Inborn Errors of Metabolism Robert D. Steiner, MD Associate Professor, Pediatrics and Molecular and Medical Genetics Head: Division of Metabolism OHSU.
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Inborn Errors of Metabolism Robert D. Steiner, MD Associate Professor, Pediatrics and Molecular and Medical Genetics Head: Division of Metabolism OHSU Inborn Errors of Metabolism • IEM as a group are not rare: occur 1 in 5000 births collectively • Often treatable if diagnosed • Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation • Don’t be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM • Clues to presence of IEM may often be found in FH Incidence of Inborn Errors Class No. of Disorders Known Critical, life threatening disorders of infancy 70-80 Incidence ~1:5,000 Serious disorders compromising health in infants/adults >300 ~1:1,000 Common disorders of any age >300 ~1:50 Metabolic Diseases Which Can Present in Crisis • Defects of glucose homeostasis (20) • Defects of amino acids (10) Defects of fatty or organic acids • Defects of Lactate/Pyruvate • Defects of Peroxisomes • Others (20) (20) “Stumbling Blocks” in Diagnosing Inborn Errors of Metabolism • Signs and symptoms are often nonspecific – Routine childhood illnesses excluded 1st – Inborn errors considered only secondarily • Unfamiliarity with biochemical interrelationships/ diagnostic tests – Inappropriate sample collection – Inappropriate sample storage • Every child with unexplained . . . – Neurological deterioration – Metabolic acidosis – Hypoglycemia – Inappropriate ketosis – Hypotonia – Cardiomyopathy – Hepatocellular dysfunction – Failure to thrive . . . should be suspected of having a metabolic disorder When to suspect an IEM • Infants have only a limited repertoire of symptoms--sxs non-specific – Vomiting, lethargy, FTT, sz’s, resp (tachypnea, hyperpnea, apnea), coma, cardiomyopathy – Odor, abnormal hair, dysmorphology • Labs: metabolic acidosis, hypoglycemia, hyperammonemia, reducing substances in urine, ketonuria, pancytopenia • Not all infants with life threatening IEM have either acidosis or hyperammonemia (i.e. non-ketotic hyperglycinemia, mild lactate elev). Laboratory Assessment of Neonates Suspected of Having an Inborn Error of Metabolism Routine Studies Blood lactate and pyruvate Complete blood count and differential Plasma ammonia Plasma glucose Plasma electrolytes and blood pH Urine ketones Urine-reducing substances Special Studies Plasma amino acids Plasma carnitine Urine amino acids Urine organic acids “Waiting until sepsis and other more common causes of illness are ruled out before initiating a specific diagnostic evaluation is inadvisable, as is indiscriminate study of all ill newborns for metabolic disorders.” Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the Neonate or Infant Symptoms indicating possibility of an IEM (one or all) Infant becomes acutely ill after period of normal behavior and feeding; this may occur within hours or weeks Neonate or infant with seizures and/or hypotonia, especially if seizures are intractable Neonate or infant with an unusual odor Symptoms indicating strong possibility of an IEM, particularly when coupled with the above symptoms Persistent or recurrent vomiting Failure to thrive (failure to gain weight or weight loss) Apnea or respiratory distress (tachypnea) Jaundice or hepatomegaly Lethargy Coma (particularly intermittent) Unexplained hemorrhage Family history of neonatal deaths, or of similar illness, especially in siblings Parental consanguinity Sepsis (particularly Escherichia coli) Physical Anomalies Associated With Acute-Onset Inborn Errors of Metabolism (IEM) Anomaly Ambiguous genitalia Hair and/or skin problems (alopecia, dermatitis) Structural brain abnormalities (agenesis of corpus callosum, cortical cysts) Macrocephaly Renal cysts, facial dysmorphia Facial dysmorphia Cataract Retinopathy Lens dislocation, seizures Facial dysmorphia, congenital heart disease, vertebral anomalies Possible IEM Congentital adrenal hyperplasia Multiple carboxylase deficiency, biotinidase deficiency, argininosuccinic aciduria Pyruvate dehydrogenase deficiency Glutaric aciduria, type I Glutaric aciduria, type II; Zellweger syndrome Peroxisomal disorders, (Zellweger syndrome) Galactosemia, Lowe syndrome Peroxisomal disorders Sulfite oxidase deficiency Molybdenum cofactor deficiency 3-OH-isobutyric CoA deacylase deficiency Clinical Manifestations of Inborn Errors Presenting Neonatally Neurologic Signs Poor suck Lethargy (progressing to coma) Abnormalities of tone Loss of reflexes Seizures Gastrointestinal Signs Poor feeding Vomiting Diarrhea Respiratory Signs Hyperpnea Respiratory failure Organomegaly Liver Heart Inborn Errors of Metabolism of Acute Onset: Nonacidotic, Nonhyperammonemic Features Neurologic Features