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When do you suspect common or rare problems in metabolic pathways?
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 common or rare problems in metabolic pathways? Eric Niederhoffer Medical Biochemistry
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Metabolism and Rare Disorders in Skeletal Muscle and Nervous Tissue
Metabolism in skeletal muscle Pathways overview Regulation in skeletal muscle Ischemic forearm test Metabolism in nervous tissue Clinical aspects (muscle) Clinical aspects (nervous tissue) 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
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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 Faster rate of glycogen use, slower rate of fatty acids use (50% compared with glycogen) Liver/muscle store glycogen, liver releases glucose, muscle uses glucose-6-phosphate Fats from adipose tissue (hormone sensitive lipase), VLDL (lipoprotein lipase), intramuscular triacylglycerols (less important)
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Phosphorylase kinase a
Pathways Overview Ketone bodies Glucose Glycolysis Glycogen Glycogenolysis Fatty acids β-Oxidation G6P Ca2+ Phosphorylase kinase a Pyruvate Ca2+ PDH Lactate No O2 Acetyl-CoA Krebs cycle Electron Transport Chain Branched-chain amino acids Ile, Leu, Val Ca2+ ICDH, αKGDH G6P: glucose-6-phosphate PDH: pyruvate dehydrogenase Ile: isoleucine & Val: valine (enter as succinyl CoA); Leu: leucine (enters as acetyl CoA) ICDH: isocitrate dehydrogenase aKGDH: a-ketoglutarate dehydrogenase ATP: adenosine triphosphate Fast twitch (Type 2) fibers (white) use anaerobic glycolysis, glycogen Slow twitch (Type 1) fibers (red, myoglobin) use oxidative metabolism, -oxidation, fatty acids Branched-chain amino acid (BCAA) aminotransferase higher than BCAA dehydrogenase, but increases in starvation. Both PDH and aKGDH are regulated by kinase/phosphatase modifications. Lactate dehydrogenase is also found associated with outer mitochondrial membrane to oxidize lactate. Production of ATP
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Regulation in Skeletal Muscle
PKA AC cAMP ATP Ep AR Glc Glycolysis G6P PP ATP Citrate Acetyl-CoA Pyr F6P F16BP PEP Ca2+ Phosphorylase kinase a PFK-2 F26BP NH4+ AMP Pi Pi IMP AMP PFK-1 Glycogen Glycogenolysis β-Oxidation Ep: epinephrine AR: adrenergic receptor AC: adenylyl cyclase cAMP: cyclic adenosine monophosphate PKA: protein kinase A PP: glycogen phosphorylase Pi: inorganic phosphate IMP: inosine monophosphate Glc: glucose F6P: fructose-6-phosphate G6P: glucose-6-phosphate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase PDHP (or K): pyruvate dehdrogenase phosphatase (or kinase) 2ADP to ATP + AMP by adenylate kinase; AMP to IMP by AMP-deaminase AMP to adenosine by 5’-nucleotidase, adenosine binds to A2 receptors leading to vasodilation (increased blood supply to muscles) AMP regulates glycogen phosphorylase in brain & muscle but not liver. Ca2+ PDHP PDHK PDH Fatty acids PK PDH
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(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 minutes Acetyl-CoA Lactate hypoxia G6P Glucose Glycolysis Pyruvate Glycogen Glycogenolysis ATP AMP Adenylate kinase 2ATP 2ADP IMP AMP deaminase (hypoxia, low energy charge) NH4+ ATP: adenosine triphosphate ADP: adenosine diphosphate AMP: adenosine monophosphate IMP: inosine monophosphate AMP deaminase = myoadenylate deaminase
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Metabolism in Nervous Tissue
Glycolysis Glycogenolysis (stress) -oxidation (ketone bodies) Krebs (tricarboxylic acid) cycle Branched-chain amino acids Electron transport chain Nervous tissue is ~2.5% of body weight (83% of this is brain) Brain uses 15% of cardiac output, 20% of total oxygen consumption Recall that nitrogen metabolism removes excess ammonia (NH4+) from the body through the use of the urea cycle, which otherwise would enter neurons and glia to unbalance glutamate and glutamine concentrations.
