Eric Niederhoffer SIU-SOM

1. A 54-year-old female presents to her family physician's office with a 2 week history of pain and numbness in her left hand A 7-year-old boy is brought to the physician with a recent history of decreased activity A 63-year-old woman is brought to the physician for evaluation of her “parkinsonism” When do you suspect problems in metabolic pathways? Eric Niederhoffer SIU-SOM

2. Metabolism in skeletal muscle Pathways overview Regulation in skeletal muscle Ischemic forearm test Metabolism in nervous tissue Pathways overview Clinical aspects Clinical aspects Clinical/laboratory findings Examples of inherited metabolic disorders Glycogen storage disease type VII Pyruvate dehydrogenase complex deficiency Maple syrup urine disease Inborn errors of metabolism Review questions Metabolism in Skeletal Muscle and Nervous Tissue

3. Metabolism in Skeletal Muscle • Glycolysis • Glycogenolysis • -oxidation (ketone bodies) • Krebs (tricarboxylic acid) cycle • Branched-chain amino acids • Electron transport chain • Calcium regulation • Key enzyme regulation

4. Ketone bodies Glucose Glycogen Glycolysis Fatty acids Glycogenolysis b-Oxidation Ca2+ Phosphorylase kinase a Ca2+ PDH No O2 Lactate Pyruvate Acetyl-CoA Electron Transport Chain Krebs cycle Branched-chain amino acids Ile, Leu, Val Ca2+ ICDH, aKGDH Pathways Overview G6P Production of ATP

5. Ep AR ATP Citrate AC cAMP ATP G6P PKA Ca2+ Phosphorylase kinase a F6P PFK-2 PP F26BP Pi IMP AMP NH4+ AMP Pi F16BP PEP PDHP Ca2+ PDHP PDHK Pyr Acetyl-CoA PDH Regulation in Skeletal Muscle Glc Glycolysis PFK-1 Glycogen Glycogenolysis b-Oxidation Fatty acids PK PDH

6. Glucose Glycogen Glycolysis Glycogenolysis G6P hypoxia Lactate Pyruvate Acetyl-CoA Adenylate kinase 2ADP ATP NH4+ AMP IMP 2ATP AMPdeaminase (hypoxia, low energy charge) Ischemic Forearm Test • Obtain baseline lactate and ammonia levels • Inflate blood pressure cuff and perform repetitive rapid grip exercise • Once fatigued, remove cuff and obtain blood samples for lactate and ammonia levels • Normal result is elevated lactate and ammonia then return to baseline in 10-15 minutes

7. Metabolism in Nervous Tissue • Glycolysis • Glycogenolysis (stress) • -oxidation (ketone bodies) • Krebs (tricarboxylic acid) cycle • Branched-chain amino acids • Electron transport chain

8. Glucose Ketone bodies Fatty acids Glycogen Glycolysis Glycogenolysis G6P b-oxidation Lactate (glial) No O2 Lactate Pyruvate Acetyl-CoA Electron Transport Chain Krebs cycle Branched-chain amino acids Ile, Leu, Val Pathways Overview Production of ATP

9. Clinical Aspects for Inborn Errors of Metabolism in Muscles • Toxic accumulation disorders • Protein metabolism disorders (amino acidopathies, organic acidopathies, urea cycle defects) • Carbohydrate/intolerance disorders • Lysosomal storage disorders • Energy production/utilization disorders • Fatty acid oxidation defects • Carbohydrate utilization, production disorders (glycogen storage, gluconeogenesis, and glycogenolysis disorders) • Mitochondrial disorders • Peroxisomal disorders • Metabolic acidosis (elevated anion gap) • Hypoglycemia • Hyperammonemia

10. Clinical Aspects for Inborn Errors of Metabolism in Nervous Tissue • Evidence of familial coincidence • Progressive decline in nervous functioning • Appearance and progression of unmistakable neurologic signs • General symptoms • State of consciousness, awareness, reaction to stimuli • Tone of limbs, trunk (postural mechanisms) • Certain motor automatisms • Myotatic and cutaneous reflexes • Spontaneous ocular movements, fixation, pursuit; visual function • Respiration and circulation • Appetite • Seizures

