Molecular and Biochemical Genetics

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==Molecular and Biochemical Genetics==
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===Objectives===
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*Important terms:
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**'''"Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).'''
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**"Distinct disorder": consistent clinical and radiological findings.
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*Important concepts:
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**Types of mutations:
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***Missense: changed amino acid
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***Nonsense: introduced stop codon
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***Neutral / silent: no amino acid change
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***Polymorphisms are a population term; it means 1% of the pop has it; it does not infer whether it causes disease or not
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***RNA splicing: gain or loss of splice site
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***Regulation mutation: affects gene regulation
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***Indels: gain or loss of one or more bases; leads to frameshift if not a multiple of 3
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***Repeat expansion: repeated segment (usually 3 bases) expands as nucleotide copy / repair mechanisms get hung up
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**Haploinsufficiency:
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**Dominant-negative effect:
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*For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)
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===Review your fundamentals===
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===Dominant Diseases===
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*Dominant disease are defined as those manifested when only one allele is mutated.
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**Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.
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*There are multiple ways a single allele (not both copies) can cause disease:
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**''Qualitative effects'': the protein product gains a function.
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**''Quantitative effects'': the protein product is broken.
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**Combination of qualitative and quantitative.
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**Others
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*It is important to understand the disease pathogenesis in order to think wisely about treatment.
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====[[Achondroplasia]]====
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====[[Osteogenesis imperfecta]]====
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====[[Ehlers Danlos Syndrome]]====
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====[[Marfan syndrome]]====
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====[[Familial Hypercholesterolemia]]====
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===Recessive Diseases===
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*Requires two mutant alleles to show the phenotype or disease state.
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*Recall that a proband with a recessive disease usually has parents who are both carriers.
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**However, there are exceptions: uniparental disomy, skewed lyonization.
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*Recessive disorders usually result from a missing component of a pathway.
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**Phenotype usually results from the accumulation of a precursor / metabolite.
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====[[Homocysteinuria]]====
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====[[Cystic Fibrosis]]====
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====[[Hemochromatosis]]====
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====[[Alpha-1-Anti-Trypsin deficiency]]====
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====[[Phenylketonuria]]====
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====[[Tay-Sachs Disease]]====
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====[[Galactosemia]]====
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====[[Maple Syrup Urine Disease]]====
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====[[Biotinidase Deficiency]]====
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===X-linked Diseases===
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====[[Rett Syndrome]]====
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====[[Lesch-Nyhan syndrome]]====
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====[[Inherited Muscular Dystrophies]]====
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===Newborn Screening===
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*The following criteria for newborn screening assure that our screening has ''analytic validity'', ''clinical validity'', and ''clinical utility'':
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**The disorder must be '''well defined'''.
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**The disorder must be '''fairly high in population frequency''' (to justify the cost of newborn screening by the cost saved in care for the true-positives).
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**The disorder must be '''poorly clinically detected early in life (assymptomatic)''' (otherwise it is more cost effective to let physicians identify the disease at newborn checkups).
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**The disorder must be '''significant in morbidity / mortality if left untreated''' (otherwise we might start treating things that have little consequence).
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**The disorder must be '''treatable such that there is an improved condition''' (lest we start adding anxiety to insult).
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**The test must be '''rapid, inexpensive, specific AND sensitive over an entire population'''.
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**The test must be '''acceptable and cost-effective'''.
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**The test must be '''appropriately administered'''.
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*Newborn screening is required by law on all infants
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**A second test is required if the first screen is done prior to 48 hours
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*In Indiana we screen for:
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**Metabolic disorders:
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***[[Phenylketonuria]]
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***[[Galactosemia]]
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***[[Maple Syrup Urine Disease]]
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***[[Homocysteinuria]]
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***[[Biotinidase Deficiency]]
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**Endocrine disorders:
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***Hypothyroidism
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***Congenital Adrenal Hyperplasia
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**Hemoglobinopathies:
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***Sickle Cell Disease
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**[[Cystic Fibrosis]]
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*Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem mass spectrometry
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====Pitfalls of Screening====
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*False positives cause unecessary stress / anxiety and investigation / treatment.
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*False negatives cause false security.
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*Recalling the requirement that a screened disease must be "treatable" in some effective way, we see that prolonging the knowledge of a disease may be a form of harm if the disease cannot be treated.
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*Medical procedures initiated because of screen results may be uncomfortable and unnecessary.
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===General Molecular / Biochemical Pathogenesis Principles===
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*Dominant diseases usually result from:
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**Gain of abnormal function
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**Haploinsufficiency
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**Dominant-negative effects (think multi-subunit proteins)
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**Combinations of these reasons
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*Recall that dominant disease can be "incomplete" and thus have more severe phenotypes when presented as homozygous conditions.
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*Recessive diseases usually result from:
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**Loss of normal function
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*Heterozygotes of recessive diseases (carriers) usually have enough wild-type gene product to function properly
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Current revision as of 13:55, 8 March 2012

qE5m7O Enjoyed every bit of your blog article.Thanks Again. Much obliged.

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