Eric Niederhoffer SIU-SOM

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Year Two Review Part 1. Eric Niederhoffer SIU-SOM. Outline. Newborn screening Glycolytic pathway Pentose phosphate pathway Fructose pathway Pyruvate metabolism and citric acid cycle β-Oxidation Urea cycle Branched-chain amino acids Aromatic amino acids Cholesterol pathway - PowerPoint PPT Presentation

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Eric NiederhofferSIU-SOMYear Two ReviewPart 11OutlineNewborn screeningGlycolytic pathwayPentose phosphate pathwayFructose pathwayPyruvate metabolism and citric acid cycleFatty acid/-oxidationUrea cycleBranched-chain amino acidsAromatic amino acidsCholesterol pathwaySteroid pathway2Newborn ScreeningAmino acid disordersArginemia/arginase deficiencyArginosuccinyl CoA lyase deficiencyCitrullinemia/argininosuccinate synthetase deficiencyHomocystinemia/cystathionine -synthase deficiencyMaple syrup urine diseasePhenylketonuriaTyrosinemiaFatty acid oxidation disordersCarnitine transporter deficiencyCarnitine/acylcarnitine translocase deficiencyCarnitine palmitoyl transferase deficiency Type 1Carnitine palmitoyl transferase deficiency Type 2Glutaric acidemia Type 2Long-chain 3-hydroxyacyl CoA dehydrogenase deficiencyMedium-chain acyl CoA dehydrogenase deficiencyShort-chain acyl CoA dehydrogenase deficiencyShort-chain 3-hydroxyacyl CoA dehydrogenase deficiencyTrifunctional protein deficiencyVery long-chain acyl CoA dehydrogenase deficiency3From http://www.newbornscreening.info/Parents/facts.htmlNewborn ScreeningOrganic acids disorders-Ketothiolase deficiencyGlutaric acidemia Type 1Glutaric acidemia Type 2Holocarboxylase synthetase deficiency3-Hydroxy-3-methylglutaryl CoA lyase deficiencyIsobutyryl CoA dehydrogenase deficiencyIsovaleic aciduriaMethylmalonic acidemiaMethylmalonic acidemia with homocystinuriaPropionic acidemia3-Methylcrotonyl CoA carboxylase deficiency2-Methylbutyryl CoA dehdrogenase deficiencyOther disorders-ThalassemiaCongenital adrenal hyperplasiaCystic fibrosisCritical congenital heart diseaseCongenital hypothyroidismGalactosemiaSickle cell disease4From http://www.newbornscreening.info/Parents/facts.htmlGlycolytic Pathwayglucoseglucose-6-phosphatefructose-6-phosphatefructose-1,6-bisphosphatedihydroxyacetone phosphateglyceraldehyde-3-phosphate1,3-bisphosphoglycerate3-phosphoglycerate2-phosphoglyceratephosphoenolpyruvatepyruvatelactate2,3-bisphosphoglycerateHexokinase (glucokinase)Glucose phosphate isomerasePhosphofructokinase-1AldolaseGlyceraldehyde-3-phosphate dehydrogenase3-Phophoglycerate kinaseEnolasePyruvate kinasePhosphoglycerate mutaseAldolaseTriose phosphate isomeraseBisphosphoglycerate mutase2,3-Bisphosphoglycerate phosphataseLactate dehydrogenaseATPATPATPATPNAD+NADHNAD+NADH5Glycolytic Pathway DisordersHexokinase rare autosomal recessive, nonspherocytic hemolytic anemia.Phosphoglucose isomerase rare autosomal recessive, hemolytic anemia, less common neurological problems.Phosphofructokinase (Glycogen storage disease type VII; Tarui disease) rare autosomal recessive, three subtypes (classic, infantile onset, and late onset), myoglobinuria, hyperuricemia, hemolytic anemia when erythrocyte isoform is involved. Avoid high carbohydrate meals.Adolase rare autosomal recessive, three genes (ALDOA, mainly muscle; ALDOB, mainly liver, some kidney and intestine; ALDOC, mainly brain), ALDOA has myopathy and hemolytic anemia. ALDOB (hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis, treat by restricting fructose.Triosephosphate isomerase rare autosomal recessive, congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy.Glyceraldehyde-3-phosphate dehydrogenase rare autosomal recessive, very little information available.