11. Clinical/Laboratory Findings http://emedicine.medscape.com/article/804757-workup

12. Pentose Phosphate Pathway Glucose Glycogen R5P nucleotides G6P Glycogenolysis Glycogenesis Glycolysis Tarui disease Glycogen Storage Disease Type VII F6P PFK F16BP PDH complex deficiency PDH Acetyl-CoA Pyruvate Branched-chain amino acids Ile, Leu, Val Branched-chain -keto acids KMV, KIC, KIV BCKADH Krebs cycle Maple syrup urine disease Branched-chain ketoaciduria Examples of Inherited Metabolic Disorders

13. Glycogen Storage Disease Type VII (Tarui Disease) • Classic, infantile onset, Late onset • Exercise intolerance, fatigue, myoglobinuria • Phosphofructokinase • Tetramer of three subunits (M, L, P) • Muscle/heart/brain - M4; liver/kidneys - L4; erythrocytes - M4, L4, ML3, M2L2, M3L • General symptoms of classic form • Muscle weakness, pronounced following exercise • Fixed limb weakness • Muscle contractures • Jaundice • Joint pain • Laboratory studies • Increased serum creatine kinase levels • No increase in lactic acid levels after exercise • Bilirubin levels may increase • Increased reticulocyte count and reticulocyte distribution width • Myoglobinuria after exercise • Ischemic forearm test - no lactate increase with ammonia increase

14. Pyruvate Dehydrogenase Complex Deficiency • Neonatal, infantile, childhood onset • Abnormal lactate buildup (mitochondrial disease) • Pyruvate dehydrogenase complex • E1 -  (thiamine dependent) and  subunits, 22 tetramer • E2 - monomer (lipoate dependent) • E3 - dimer (riboflavin dependent) common to KGDH and BCαKDH • X protein - lipoate dependent • Pyruvate dehydrogenase phosphatase • Nonspecific symptoms (especially with stress, illness, high carbohydrate intake) • Severe lethargy, poor feeding, tachypnea • Key feature is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem (Leigh syndrome) • Infants with less than 15% PDH activity generally die • Developmental nonspecific signs • Mental delays • Psychomotor delays • Growth retardation • Laboratory studies • High blood and cerebrospinal fluid lactate and pyruvate levels • Elevated serum and urine alanine levels • If E2 deficient, elevated serum AAs and hyperammonemia • If E3 deficient, elevated BCAA in serum, KG in serum and urine • Ischemic forearm test – lactate increases baseline

15. Maple Syrup Urine Disease (Branched-Chain -Ketoaciduria) • Classic (early) and late onset (5 clinical phenotypes; classic, intermediate, intermittent, thiamine-responsive, and E3-deficient) • Encephalopathy and progressive neurodegeneration • Branched-chain -ketoacid dehydrogenase complex • E1 -  (thiamine dependent) and  subunits, 22 tetramer • E2 - monomer (lipoate dependent) • E3 - dimer (riboflavin dependent) common to KGDH and PDH • BCαKADH kinase • BCαKADH phosphatase • Initial symptoms • Poor feeding, vomiting, poor weight gain, and increasing lethargy • Neurological signs • Alternating muscular hypotonia and hypertonia, dystonia, seizures, encephalopathy • Laboratory studies • Elevated BCAA in serum • Presence of alloisoleucine in serum • Presence of -HIV, lactate, pyruvate, and KG in urine • Treatment • Restriction of BCAA • Supplementation with thiamine

16. Inborn Errors of Metabolism Carbohydrates (Glycogen storage diseases) Amino acids (Maple syrup urine disease) Organic acids (Alkaptonuria) Mitochondrial function (Pyruvate dehydrogenase deficiency) Purines and pyrimidines (Lesch-Nyhan disease) Lipids (Familial hypercholesterolemia) Porphyrins (Crigler-Najjar syndromes) Metals (Hereditary hemochromatosis) Peroxisomes (X-linked adrenoleukodystrophy) Lysosomes (GM2gangliosidoses - Tay Sachs disease) Hormones (hyperthyroidism) Blood (Sickle cell disease) Connective tissue (Marfan syndrome) Kidney (Alport syndrome) Lung (1-antitrypsin deficiency) Skin (Albinism)

17. How does muscle produce ATP (carbohydrates, fatty acids, ketone bodies, branched-chain amino acids)? How is skeletal muscle phosphofructokinase-1 regulated? What are the key Ca2+ regulated steps? How does nervous tissue (neurons and glial cells) produce ATP (carbohydrates, fatty acids, ketone bodies, branched-chain amino acids)? How do glial cells (astrocytes) assist neurons? What are some key clinical features (history, physical, laboratory test results) associated with defects in metabolism that affect muscles and nervous tissue? Review Questions