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Western University
Biochemistry 4463G
P Ferguson

Biochemistry of Genetic Disease 4463G Topic 1: Introduction to Biochemical Genetics - Some diseases are almost completely genetically determined (ex. CF, Huntington’s) - Both CF and Huntington’s follow Mendelian genetics – typical inheritance patterns - Many traits often “run” in families but don’t have a single genetic cause (ex. diabetes, high blood pressure, mental health, alcoholism, personalities, appearance) - Such traits tend to be influenced in by the environment (similar for families) - Overlap of genetic & environmental creates complications in determining causes - Single gene disorders are inherited in predictable patterns - CF = autosomal recessive – more carriers – horizontal inheritance - Huntington’s = autosomal dominant – ¼ chance for child – vertical inheritance - X-linked inheritance results in males expressing affected phenotype - Mitochondrial inheritance is strictly maternal inheritance (separate DNA from other cells) - Most genetic diseases present themselves early (embryonic/fetal) - 50-70% of conceptions do NOT result in a healthy baby due to genetic causes ~50% of spontaneous miscarriages are due to chromosomal aberrations - When presented in children, 0.6% have chromosomal anomalies & 1% single gene defects - Prevalence of genetic disease in pediatric hospitals is about 50% - Determining a number of genetically affected adults in difficult (a lot we still don’t know) - Common Genetic Diseases in Children: - Chromosome Level = Down syndrome (1/600) - Single Gene Level = CF (1/2500), PKU (1/16000) - CF is an autosomal recessive disease – people can find out they’re carriers by genetic tests - Most people either look at their family history or find out by having a child with CF - Duchene Muscular Dystrophy is single gene X-linked (1/3000 males) - Usually we understand the disease incidence (NOT carrier incidence – calculated after) - Inborn Errors of Metabolism: - Usually enzyme deficiencies – most are inherited in autosomal recessive manner - Individually they are rare, however they are many different kinds - Understanding IEM has greatly increased our knowledge of normal metabolism - Helps lead to the understanding of Multifactorial disorders and treatments - When we inhibit a metabolic pathway = diseased phenotype - Biochemical Basis of Dominance and Recessiveness: - The effect of the mutation on the function of the gene product - The tolerance of the biological system for functional perturbation - Acute intermittent porphyria – ½ gene product is NOT sufficient - Dominant negative – abnormal proteins preventing P:P interactions - Somatic mutation leading to homozygosity at single cell level - 1908: Garrod discussed albinism, alcaptonuria/cystinuria – noted AR Mendel inheritance Parents unaffected; siblings more likely to be affected than general population - 1934: Folling recognized PKU as cause of severe mental retardation (pushed by mother) - 1946: Beadle & Tatum develop “one gene one enzyme” concept - 1949: Pauling identifies E  V substitution causes Sickle cell anemia - 1952: Cori & Cori identify GSD 1a glucose-6-phosphatase deficiency - 1953: Jervis discovers that PKU is due to PAH mutations - Early 1950s was when we started gaining understanding of enzyme defs linked to diseases - Allelic: different mutations in the same locus giving a variable phenotype (DMD v. Becker MD) - Non-Allelic: mutations in different loci giving similar phenotype (PKU) - We are a distance away from being about the predict the impact of disease from the genotype - It is hard to find the predictability is because genetic defects do NOT work in isolation - Most gene products have some sort of function that is impacted by the environment - Environmental/Genetic Interactions: - Drugs = Acute Intermittent Porphyria – AD, 80% non-symptomatic, dark urine, ab pain etc - Diet = PKU (high protein intake) & galactosemia (high lactose intake) - Sunlight = albinism (patients must stay out of sunlight – reduces problems/symptoms) - Mechanical = Osteogenesis imperfecta (fragile bones – avoid doing dangerous activities) - Smoking = emphysema (can develop alpha-1-antitypsin deficiency if they smoke) - Prenatal diagnosis is the ability to determine whether a fetus is affected with a disease or not - Methods include: ultrasound, CVS, amniocentesis - CVS membrane has fetal origin – if access (trans-cervically/ab) can be cultured to give fetal genotype - Amniocentesis has been around longer than CVS (obtained trans-ab) – gives fetal genotype - Differences between amnio and CVS is the timing (amnio = 18 weeks; CVS = 11-12 weeks) - Greater risk in CVS but in both cases risk is >1% - Once the fetal genotype is obtained, we can apply our genetics techniques – when is right to do so? - Pre-implantation coupled to IVF is very tricky and expensive - Population screening – in ON we screen newborns for ~30 diseases (good use of resources?) - Certain populations are at high risk for certain diseases (ex. Jews for Tay-Sachs) - We can look at affected family history or perform tests to screen if someone is a carrier - Should we be screening the population? – requires resources for population to understand results - Pre-symptomatic dilemmas include: - Lack of confidentiality (ex. conflict of interest when daughter gets tests; mom is against) Big problem with late-onset diseases (esp. Huntington’s since there’s no treatment) - Information Handling (ex. 3 siblings tested – 2 unaffected and 1 affected) - There are big issues with ACCESS to genetic information – ex. - Someone’s right to be t
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