6Glycolytic Pathway DisordersBisphosphoglycerate mutase/phosphatase rare, hemolytic anemia, polycythemia, increased hemoglobin affinity for O2.Phosphoglycerate kinase rare X-linked recessive, two forms, chronic hemolytic anemia, myopathic (myoglobinuria) with muscle symptoms especially upon exercise.Phosphoglycerate mutase rare autosomal recessive, mainly affects skeletal muscle.Enolase rare autosomal recessive, affects muscle, exercise intolerance.Pyruvate kinase autosomal recessive, most common inherited cause of nonspherocytic hemolytic anemia (normochromic, normocytic, and reticulocytosis), pallor, jaundice, fatigue, dyspnea, tachycardia and splenomegaly. Treatment is primarily supportive, avoid impact sports with splenomegaly, avoid large doses of salicylates, supplement with folic acid and B vitamins, use blood transfusions with decreased hemoglobin concentrations.Lactate dehydrogenase rare autosomal recessive, two forms, LDHA is mainly skeletal muscle, LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB subunits. LDHA deficiency symptoms include fatigue, muscle pain, exercise intolerance, rhabdomyolysis, and myoglobinuria. LDHB deficiency is asymptomatic.

7Pentose Phosphate Pathwayglucose-6-phosphate6-phosphoglucono--lactone6-phosphogluconateribulose-5-phosphatexylulose-5-phosphateribose-5-phosphatesedoheptulose-7-phosphateglyceraldehyde-3-phosphateerythrose-4-phosphatefructose-6-phosphatefructose-6-phosphateglyceraldehyde-3-phosphateGlucose-6-phosphate dehydrogenase6-Phosphogluconate dehydrogenaseLactonaseRibose-5-phosphate isomeraseRibulose phosphate 3 epimeraseTransketolaseTransaldolaseTransketolaseNADP+NADPHNADP+NADPH8Pentose Phosphate Pathway DisordersGlucose-6-phosphate dehydrogenase X-linked recessive, most common disease-producing enzymopathy, hemolytic anemia most often triggered by bacterial or viral infections, oxidative drugs (sulfonamides and malarials), or eating fava beans (favism). Treatment is supportive, bed rest and oxygen, avoid triggers (drugs, diet, environmental).Ribose-5-phosphate isomerase very rare (single report), leukoencephalopathy and peripheral neuropathy.Transketolase very rare (single report), liver cirrhosis and hepatosplenomegaly.9Fructose Pathwayfructosefructose-1-phosphateglyceraldehydeglyceraldehyde-3-phosphatedihydroxyacetone phosphateATPATPFructokinaseAldolase BTriose kinaseTriose phosphate isomerase10Fructose Pathway DisordersFructokinase autosomal recessive, benign.Aldolase B autosomal recessive, (hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis. Treatment by restricting fructose intake.11Pyruvate Metabolism and Citric Acid Cycleacetyl-CoAisocitrateAconitasemalateFumarase-ketoglutarateIsocitrate dehydrogenaseNAD+NADHsuccinyl-CoA-Ketoglutarate dehydrogenaseNAD+NADHsuccinateSuccinyl-CoA synthetaseGDPGTPcitrateoxaloacetateCitrate synthasefumarateSuccinate dehydrogenaseFAD+FADH2Malate dehydrogenaseNAD+NADHpyruvatePyruvate dehydrogenasePyruvate carboxylaselactateLactate dehydrogenaseNAD+NADH2ATP12Pyruvate and Citric Acid Cycle DisordersPyruvate dehydrogenase rare, mostly sporadic, X-linked recessive (E1 -subunit), autosomal recessive (X protein and E3 subunit), developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, seizures (all dependent on amount of residual enzyme activity,