Inborn Errors of Metabolism Monica Egan

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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 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 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 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.

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