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 Incidence Critical, life threatening disorders of infancy 70-80 ~1:5,000 Serious disorders >300 ~1:1,000 compromising health in infants/adults 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 (20) Defects of Lactate/Pyruvate (20) Defects of Peroxisomes Others

“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).

“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.”

Theoretical consequences of an enzyme deficiency. defective enzyme Substrate (increased) Product (decreased) action Co-factor B Co-factor A other enzymes Metabolites (decreased) Metabolites (increased) EFFECT ON OTHER METABOLIC ACTIVITY e.g., activation, inhibition, competition Theoretical consequences of an enzyme deficiency.

An integrated view of the metabolic pathways GLYCOGEN FAT PROTEIN FRUCTOSE GALACTOSE AMINO ACIDS GLUCOSE FREE FATTY ACIDS ORGANIC ACIDS AMMONIA PYRUVATE LACTATE ACETYL CoA UREA CYCLE KETONES UREA KREBS CYCLE NADH ATP An integrated view of the metabolic pathways

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 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-4-epimerase 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 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 Urea Cycle Defects and Hyperammonemia 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 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