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Metabolic Disorders

Metabolic disorders are caused by an abnormal metabolic process. It can be congenital due to inherited enzyme abnormality or acquired due to disease of an endocrine organ or failure of a metabolically important organ such as the liver. Inherited metabolic disorders are caused by a defect in a single gene. There are many inborn errors of metabolism. Some produce relatively unimportant physical features or skeletal abnormalities. Others produce serious disease and even death. Some of the more familiar inborn errors of metabolism are cystic fibrosis, hypothyroidism, sickle cell anemia, phenylketonuria (PKU) and Tay-Sachs disease.

Who is at Risk?

Inborn errors of metabolism affect about 1 in every 5,000 babies born. Parents who have had one child with an inborn error of metabolism are at risk to have other affected children. One in 4 pregnancies of such couples is expected to result in an affected child. Some inborn errors of metabolism are more often found in certain racial and ethnic groups. Sickle cell anemia, for example, is found among those of African descent. Those of European heritage are more likely to pass on defective genes for cystic fibrosis. The children of women with some inborn errors of metabolism are at risk because of an unfavorable environment in the womb.

Sources: Health On the Net Foundation, Patient Marketing Group, Inc.

Curtailing The Development Of Diabetes
TSRI scientists are proposing a new hypothesis about the cause of autoimmunity, in which components of a person's immune system attack his/her own tissues leading to diseases such as Type 1 diabetes and rheumatoid arthritis. While autoimmunity has traditionally been considered a condition of too much stimulation, the scientists led by TSRI Professor Nora Sarvetnick, Ph.D. saw a condition of not enough stimulation to fill the body with immune cells, resulting in too few T cells. The hypothesis provides a new way of thinking about how to make autoimmune diseases more preventable through stimulating the immune system by priming people with germs.

Type 1 (insulin-dependent) diabetes mellitus manifests when T cells become autoreactive and attack and kill beta cells in the pancreas, the body's source of insulin. Without insulin, the glucose in the bloodstream increases and is maintained at levels much greater than normal. Over time, this can lead to nerve and kidney damage, reduced eyesight, and an increased risk of developing heart disease and vascular degeneration. Insulin is a reasonable treatment, but Type1 diabetes is still a chronic infection for which there is no prevention and no cure. In the study, Sarvetnick and her colleagues look at the immune systems of a type of mouse called NOD, which is genetically prone to developing diabetes. The researchers infused and passively stimulated the immune systems of NOD mice with T cells, which prevented the NOD mice from developing diabetes.

This project is part of a program focusing on the basic mechanisms of autoimmunity that combines the research interests of Sarvetnick, Professor Linda Sherman, Ph.D., and Associate Professor Sue Webb, Ph.D. The program project grant funds studies in all three labs that focus on the specific goal of better understanding how the immune system goes awry in the development of Type 1 diabetes. Ultimately, the three scientists would like to understand the problems leading to Type 1 diabetes in order to be able to suggest new strategies for treatment as well as prevention.

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TSRI Scientists Develop Potential New Treatment for Gaucher Disease
A group of TSRI scientists have developed a compound that could potentially be used as a new treatment for Gaucher disease, the most common genetic disorder affecting Jewish people of Eastern European ancestry. Although not tested in humans, the compound has shown great promise in human cell lines cultured from patients who suffer from the disease. Patients with Gaucher disease may bruise easily due to low blood platelets, and they may have enlargement of the liver and spleen. Sometimes they experience fatigue due to anemia. The disease also causes cells in the bone marrow to become engorged with a fatty storage material, which may lead to bone lesions, weakening the skeleton, and sometimes resulting in painful fractures. In some instances, the disease also impairs the function of the lungs. The TSRI group used small molecules to partially correct the genetic defect that underlies most cases of Gaucher disease. The defect prevents a crucial metabolic enzyme from reaching the location in the cell where it normally functions, but the small molecules act as "chaperones," guiding the mutant enzyme to the right location and allowing it to survive and function.

