INBORN ERRORS

OF METABOLISM
INBORN ERRORS OF METABOLISM
IEM 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
Clues to presence of IEM may often be found in
FH
DIAGNOSING INBORN ERRORS OF
METABOLISM
Signs and symptoms are often
nonspecific
Routine childhood illnesses excluded 1st
Inborn errors considered only secondarily
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, szs, 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 elevations).
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
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 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
Metabolites
(increased)
Co-factor A
Co-factor B
other
enzymes Metabolites
(decreased)
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.
PROTEIN
GLYCOGEN FAT
AMINO ACIDS
FRUCTOSE
GALACTOSE
FREE FATTY ACIDS
AMMONIA
UREA
UREA CYCLE
ORGANIC ACIDS
GLUCOSE
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 IVFs with glucose to give 12-15
mg/kg/min glu and at least 60 kcal/kg to prevent
catabolism
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

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-OHase 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