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