3. Inborn errors of metabolism
A group of diseases caused by
a defect in the activity of an enzyme
that affect a wide variety of
metabolic processes;
defective processing or transport of
amino acids, fatty acids, sugars or metals
4. 15 August 2019 Total slide. 132 4
Inborn Errors of Metabolism
• An inherited enzyme deficiency leading to
the disruption of normal bodily
metabolism
• Impaired formation of a product normally
produced by the deficient enzyme
• Accumulation of a toxic substrate
(compound acted upon by an enzyme in a
chemical reaction)
5. 15 August 2019 Total slide. 132 5
What is a metabolic disease?
• Garrod’s hypothesis
product deficiency
substrate excess
toxic metabolite
A
D
B C
6. Inborn Errors of Metabolism
• Uneventful delivery
• Normal birth weight
• No dysmorphic features
• Uneventful days /months /years
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7. Clinical Presentations
• Type 1: Silent Disorders
• Type 2: Acute Metabolic Crises
• Type 3: Neurological Delay or Deterioration
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8. Type 1: Silent Disorders
• Do not manifest life-threatening crises
• Untreated could lead to brain damage and
developmental disabilities
• Example: Wilson disease
15 August 2019 Total slide. 132 8
9. Type 2: Acute Metabolic Crisis
• Life threatening in infancy
• Children are protected in utero by maternal
circulation which provide missing product or
remove toxic substance
• Example: OTC (Urea Cycle Disorders)
MSUD
MMA
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10. Type 3: Progressive Neurological
Deterioration
• Examples
• Tay Sachs disease
• Gaucher disease
• Metachromatic leukodystrophy
• Phenylketonuria
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11.
12. How do metabolic diseases present in
the neonate ??
• Acute life threatening illness
–encephalopathy - lethargy, irritability,
coma
–vomiting
–respiratory distress
• Seizures, Hypertonia
• Hepatomegaly , Hepatic dysfunction
• Dysmorphism,
• FTT (failure to thrive)
15 August 2019 Total slide. 132 12
14. Chronic IEM Presentation
• Development delay
• FTT / Poor Weight gain
• Seizures resistent to anticonvulsant therapy
• Hypoglycemia
• Metabolic acidosis
• Cardiomyopathy / Peripheral muscle weakness
• Hepatosplenomegaly
• Cataracts
• Retinal abnormalities
• Dysmorphic features
• Unsual body odours
15. Types of
Metabolic Disorders
Disorders of Acute or Progressive
Intoxication or Encephalopathy
Disorders Associated with Energy
Deficiency
Disorder of Biosynthesis &
Breakdown of Complex Molecules
16. Disorders of Acute or Progressive
Intoxication or Encephalopathy
Organic acidemias
Aminoacidurias
Urea cycle defects
Disorders of carbohydrate
intolerance (Galactosemia)
33. Global developmental delay –
How to make a Specific Diagnosis
Birth history
Complete Physical Examination
Neurological Examination
Appropriate investigations
52. MSUD: Maple syrup urine disease, - usually absent
OA: Organic academia, ± sometimes present
UCD: Urea cycle disorders, + usually present
DCM: Disorders of carbohydrate
metabolism
++ always present
FAO: Fatty acid oxidation A appropriate
H inappropriate high
L inappropriate low
54. Approach to sick Neonate with
Hyperammonemia
Hyperammonemia
Metabolic
Acidosis
No acidosis
Lactic
acidosis
Abnormal urine
Organic acids
Abnormal
Plasma amino
acids
Early onset
sepsis
and normal
amino acids