Inborn Errors of Metabolism

1. Inborn Errors of Metabolism Monica Egan

2. Video Links • Part 1: • http://www.youtube.com/watch?v=Zy5MwyjxWwY&feature=plcp Part 2: http://www.youtube.com/watch?v=JZ4sxrg-fKY

3. Chapter 20 Overview • What to expect from this chapter: • Knowledge of Inborn Errors of Metabolism (IEM) • Types of IEM • Treatments

4. 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.

5. 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.

6. Types of IEM • Silent • Acute Metabolic Crises • Progressive Organ Damage

7. 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)

8. 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.

9. 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.

10. 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.

11. 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

12. 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.

13. 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

14. 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.

15. Providing a Vitamin Co-Factor • 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.

16. 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

17. 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

18. Gene Therapy • Simply replacing affected genes with normal, healthy genes. • Has not been successful • Has been linked with adverse effects.

19. 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