This new approach may be less costly and more convenient than the current treatment, according to the researchers, Professor Jeffery W. Kelly, Ph.D., who is the Lita Annenberg Hazen Professor of Chemistry and vice president of academic affairs, and Professor Ernest Beutler, M.D. Gaucher disease is a genetic disease caused by heritable defects of an important metabolic enzyme called lysosomal beta-glucosidase. People with Gaucher disease have one or more defects in their beta-glucosidase genes, and these defects corrupt their beta-glucosidase enzyme. Most at risk for the disease are individuals of Eastern European Jewish ancestry (the so-called Ashkenazi Jews), among whom about 1 in 14 carry one copy of one of the mutations of beta-glucosidase. As a result, the prevalence of Gaucher disease among Ashkenazi Jews has been estimated to be about 1 in 800. In the general population, about 1 in every 40,000 to 100,000 people have Gaucher disease. The current approaches to treating Gaucher disease are extremely expensive, costing between $100,000 and $750,000 per year per patient. The current approach involves replacing the mutant enzyme; Kelly and Beutler's approach uses a small molecule to partially correct its imperfections.

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Promising Research On Potential Treatment Strategy For PKU
Children with phenylketonuria (PKU), an inherited metabolic disorder, cannot convert phenylalanine, a part of a protein, to tyrosine in the liver. Phenylalanine thus becomes toxic to the central nervous system, especially the brain. Since phenylalanine occurs in meat, fish, all dairy, flour, and even fruits and vegetables, children with PKU must go through life on a severely restricted diet and be monitored by frequent blood tests. Limiting phenylalanine in the diet is so difficult that many fail to avoid behavioral and intellectual problems as adolescents and adults.

TSRI Professor Raymond Stevens, Ph.D., is working with BioMarin Pharmaceuticals on a potential treatment strategy for PKU and similar diseases. This research shows the promise of using natural cofactors to provide some protection against the toxic effects of phenylalanine for patients with mild PKU and an enzyme replacement strategy for patients with severe PKU.

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Study Shows Enzyme Builds Neurotransmitters Via Newly Discovered Pathway - Findings Could Mean More Selective Treatment Options For Metabolic, Central Nervous System Disorders
Scientists at The Scripps Research Institute have uncovered a previously unknown function of an enzyme that appears to play a primary role in the biosynthesis of a large class of lipids that help modulate diverse physiological processes, including anxiety, inflammation, learning and memory, and appetite. The study was directed by Scripps Research Professor Benjamin Cravatt, Ph.D. The new study describes a pathway - different than the one previously suggested - for the biosynthesis of neurotransmitter lipids, N-acyl ethanolamines (NAEs), which include the endogenous cannabinoid ("endocannabinoid") anandamide. The high activity of the enzyme a/b hydrolase4 (Abh4) in areas such as the central nervous system suggests that the pathway makes a "potentially major contribution" to endocannabinoid signaling. Endocannabinoids are naturally produced substances similar to the active ingredient D9-tetrahydrocannabinol ( THC) in marijuana. Cannabinoid receptors were first discovered in 1988; the first endocannabinoid, anandamide, which shares some of the pharmacologic properties of THC, was identified in 1992. Other research has shown that the endogenous cannabinoid system helps control food intake, among other critical processes, by acting on cannabinoid receptors in the central nervous system. The system drives consumption of fat and calorie-rich foods and the amount of fat stored or expended and plays a significant role in energy homeostasis.

At least one cannabinoid receptor antagonist is on the verge of approval for the treatment of obesity-metabolic disorders. Enzymes involved in endocannabinoid biosynthesis, such as the one highlighted in the study, can be viewed as complementary drug targets. One potential advantage of this approach is that it may prove more selective than a receptor antagonist. By inhibiting enzymes such as Abh4, scientists may be able to disrupt the activity of a single class of endocannabinoids, rather than all of them. In the new study, the researchers provide biochemical evidence of an alternative pathway for NAE biosynthesis in vivo and demonstrate that these new routes are especially important for the creation of a number of NAEs, including anandamide. The researchers also isolated and identified the enzyme Abh4 by combining traditional protein purification and functional proteomic technologies, concluding that Abh4 "displayed multiple properties" that would be expected of an enzyme involved in NAE biosynthesis. However, the authors of the study noted, the unique contribution that this Abh4-mediated route makes to the production of NAEs in vivo is yet to be determined and will require the generation of genetic or pharmacological tools that selectively interrupt this pathway. The continued pursuit of additional enzymes involved in NAE biosynthesis should further enrich understanding of the complex metabolic network that supports the endocannabinoid/NAE system in vivo. From a therapeutic perspective, any of these enzymes could represent an attractive drug target for a range of human disorders in which disruption of endocannabinoid signaling by cannabinoid receptor antagonists has proven beneficial.

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