Metabolic Diseases/Newborn Screening, Treatment of Genetic Diseases, Multifactorial Genetics , Nutrition Flashcards
What type of mutations cause most metabolic diseases?
What can we look at to determine which enzymes aren’t functioning?
Recessive loss of function mutations to metabolic enzymes.
Can look at level of compounds/intermediates to determine.
Phenylketonuria (PKU)
- Caused by?
- Detected by? Can lead to?
- Diagnosis and treatment?
- Phenotype?
- Maternal PKU
Mutation to enzyme PAH that catalyzes synthesis of tyrosine from phenylalanine (using BH4 cofactor).
Detected by high level of phenylalanine in urine. Can lead to developmental delay, microcephaly, etc.
Difficult to diagnose until after 6 months. Treated by restricting protein and low phenylalanine diet.
Large variability in phenotype between and within families
Maternal PKU: children born to mothers with PKU. Need to regulate diet prior to conception to optimize prenatal environment.
Galactosemia
- Caused by?
- Leads to?
- Treatment?
Galactose is product of lactose metabolism.
Mutation to Gal-1-P uridyltransferase usually but can happen at other points in pathway.
Leads to high levels of galactose/galactose-1-P. Developmental problems, seizures, liver problems, etc.
Treat by giving lactose free formula.
Tyrosinemia
Mutation results in productino of succinylacetone. Liver disease and kidney problems. Treated with low tyrosine phenylalanine diet.
Test vs. Screening
Screening
- current screens for?
- how done?
- examples?
Test is done when something suspected due to symptoms or family history.
Screening is done independent of family history or clinical signs. Currently screens for organic acidurias, fatty acid oxidation defects, amino acid disorders. Done by sending newborn blood through mass spec to see which compounds elevated.
Screenings for cystic fibrosis and lysosomal storage diseases (defects in enzymes involved in degradation pathways). e.g., Krabbe, Hurler, Pompe
Strategies for treatment of genetic diseases can be at what levels? Most treatment of metabolic diseases do what?
Single gene, mRNA, protein level, metabolic problem, or family level. Most metabolic diseases treated by replacing or altering substrate that is lacking.
Some methods of treating genetic diseases (6)
(1) Genetic counseling
(2) Gene therapy/transplantation
(3) Modulation of gene expression
(4) Infusion therapy
(5) Pharmacogenetics
(6) Treatment aimed at pathophysiology itself.
Gene therapy/transplantation
Wild type gene introduced to replace mutated gene using a viral or plasmid vector to incorporate DNA. Problem because insertion of gene into genome is random, can disrupt other genes and can be limited bc of immune response.
Modulation of gene expression
Can involve induction of promoter methylation (DNA hypomethylation therapy), using ASOs to skip mutant exons (in Duchenne’s muscular dystrophy), miRNAs, molecular chaperones…
Infusion therapy
- ex. of disease that uses this treatment
Introducing functional gene products. Lysosomal storage diseases, Pompe’s disease
Pharmacogenetics
Difference in the way a person’s body absorbs and metabolizes the drug affects how long it’s at effective levels in the body and impacts its therapeutic effect. Examples are irinotecan, Warfarin (Vit K cycle variations)
Treatment based on pathology examples
Treating Marfan syndrome with Iosartan, a drug that doesn’t fundamentally fix the underlying genetic issue but ameliorates its symptoms.
Macronutrients are required in ___ amounts, and include ____.
Macronutrients are required in gram amounts, and include carbohydrates, lipids, and proteins.
Nitrogen balance
- Ideally
- Negative nitrogen balance leads to
Is the net flow of nitrogen through the body. Ideally this should be zero. Negative nitrogen balance leads to muscle wasting
Protein needs are greater during periods of ___.
High catabolism. Trauma, burns, sepsis, etc.