Predominant (Seizures, Hypotonia, Optic Abnormality) Glycine encephalopathy (nonketotic hyperglycinemia) Pyridoxine-responsive seizures Sulfite oxidase/santhine oxidase deficiency Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile refsum disease) Jaundice Prominent Galactosemia Hereditary fructose intolerance Menkes kinky hair syndrome 1-antitrypsin deficiency Hypoglycemia (Nonketotic): Fatty acid oxidation defects (MCAD, LCAD, carnitine palmityl transferase, infantile form) Cardiomegaly Glycogen storage disease (type II phosphorylase kinase b deficiency 18) Fatty acid oxidation defects (LCAD) Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD) Skeletal Muscle Weakness : Fatty acid oxidation defects (LCAD, SCAD, multiple acyl-CoA dehydrogenase defective enzyme Substrate (increased) Product (decreased) action Co-factor B Co-factor A Metabolites (increased) other enzymes Metabolites (decreased) EFFECT ON OTHER METABOLIC ACTIVITY e.g., activation, inhibition, competition Theoretical consequences of an enzyme deficiency. GLYCOGEN PROTEIN FAT FRUCTOSE GALACTOSE AMINO ACIDS ORGANIC ACIDS GLUCOSE FREE FATTY ACIDS AMMONIA PYRUVATE UREA CYCLE LACTATE ACETYL CoA KETONES UREA KREBS CYCLE NADH An integrated view of the metabolic pathways ATP First Steps in Metabolic Therapy for Inborn Errors of Metabolism • • • • • • Reduce precursor substrate load Provide caloric support Provide fluid support Remove metabolites via dialysis Divert metabolites Supplement with cofactor(s) Therapeutic Measures for IEM • D/C oral intake temporarily • Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH) • Bicarb/citrate Carnitine/glycine • Na benzoate/arginine/citrulline • Dialysis--not exchange transfusion • Vitamins--often given in cocktails after labs drawn before dx is known – Biotin, B6, B12, riboflavin, thiamine, folate Treatment of the Acutely Sick Child General Therapy • Maintain vital functions – Oxygenation – Hydration – Acid/Base balance Specific Therapy • Treat infection • High dose I.V. glucose • Carnitine supplementation STRIVE TO IDENTIFY PRIMARY METABOLIC DISORDER TREATMENT OF GENETIC DISEASES • MODIFY ENVIRONMENT, e.g., diet, drugs • SURGICAL, correct or repair defect or organ transplantation • MODIFY OR REPLACE DEFECTIVE GENE PRODUCT, megadose vitamin therapy or enzyme replacement • REPLACE DEFECTIVE GENE • CORRECT ALTERED DNA IN DEFECTIVE GENE Newborn Screening • PKU - must do on all infants in NICU even if not advanced to full feeds – Positive--transient HPA, tyr, liver disease, benign HPA, classical PKU • Galactosemia• Hypothyroidism • Hemoglobinopathies • Biotinidase def, CAH (21-OH’ase def), • MSUD Metabolic Disorders Presenting as Severe Neonatal Disease 1. Disorders of Carbohydrate Metabolism • • Galactosemia - presents with severe liver disease, gram negative sepsis, and/or cataracts • Enz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4epimerase Glycogen storage disease type 1a & 1b - presents as hypoglycemia • Enz deficiency: Glucose-6 phosphatase • • • Lactic Acidosis - presents as lactic acidosis +/- hypoglycemia Enz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc. Fructose intolerance - Needs fructose exposure, hypoglycemia and acidosis Metabolic Disorders Presenting as Severe Neonatal Disease 2. Amino Acid Disorders • • • Maple syrup urine disease - presents with odor to urine and CNS problems • Enz deficiency: Branched chain ketoacid decarboxylase Nonketotic hyperglycinemia - presents with CNS problems • Enz deficiency: Glycine cleavage system Tyrosinemia - Severe liver disease, renal tubular dysfunction • Enz deficiency: Fumaryl acetate • Transient tyrosinemia of prematurity - progressive coma following respiratory distress Metabolic Disorders Presenting as Severe Neonatal Disease 3. Urea Cycle Defects and Hyperammonemia 4. All present with lethargy, seizures, ketoacidosis, neutroenia, and hyperammonemia Ornithine carbamyl transferase (OTC) deficiency Carbamyl phosphate synthetase deficiency Citrullinemia Arginosuccinic Aciduria Argininemia Transient tyrosinemia of prematurity • • • • • • Metabolic Disorders Presenting as Severe Neonatal Disease 4. 5. All present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemia Organic Acid Defects • Methylmalonic acidemia • Proprionic acidemia • Isovaleric acidemia - odor of “sweaty feet” • Glutaric aciduria type II • Dicarboxylic aciduria Miscellaneous • Peroxisomal disorders • Lysosomal storage disease • Pyridoxine dependent seizures What to do for the Dying Infant Suspected of Having an IEM • Autopsy--pref. performed within 4 hours of death • Tissue and body fluid samples – Blood, URINE, CSF (ventricular tap), aqueous humour, skin biopsy, muscle and liver--frozen in liquid nitrogen • Filter paper discs from newborn screen--call lab and ask them not to discard