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Pathways Overview Production of ATP Glycolysis G6P Glucose Pyruvate
Ketone bodies Glycogen Glycogenolysis Fatty acids β-oxidation Lactate (glia) Lactate No O2 Acetyl-CoA Krebs cycle NH4+ + Glutamate Glutamine Gln synthetase (astrocytes) Electron Transport Chain Branched-chain amino acids Ile, Leu, Val G6P: glucose-6-phosphate Gln: glutamine Ile: isoleucine & Val: valine (enter as succinyl CoA); Leu: leucine (enters as acetyl CoA) ATP: adenosine triphosphate Ketone bodies come from from liver GLUT1, GLUT3 in nervous tissue Brain accounts for 25% total body Glc utilization Energy - 80% from Glc, up to 20% from ketone bodies, 5% from glycogen (main stores are astrocytes) Astrocytes make lactate and pyruvate (does not cross blood brain barrier). BBB appears to be permeable to lactate, up to 50% that of glucose. Unsaturated fatty acids can go through BBB (astrocytes do -oxidation, mitochondrial and peroxisomal) Neurons do not appear to express PFK-2. Ketogenesis from fatty acid (palmitic acid) occurs in retinal pigment epithelium. Production of ATP
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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 Collectively, 1 in 4,000 incidence ( Up to 20% of newborns who develop sepsis symptoms (without known risk factors) may have a metabolic defect
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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 With hepatic encephalopathy, serum NH4+ increases beyond the capacity of muscle, kidneys, and astrocytes. Within the brain (CNS), NH4+ + α-ketoglutarate forms glutamate as catalyzed by glutamate dehydrogenase using NADPH. The concentrations of αKG as well as oxaloacetate decrease, which decrease the activity of the TCA cycle. Collectively, 1 in 4,000 incidence ( Up to 20% of newborns who develop sepsis symptoms (without known risk factors) may have a metabolic defect
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Clinical/Laboratory Findings
Clinical findings AA OA UCD CD GSD FAD LSD PD MD Episodic decompensation X + ++ - Poor feeding, vomiting, failure to thrive Dysmorphic features and/or skeletal or organ malformations Abnormal hair and/or dermatitis Cardiomegaly and/or arrhythmias Hepatosplenomegaly and/or splenomegaly Developmental delay +/- neuroregression Lethargy or coma Seizures Hypotonia or hypertonia Ataxia Abnormal odor Laboratory Findings* Primary metabolic acidosis Primary respiratory alkalosis Hyperammonemia Hypoglycemia Liver dysfunction Reducing substances Ketones A H L/A L H/A *Within disease categories, not all diseases have all findings. For disorders with episodic decompensation, clinical and laboratory findings may be present only during acute crisis. For progressive disorders, findings may not be present early in the course of disease.++ = Always present.+ = Usually present.X = Sometimes present.- = Absent.H = Inappropriately high.L = Inappropriately low.A = Appropriate. AA: aminoacidopathies OA: organic acidopathies UCD: urea cycle defects CD: carbohydrate disorders GSD: glycogen storage diseases FAD: fatty acid oxidation defects LSD: lysosomal storage disorders PD: peroxisomal disorders MD: mitochondrial disorders
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Examples of Inherited Metabolic Disorders
R5P nucleotides Pentose Phosphate Pathway G6P Glucose Glycolysis Glycogen Glycogenolysis Glycogenesis F6P F16BP PFK Tarui disease Glycogen Storage Disease Type VII Acetyl-CoA Pyruvate PDH PDH complex deficiency Branched-chain amino acids Ile, Leu, Val BCKADH Maple syrup urine disease Branched-chain ketoaciduria Branched-chain -keto acids KMV, KIC, KIV Krebs cycle G6P: glucose-6-phosphate F6P: fructose-6-phosphate PFK-1: phosphofructokinase-1 F16BP: fructose-1,6-bisphosphate Ile: isoleucine Leu: leucine Val: valine PDH: pyruvate dehydrogenase R5P: ribose-5-phosphate KMV: -keto--methylvalerate KIC: -ketoisocaproate KIV: -ketoisovalerate BCαKADH: branched-chain α-keto acid dehydrogenase Brain normally has BCKADH, peripheral nerves don’t. BCKADH regulated by kinase/phosphatase. Inner mitochondrial membrane transporter for pyruvate.
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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 Autosomal recessive
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Pyruvate Dehydrogenase Complex Deficiency
Neonatal, infantile, childhood onset Abnormal lactate buildup (mitochondrial disease) Pyruvate dehydrogenase complex E1 - (thiamine dependent) and subunits, 22 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 Most common form is X-linked dominant PDH: pyruvate dehydrogenase KGDH: -ketoglutarate dehydrogenase BCAA: branched-chain amino acids BCαKDH: branched-chain -ketoacid dehydrogenase AAs: amino acids For additional examples of mitochondrial disease, see Types of mitochondrial disease and Mitochondrial disorders overview
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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, 22 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 Autosomal recessive Special diet needed; 4 children in St. Louis. KGDH: -ketoglutarate dehydrogenase PDH: pyruvate dehydrogenase BCαKADH: branched-chain -ketoacid dehydrogenase BCAA: branched-chain amino acids -HIV: -hydroxyisovalerate
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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 (GM2 gangliosidoses - Tay Sachs disease) Hormones (hyperthyroidism) Blood (Sickle cell disease) Connective tissue (Marfan syndrome) Kidney (Alport syndrome) Lung (1-antitrypsin deficiency) Skin (Albinism) For additional examples (Year Two Review 1, 2) Lyon, G., R. D. Adams, and E. H. Kolodny Neurology of hereditary metabolic diseases in children, 3rd ed. McGraw-Hill, Inc., New York. Scriver, C. R., A. L. Beaudet, D. Valle, W. S. Sly, B. Childs, K. Kinzler, and B. Vogelstein (ed.) The metabolic and molecular bases of inherited disease, 8th ed. McGraw-Hill, Inc., New York.
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Review Questions 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?
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