Inborn Errors of Metabolism

Question 1

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

Answer 1

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.

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

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

Answer 5

Neonate:

• Galactosemia
• Tyrosinemia
• Neonatal hemochromatosis

Infant/Child:

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

Question 6

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

Answer 6

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

Question 7

List some metabolic acidosis disease examples.

Answer 7

Neonate:

• proprionic and methymalanic acidemia
• fatty acid oxidation defects

Infant/Child:

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

Question 8

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

Answer 8

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

Question 9

List some neurologic syndromes.

Answer 9

Neonate:

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

Infant/Child:

• undiagnosed PKU
• homocystinuria
• mitochondrial oxidative phosphorylation defects

Question 10

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

Answer 10

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

Question 11

List some storage diseases.

Answer 11

Neonate:

• 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.

Question 12

What tests would you use to diagnose inborn errors?

Answer 12

• 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

Question 13

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

Answer 13

enzymes
enzyme complex
enzyme receptor
enzyme cofactor

Question 14

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

Answer 14

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

Question 15

Consanguinity (increases/decreases) risk of inheriting IEM.

Answer 15

increases

Question 16

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.

Answer 16

myelination

Question 17

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

Answer 17

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

Question 18

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

Answer 18

To make sure no baby gets missed

Question 19

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

Answer 19

referred for amino acid analysis for a definitive diagnosis

Question 20

How does maternal PKU affect the fetus?

Answer 20

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.

Question 21

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

Answer 21

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

Question 22

What dietary adjustments can be made?

Answer 22

Reduce substrate accumulation:

• PKU - low Phe diet
• Galactosemia - lactose free diet

Supplement product deficiency

• Argininoscuccinic aciduria - arginine
• Biotinidase deficiency - biotin

Question 23

What vitamin supplements are helpful?

Answer 23

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

Question 24

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

Answer 24

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)

Question 25

What diseases might use organ transplantation? which organ?

Answer 25

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

Question 26

Describe the 4 phases of clinical trials.

Answer 26

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.

Question 27

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

Answer 27

Tyrosinemia Type 1