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 ErrorsClass 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).

Laboratory Assessment of Neonates Suspected of Having an Inborn Error of Metabolism Routine Studies Special Studies Blood lactate and pyruvate Complete blood count and differential Plasma amino acids Plasma ammonia Plasma carnitine Plasma glucose Urine amino acids Plasma electrolytes and blood pH Urine organic acids Urine ketones Urine-reducing substances

“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 Possible IEM Ambiguous genitalia Congentital adrenal hyperplasia Hair and/or skin problems (alope- Multiple carboxylase deficiency, biotinidase cia, dermatitis) deficiency, argininosuccinic aciduria Structural brain abnormalities Pyruvate dehydrogenase deficiency (agenesis of corpus callosum, cortical cysts) Macrocephaly Glutaric aciduria, type I Renal cysts, facial dysmorphia Glutaric aciduria, type II; Zellweger syndrome Facial dysmorphia Peroxisomal disorders, (Zellweger syndrome) Cataract Galactosemia, Lowe syndrome Retinopathy Peroxisomal disorders Lens dislocation, seizures Sulfite oxidase deficiency Molybdenum cofactor deficiency Facial dysmorphia, congenital heart 3-OH-isobutyric CoA deacylase deficiency

disease, vertebral anomalies

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 adrenoleuko- dystrophy, 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 deficiency18) 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

Metabolites(increased)

Co-factor A Co-factor B

otherenzymes Metabolites

(decreased)

EFFECT ON OTHER METABOLIC ACTIVITYe.g., activation, inhibition, competition

Theoretical consequences of an enzyme deficiency.

PROTEIN GLYCOGEN FAT

AMINO ACIDSFRUCTOSE

GALACTOSE

FREE FATTY ACIDS

AMMONIA

UREA

UREA CYCLE

ORGANIC ACIDSGLUCOSE

PYRUVATE

ACETYL CoA

KREBS CYCLE

NADH

KETONES

ATP

LACTATE

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 ChildGeneral 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-

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

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

All present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemia

4. Organic Acid Defects• Methylmalonic acidemia• Proprionic acidemia• Isovaleric acidemia - odor of “sweaty feet”• Glutaric aciduria type II• Dicarboxylic aciduria

5. 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