Inborn Errors of Metabolism 1 Flashcards
What are inborn errors of metabolism? (4)
- Congenital disorders caused by an inherited defect in a single specific enzyme that results in a disruption or abnormality in a specific metabolic pathway.
- Inborn errors of metabolism (IEM) are genetic/congenital disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat.
- Enzyme deficiency metabolic pathway disruption → abnormality
- Many IEM are detected through state newborn screening (NBS) programs
Classification of IEM: Time of onset (4)
- Onset in the neonatal period and early infancy
- Onset can occur in later infancy or adolescence and this presentation should not exclude IEM diagnosis
- Some present clinically before they are detected on NBS
- NBS – results must be followed up
i. Some are initially asymptomatic (PKU) so NBS results must be checked!
Classification of IEM: Clinical presentation (3)
- Most useful approach to correct diagnosis
- Will discuss 5 major presentations
i. Encephalopathy, liver, cardiac, dysmorphic and nonimmune hydrops - Some clinically asymptomatic in the newborn period
i. PKU
Classification of IEM: According to biochemical basis of disease (3)
- Divides IEM according to the biochemical characteristics
- Helps in understanding the pathogenesis of symptoms and treatment approaches
- But less useful for those providing patient care
Disorders of Protein metabolism (3)
If you feed a child protein the child gets sicker:
- Urea cycle disorders (Think elevated ammonia Levels)
- Amino Acidopathies (PKU)
- Organic Acidurias (Propyonic academia)
Disorders of fatty acid metabolism
Fatty acids are bring broken & used for energy → LCFA-MCFA→Hypoglycemia
Disorders of carbohydrate metabolism (3)
- These are gluconeogenesis disorders → Galactosemia
- Pts are not able to metabolize galactose that is found in milk
- This baby will be doing really well initially, then doing ok, then around day 4 they aren’t eating well and they are very lethargic
* Due to the influx of milk, whether breast or formula of cow’s milk protein
Storage Disorders (4)
a. Lysosomal and Glycogen storage disorders
b. Purely neurologic – nerves and spinal cord destroy
c. Tay Sachs and Pompe
d. Think Dor Yeshorim
Peroxismal Disorders (3)
- Defects in function can → severe neurodegenerative disorders
- Zellweger Syndrome
- ALD (X-linked adrenoleukodystrophy)
Mitochondrial Disorders (2)
- Complex multi-systemic conditions from mutations in the mitochondrial genome
- MELAS
Incidence (4)
- Presentation is usually in the neonatal period
- 1:500 live births (1:800)
- The frequencies for each individual inborn error of metabolism vary, but most are very rare
- Term infants who develop symptoms of sepsis without known risk factors
* (As many as 20%) may have an inborn error of metabolism
Pathophysiology of IEMs (3)
- Metabolic processes are catalyzed by genetically encoded enzyme proteins
- The classical mechanism of a metabolic defect is
a. Lack or deficiency of an enzyme resulting in substrate accumulation…increased level of normal substrate
b. And conversion of metabolites to products not usually not present
* *Ex. Urea cycle disorders (substrate ammonia is toxic) –> cerebral edema - End products of the normal pathway will be deficient
IEM symptoms result from (4 w/ description)
- Increased level of the normal substrate
* Ex- Urea cycle disorders → (substrate ammonia is toxic) → cerebral edema - Lack of normal end products
* Ex- 21-hydroxylase deficiency –> lack of cortisol - Alternative products interfere with normal metabolic processes
* propionic acidemia –> Accumulated propionyl-CoA may interfere with the reactions normally using acetyl- CoA - Inability to degrade end products
* Ex- GSD type 2→myocardial dysfunction
* GSD type →hepatomegaly
IEM Risk Factors (5)
- IEMs are genetic disorders
- No definite behavioral or environmental risk factors
- Most IEM’s are recessive – a negative family history is not reassuring
- History (may be risk factors)
a. FAMILY HISTORY:
i. Relatives with MR
ii. Relatives with protein-avoidance/special diet
iii. Unexplained neonatal death / SIDS?
iv. Consanguinity
v. Ethnic background - Positive family history may be helpful!
Infant history (3)
a. Onset of symptoms after a period of “healthy infancy”
b. Onset after introduction of enteral feeds
c. Failure of “usual therapies” to improve condition
i. EX- antibiotics do not work for rule out sepsis
Clinical symptoms that strongly indicate IEM (5)
- History of unexplained neonatal death in the family
- Consanguinity
- Onset of symptoms after a period of “healthy infancy”
- Onset after introduction and progression of enteral feedings
- Failure of ‘usual’ therapies to alleviate symptoms – abx
