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Flashcards in Inborn Errors of Metabolism Deck (27)

What are the 5 MAJOR clinical presentations that characterize the Inborn Errors of Metabolism?

1. Neonatal Catastrophe
2. Hepatic Disease
3. Metabolic Acidosis
4. Neurologic Syndrome
5. Storage Disease

**These typically occur in an infant/child who was normal at birth.


Infants whose inborn error of metabolism presents with neonatal catastrophe typically present with:

- feeding problems
- tachypnea
- lethargy and hypotonia
- progress to seizures and coma
- appear "septic"
- have secondary metabolic abnormalities (metabolic acidosis, elevated ammonia levels)


What are some of the classic examples of neonatal catastrophe diseases?

urea cycle defects - protein metabolism disorder ; hyperammonemia (levels above 2000)

Galactosemia - can present before screening results get back
-hepatic disfunction
-E. coli sepsis

Organic acidemias like proprionic academia
-problems converting methionine, threonine, valine, isoleucine


Infants whose inborn error of metabolism presents with hepatic disease typically present with:

- jaundice
- hepatomegaly
- bleeding and bruising (coagulopathy)
- hepatocellular dysfunction
- Hypoglycemia
- Hyperammonemia


List some hepatic diseases (can coexist) that can present in the neonate or the infant/child.

- Neonatal hemochromatosis

- Wilson disease
- Fatty acid oxidation defects
- Alpha-1-antitrypsin


Infants whose inborn error of metabolism presents with metabolic acidosis typically present with:

vomiting, poor feeder
failure to thrive
metabolic decompensation w/ mild illness (ear infection)
apparent intolerance of certain food types


List some metabolic acidosis disease examples.

- proprionic and methymalanic acidemia
- fatty acid oxidation defects

- later onset of proprionic and methymalanic academia
- later onset of fatty acid oxidation defects
- Biotinidase deficiency


Infants whose inborn error of metabolism presents with neurologic syndrome typically present with:

-altered muscle tone and reflexes, not focal
- ataxia
-seizure disorder, particularly is progressive
- developmental delay
- movement disorder
-altered state of consciousness


List some neurologic syndromes.

- urea cycle defects
- organic acidemias
- mitochondrial oxidative phosphorylation defects

- undiagnosed PKU
- homocystinuria
- mitochondrial oxidative phosphorylation defects


Infants whose inborn error of metabolism presents with storage disease typically present with:

- somatic dysmorphism
- skeletal / joint dysplasia
- ophthalmologic signs
- thickened skin/loss of elasticicty
- nonimmune fetal hydrops
- progressive, degenerative course
- developmental regression


List some storage diseases.

- mucopollysaccharidosis type VII
- Neimann-Pick type A

Note: most of the storage diseases have several forms dependent on the age of onset. Infantile forms usually present in the latter half of the first year of life.


What tests would you use to diagnose inborn errors?

- basic chemistries, glucose, Anion group
- blood ammonia levels
- liver function test
- blood lactate and pyruvate levels
- urinalysis
-plasma and urine amino acids
-urine organic acids


Most inborn errors of metabolism (IEM) are related to defects in:

enzyme complex
enzyme receptor
enzyme cofactor


In inborn errors of metabolism, the protein/vitamin can be:

-not present
-present but not functional
-present but diminished activity
- present but there is a receptor problem


Consanguinity (increases/decreases) risk of inheriting IEM.



As a result of PKU, neurotransmitter synthesis and protein synthesis in the brain is disrupted. The structure of the brain cell is abnormal and ___________ is defective.



What is a new treatment for PKU? How does it work?

Kuvan -
enzyme cofactor and oral form of tetrahydrobioprotein

works with phenylalanine hydroxylase to metabolize (Phe)

-works with tetrahydrobioprotein - (BH4-) responsive patients

- used in conjunction with diet


Why are the cutoffs for Phe levels so high in the newborn screening?

To make sure no baby gets missed


What test is done if the screening for PKU is positive?

referred for amino acid analysis for a definitive diagnosis


How does maternal PKU affect the fetus?

High plasma PHE acts as a fetal teratogen.

Nearly 80% of fetuses exposed to high levels of PHE during development have microcephaly, mental retardation and growth retardation.

The level of fetal abnormalities correlates with the maternal plasma Phe levels.


What is the general approach to the treatment of metabolic disorders?

-dietary adjustments
-vitamin supplementation
- drug therapies
- organ transplants
- proposed therapies


What dietary adjustments can be made?

Reduce substrate accumulation:
- PKU - low Phe diet
- Galactosemia - lactose free diet

Supplement product deficiency
- Argininoscuccinic aciduria - arginine
- Biotinidase deficiency - biotin


What vitamin supplements are helpful?

B6 - 50% of homocystinuria cases are responsive
B12 - methylmalonic academia
Biotin - biotinidase deficiency (10 mg/day)


What are 4 ways in which drug therapy is used to alleviate symptoms?

1. limit accumulation of toxic metabolites (Wilson-penicillamine)

2. Encourage waste nitrogen excretion (Urea cycle defect - no benzoate and phenylacetate)

3. Supplement poorly transported nutrient (Menkes - copper supplementation)

4. Enzyme replacement (Gaucher - Ceredase/Cerezyme)


What diseases might use organ transplantation? which organ?

Mucopolysaccharidosis - bone marrow
Hereditary tyrosinemia - liver
Urea cycle defects - liver


Describe the 4 phases of clinical trials.

Phase 1 - examine the safety of the new medication and understand how it will work in humans

Phase 2 - evaluate the short-term therapeutic effect of a new drug in patients who suffer from target disease and confirm safety established in Phase 1

Phase 3 - demonstrate the potential advantages of the new therapy over other therapies already on the market

Phase 4 - Post-FDA approval/post-marketing and involve thousands of patients and compare its efficacy with the gold standard.


6 month old male with several month history of failure to thrive and hepatosplenomegaly. Parents are nonconsaguinous of French-Canadian descent.

Abdominal MRI - enlarged kidney and spleen with nodular lesions in liver (Hemanioendothelioma)
Plasma amino acids - elevated tyrosine and methionine
Urine organic acids - succinylacetone
Blood enzyme test - absence of fumarylacetoacetate hydrolase

Tyrosinemia Type 1