Transcript Inborn Errors of Metabolism

Inborn Errors of Metabolism
Monica Egan
Video Links
Part 1:
– http://www.youtube.com/watch?v=Zy5Mwyj
xWwY&feature=plcp
Part 2:
http://www.youtube.com/watch?v=JZ4sxrgfKY
Chapter 20 Overview
What to expect from this chapter:
– Knowledge of Inborn Errors of
Metabolism (IEM)
– Types of IEM
– Treatments
Inborn Errors of Metabolism
Definition:
“A genetic disorder that involves an enzyme
deficiency. The enzyme block leads to the
accumulation of a toxic substrate and/or the
deficient synthesis of a product needed for
normal body function” (Figure 20.1 pg. 286).
Enzymes break down the fats, proteins &
carbohydrates from the food we eat.
Inborn Errors of Metabolism
Newly discovered (1st was PKU in
1934)
Around 300 diseases discovered with
new ones each year
Enzyme deficiency in inherited as a
autonomic recessive trait.
– Both parents are carries, but not
affected.
Types of IEM
Silent
Acute Metabolic Crises
Progressive Organ Damage
Silent
Caused by abnormal amino acids &
hormones.
Symptoms do not show up right away,
but rather later in childhood.
Non-life threatening if controlled.
– If not, brain damage can occur.
Example: PKU (phenylketonuria)
Acute Metabolic Crises
Caused by production of acute toxicity
with ammonia, amino acids, organic acids,
fatty acids, lactic acids, & carbohydrates.
Child is fine in womb, but after birth
causes life threatening conditions.
Child depends of maternal metabolic
pathway, but when independent, metabolic
pathway may be abnormal and toxicity may
take place.
Organ Damage
Caused by glycogen, lysosomal &
perioxsomal storage deficiencies.
It begins in the womb when large
molecules can not cross into the
placenta. The molecules then store
into cell of body organs, causing
neurological and physical
abnormalities.
Testing
Most common test are blood & urine test.
– Quick results, inexpensive, & accurate.
– MRI,MRS,EEG & CT scan also used.
New Born Testing:
-best to test newborns because delay of
diagnosis & treatment = less favorable
outcomes
-1959 first test for PKU -90% affect children
-Infants heel is pricked for blood. Test results
show higher chances of dieses, not diagnosis.
Test is used for >30 disorders.
Therapeutic Approaches
Figure 20.3 on page 291
Substrate Deprivation
Externally supplement the deficient
product
Stimulating an alternative pathway
Providing a vitamin co-factor
Replacing an enzyme
Organ Transplant
Gene Therapy
Substrate Deprivation
Dietary Restriction
– Example: PKU with a phenylalanine free diet.
– Phenylalanine build up causes brain damage.
1988 Study: showed that children on diet until
age of 10 had higher IQ scores than children
who were on the diet until age of 6.
Pregnant Woman: Higher levels of Phenylalanine
had children with abnormalities.
Externally Supplementing
the Deficient Product
Child is given a treatment to replace
the missing enzyme.
Example:
– Hypothyroidism: given thyroid
supplement
– Hyperplasia: given steroid hormone
supplement
If given early enough, normal growth, with
some attention and learning impairments
Stimulating an Alternative
Pathway
Child is given a drug that causes a
pathway around the enzyme block.
Example:
– Urea Cycle Disorder.
• Inability to excrete ammonia.
• Biphenyl is given to convert ammonia to
phenylacetylclglutamine.
• Allows child to survive, but may have
developmental delays.
Providing a Vitamin CoFactor
Vitamin Co-Factor amplifies the
enzymes activity & stability.
Example:Multiple Carboxylase
Deficiency
– Defect in Enzyme (Holocarboxylase)
– Biotin given at high dosages amplifies
the enzymes activity.
Replacing an Enzyme
First used with lysosomal storage
disorders.
Child is given injections of enzyme
Study in 2004 showed improvement in
children with Gaudner disease.
– Except with sever cases
*Problem: very expensive & antibodies
could fight against foreign invaders
Transplanting an Organ
Enzymes can be replaced by replacing
an organ that has the enzyme.
Example:
– Bone Marrow Transplant.
• Lysosomal & Perioxisomal storage disorders
• Diseases caused by lack of enzyme found in
bone marrow.
*Problem: Donors & matches
Gene Therapy
Simply replacing affected genes with
normal, healthy genes.
Has not been successful
Has been linked with adverse effects.
Review of Chapter 20
Inborn Errors of Metabolism are
disorders caused by enzyme
deficiency.
Three types of IEM: Silent, Acute
Metabolic,& Organ Damaging.
Testing: Blood & Urine &Newborn
Testing
Treatments: Table 20.2 on page 292