Eric Niederhoffer SIU-SOM Year Two Review Part 1

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Eric Niederhoffer SIU-SOM Year Two Review Part 1 Slide 2 Outline Newborn screening Glycolytic pathway Pentose phosphate pathway Fructose pathway Pyruvate metabolism and citric acid cycle -Oxidation Urea cycle Branched-chain amino acids Aromatic amino acids Cholesterol pathway Steroid pathway Slide 3 Newborn Screening Amino acid disorders Arginemia/arginase deficiency Arginosuccinyl CoA lyase deficiency Citrullinemia/argininosuccinate synthetase deficiency Homocystinemia/cystathionine -synthase deficiency Maple syrup urine disease Phenylketonuria Tyrosinemia Fatty acid oxidation disorders Carnitine transporter deficiency Carnitine/acylcarnitine translocase deficiency Carnitine palmitoyl transferase deficiency Type 1 Carnitine palmitoyl transferase deficiency Type 2 Glutaric acidemia Type 2 Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency Medium-chain acyl CoA dehydrogenase deficiency Short-chain acyl CoA dehydrogenase deficiency Short-chain 3-hydroxyacyl CoA dehydrogenase deficiency Trifunctional protein deficiency Very long-chain acyl CoA dehydrogenase deficiency Slide 4 Newborn Screening Organic acids disorders -Ketothiolase deficiency Glutaric acidemia Type 1 Glutaric acidemia Type 2 Holocarboxylase synthetase deficiency 3-Hydroxy-3-methylglutaryl CoA lyase deficiency Isobutyryl CoA dehydrogenase deficiency Isovaleic aciduria Methylmalonic acidemia Methylmalonic acidemia with homocystinuria Propionic acidemia 3-Methylcrotonyl CoA carboxylase deficiency 2-Methylbutyryl CoA dehdrogenase deficiency Other disorders -Thalassemia Congenital adrenal hyperplasia Cystic fibrosis Critical congenital heart disease Congenital hypothyroidism Galactosemia Sickle cell disease Slide 5 Glycolytic Pathway glucose glucose-6-phosphate fructose-6-phosphate fructose-1,6-bisphosphate dihydroxyacetone phosphateglyceraldehyde-3-phosphate 1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate pyruvatelactate 2,3-bisphosphoglycerate Hexokinase (glucokinase) Glucose phosphate isomerase Phosphofructokinase-1 Aldolase Glyceraldehyde-3-phosphate dehydrogenase 3-Phophoglycerate kinase Enolase Pyruvate kinase Phosphoglycerate mutase Aldolase Triose phosphate isomerase Bisphosphoglycerate mutase 2,3-Bisphosphoglycerate phosphatase Lactate dehydrogenase ATP NAD + NADH NAD + NADH Slide 6 Glycolytic Pathway Disorders Hexokinase 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. Slide 7 Glycolytic Pathway Disorders Bisphosphoglycerate mutase/phosphatase rare, hemolytic anemia, polycythemia, increased hemoglobin affinity for O 2. 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. Slide 8 Pentose Phosphate Pathway glucose-6-phosphate6-phosphoglucono--lactone 6-phosphogluconate ribulose-5-phosphate xylulose-5-phosphateribose-5-phosphate sedoheptulose-7-phosphate glyceraldehyde-3-phosphate erythrose-4-phosphate fructose-6-phosphate glyceraldehyde-3-phosphate Glucose-6-phosphate dehydrogenase 6-Phosphogluconate dehydrogenase Lactonase Ribose-5-phosphate isomerase Ribulose phosphate 3 epimerase Transketolase Transaldolase Transketolase NADP + NADPH NADP + NADPH Slide 9 Pentose Phosphate Pathway Disorders Glucose-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. Slide 10 Fructose Pathway fructose fructose-1-phosphate glyceraldehydeglyceraldehyde-3-phosphate dihydroxyacetone phosphate ATP Fructokinase Aldolase B Triose kinase Triose phosphate isomerase Slide 11 Fructose Pathway Disorders Fructokinase 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. Slide 12 Pyruvate Metabolism and Citric Acid Cycle acetyl-CoA isocitrate Aconitase malate Fumarase -ketoglutarate Isocitrate dehydrogenase NAD + NADH succinyl-CoA -Ketoglutarate dehydrogenase NAD + NADH succinate Succinyl-CoA synthetase GDPGTP citrateoxaloacetate Citrate synthase fumarate Succinate dehydrogenase FAD + FADH 2 Malate dehydrogenase NAD + NADH pyruvate Pyruvate dehydrogenase Pyruvate carboxylase lactate Lactate dehydrogenase NAD + NADH 2ATP Slide 13 Pyruvate and Citric Acid Cycle Disorders Pyruvate 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,