Lynne A. Wolfe, MS, ACNP, PNP, BC Department of Genetics Yale School of Medicine

Lynne A. Wolfe, MS, ACNP, PNP, BC Department of Genetics Yale School of Medicine

Harvey Levy, MD Mark Korson, MD Piero Rinaldo, MD, PhD Larry Sweetman, PhD K. Michael Gibson, PhD Charlie Roe, MD Jerry Vockley, MD, PhD

Organic Acidemias Alanine SUGAR FAT PROTEIN Lactate/Pyruvate TCA Abnormal Acylcarnitine Profile Abnormal Amino acids & Ammonia High Lactate Low blood sugar BCAA Carnitine Mitochondria ETC Serum Amino acids Ammonia UREA CYCLE Carnitine ATP High urine ketones Abnormal Urine Organic acids Low Carnitine

R Side chain +H3N CH C O Amino Group O Carboxyl Group

Essential* Alanine Branched Chain Amino acids (BCAA) = Leucine, Valine, Isoleucine *Phenylalanine Threonine Tryptophan *Methionine Lysine Histidine Non-essential Sulfur-based Amino acids = *Methionine Homocysteine Homocysteine Cysteine Aromatic Amino acids = *Phenylalanine Tyrosine Urea Cycle Amino acids = Arginine Citrulline Ornithine Glycine Proline Serine Glutamine

CONDITIONALLY-essential Cysteine growing children & Homocystinuria Tyrosine growing children & PKU Histidine growing children Arginine growing children & urea cycle disorders Citrulline urea cycle disorders Phenylalanine Tyrosinemia I

Glucogenic Alanine Valine Glycine Serine Threonine Histidine Arginine Cysteine Proline Methionine Glutamine/Glutamate Asparagine/Aspartate Ketogenic Leucine Lysine Both Isoleucine Threonine Phenylalanine Trytophan Tyrosine

R R R C C COOH R R R = Any Organic Residue (hydrogen, oxygen, carbon)

Organic Acids continued ONE Carboxy Group (COOH) = Monocarboxylic Acetic (2 carbons) Propionic (3 carbons) Butyric/Isobutyric (4 carbons) Valeric/Isovaleric (5 carbons) Caproic (6 carbons) TWO Carboxy Groups (COOH) = Dicarboxylic Oxalic (2 carbons) Malonic (3 carbons) Succinic (4 carbons) Glutaric (5 carbons) Adipic (6 carbons)

Organic Acids continued ONE Carboxy Group (COOH) = Monocarboxylic Propionic (3 carbons) CH 3 CH2 COOH TWO Carboxy Groups (COOH) = Dicaboxylic Malonic (3 carbons) COOH CH2 COOH

Fatty Acid Oxidation Disorders Alanine SUGAR FAT PROTEIN Lactate/Pyruvate Acetyl CoA TCA Abnormal Acylcarnitine Profile High or normal Ammonia +/- High Lactate Low blood sugar LCFA Serum Amino acids BCAA Ammonia MCFA Carnitine SCFA UREA CYCLE Mitochondria ETC Carnitine ATP Low urine ketones Abnormal Urine Organic acids Abnormal Acylglycines High or Low Carnitine

Acetone breath it off, breath smells sweet Aceto-acetic acid (AcAc) measured in urine & blood Beta (3)-hydroxy Butyrate (3HBA) measured in blood These are Organic acids

The metabolism of ketones feeds the TCA cycle (anapleurosis) by supplying fuels to run it: Even chain Acetyl CoA Odd Chain Succinyl CoA/Succinate

Fasting OR excessive energy consumption Glycogen depletion (liver & skeletal muscle) Mobilized Fatty acids from Adipose tissue in the liver

Response to fasting or excessive energy consumption Physiologic Iatrogenic Ketogenic Diet MCT Oil therapy Treatment for some Fatty Acid Oxidation disorders

Diabetes failed cellular uptake of glucose from blood triggers liver synthesis of ketones for energy. Organic Acidemias failed gluconeogenesis increases metabolism of ketogenic amino acids to meet current energy needs. Fatty Acid Oxidation disorders failed synthesis of enough ketones to meet current energy needs after glucose stores have been used up.

Less Glycogen or fat stores Immature hormonal control of glucose metabolism Higher energy needs to maintain normal body temperature, brain function & growth

Family (Genetic) tendencies Pubertal growth spurt & sexual maturity are dependent on enough body fat Adult males 5%, Adult Females 12% Mean takeoff age Boys 11 years, Girls 9 years

Peak height velocity Boys 13.5 years, Girls 11.5 years Pubertal growth spurt contribution to adult height Boys 30-31 cm, Girls 27.5-29 cm Complete skeletal maturation Boys 22-23 years, Girls 19-20 years

Endocrine Hypothyroid, Growth hormone deficiency, Cushing s syndrome Psycho-social Neglect, abuse Iatrogenic Brain/Spine Radiation, Steroid use Chronic Illness GI, Renal, Cardiac, Hematologic, Cystic Fibrosis, Inborn Errors of Metabolism, Mitochondrial disease

Nutritional Protein, carbohydrate, fat OR micro/macronutrient deficiencies Intra-Uterine Growth Retardation (IUGR) Chromosome abnormalities Trisomy 21, Turner s Syndrome, Prader-Willi Syndrome Skeletal Dysplasia

Bone & muscle growth peaks between 13-17 years & is most critical between 14-15 years of age Menses is CATABOLIC Estrogen lowers seizure thresholds Pregnancy is ANABOLIC but Post-Partem is CATABOLIC

Questions??