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).
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-
cia, 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
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 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 Product
(increased) (decreased)
action

Co-factor A Co-factor B

other
Metabolites enzymes Metabolites
(increased) (decreased)

EFFECT ON OTHER METABOLIC ACTIVITY

e.g., activation, inhibition, competition

Theoretical consequences of an enzyme deficiency.

PROTEIN GLYCOGEN FAT

FRUCTOSE
AMINO ACIDS GALACTOSE

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
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