Eric Niederhoffer SIU-SOM A 7-year-old boy is brought to the physician with a recent history of decreased activity When do you suspect 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 63-year-old woman is brought to the physician for evaluation of her “parkinsonism”

Metabolism in Skeletal Muscle and Nervous Tissue Metabolism in skeletal muscle Pathways overview Regulation in skeletal muscle Ischemic forearm test Metabolism in nervous tissue Pathways overview 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 Glycolysis Glycogenolysis  -oxidation (ketone bodies) Krebs (tricarboxylic acid) cycle Branched-chain amino acids Electron transport chain Calcium regulation Key enzyme regulation

Acetyl-CoA Lactate No O 2 Production of ATP G6P Glucose Glycolysis Pyruvate Branched-chain amino acids Ile, Leu, Val Krebs cycle Electron Transport Chain Glycogen Glycogenolysis Ca 2+ Phosphorylase kinase a Ca 2+ PDH Ca 2+ ICDH,  KGDH Fatty acids  - Oxidation Ketone bodies Pathways Overview

Fatty acids  - Oxidation Glc Glycolysis Glycogen Glycogenolysis PDH PK PFK-1 PKA AC cAMPATP Ep  AR Acetyl-CoAPyr F6P F16BP PEP Pi IMP AMP NH 4 + AMP Pi Ca 2+ Phosphorylase kinase a G6P PP Ca 2+ PDHP PDHK PDH P PDH PFK-2 F26BP ATP Citrate Regulation in Skeletal Muscle

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-CoALactate hypoxia G6P Glucose Glycolysis Pyruvate Glycogen Glycogenolysis 2ATP 2ADP ATP AMP Adenylate kinase IMP AMP deaminase (hypoxia, low energy charge) NH 4 +

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

Acetyl-CoA Lactate (glial) Production of ATP Glycolysis G6P Glucose Pyruvate Branched-chain amino acids Ile, Leu, Val Krebs cycle Electron Transport Chain Glycogen Glycogenolysis Lactate No O 2 Fatty acids  -oxidation Ketone bodies Pathways Overview

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 Clinical Aspects for Inborn Errors of Metabolism in Muscles

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 Clinical Aspects for Inborn Errors of Metabolism in Nervous Tissue

Clinical/Laboratory Findings Clinical findingsAAOAUCDCDGSDFADLSDPDMD Episodic decompensationX++++X+--X Poor feeding, vomiting, failure to thrive X++++XX+++ Dysmorphic features and/or skeletal or organ malformations XX--XX+XX Abnormal hair and/or dermatitis -XX Cardiomegaly and/or arrhythmias -X--XX+-X Hepatosplenomegaly and/or splenomegaly X++++++XX Developmental delay +/- neuroregression +++XXX++++ Lethargy or comaX++ +X --X SeizuresXX+XXX++X Hypotonia or hypertonia++++X+X+X Ataxia-X+X-XX-- Abnormal odorX+X Laboratory Findings* Primary metabolic acidosis X++++X+--X Primary respiratory alkalosis HyperammonemiaX+++X-+--X HypoglycemiaXX-+X+--X Liver dysfunctionXXX+X+XXX Reducing substancesX KetonesAHAAL/ALAAH/A

Examples of Inherited Metabolic Disorders Krebs cycle 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 BC  KADH Maple syrup urine disease Branched-chain ketoaciduria Branched-chain  -keto acids  K  MV,  KIC,  KIV R5Pnucleotides Pentose Phosphate Pathway

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 Glycogen Storage Disease Type VII (Tarui Disease)

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 Pyruvate Dehydrogenase Complex Deficiency

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 Maple Syrup Urine Disease (Branched-Chain  -Ketoaciduria)

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 ( G M2 gangliosidoses - Tay Sachs disease ) Hormones ( hyperthyroidism ) Blood ( Sickle cell disease ) Connective tissue ( Marfan syndrome ) Kidney ( Alport syndrome ) Lung (  1 -antitrypsin deficiency ) Skin ( Albinism ) Inborn Errors of Metabolism

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 Ca 2+ 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?