, Clarke LA:
Mucopolysaccharidosis I: management and treatment
guidelines. International Consensus Panel on
Management and Treatment of Mucopolysaccharidosis
I. Pediatrics. 2009 Jan;123(1):19-29.
61