Editing Molecular and Biochemical Genetics

==Molecular and Biochemical Genetics==

===Objectives===
*Important terms:
**'''"Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).'''
**"Distinct disorder": consistent clinical and radiological findings.


*Important concepts:
**Types of mutations:
***Missense: changed amino acid
***Nonsense: introduced stop codon
***Neutral / silent: no amino acid change
***Polymorphisms are a population term; it means 1% of the pop has it; it does not infer whether it causes disease or not
***RNA splicing: gain or loss of splice site
***Regulation mutation: affects gene regulation
***Indels: gain or loss of one or more bases; leads to frameshift if not a multiple of 3
***Repeat expansion: repeated segment (usually 3 bases) expands as nucleotide copy / repair mechanisms get hung up
**Haploinsufficiency:
**Dominant-negative effect:


*For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)

===Review your fundamentals===

===Dominant Diseases===
*Dominant disease are defined as those manifested when only one allele is mutated.
**Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.
*There are multiple ways a single allele (not both copies) can cause disease:
**''Qualitative effects'': the protein product gains a function.
**''Quantitative effects'': the protein product is broken.
**Combination of qualitative and quantitative.
**Others
*It is important to understand the disease pathogenesis in order to think wisely about treatment.

====[[Achondroplasia]]====

====[[Osteogenesis imperfecta]]====

====[[Ehlers Danlos Syndrome]]====

====[[Marfan syndrome]]====

====[[Familial Hypercholesterolemia]]====

===Recessive Diseases===
*Requires two mutant alleles to show the phenotype or disease state.
*Recall that a proband with a recessive disease usually has parents who are both carriers.
**However, there are exceptions: uniparental disomy, skewed lyonization.
*Recessive disorders usually result from a missing component of a pathway.
**Phenotype usually results from the accumulation of a precursor / metabolite.

====[[Homocysteinuria]]====

====[[Cystic Fibrosis]]====

====[[Hemochromatosis]]====

====[[Alpha-1-Anti-Trypsin deficiency]]====

====[[Phenylketonuria]]====

====[[Tay-Sachs Disease]]====

====[[Galactosemia]]====

====[[Maple Syrup Urine Disease]]====

====[[Biotinidase Deficiency]]====

===X-linked Diseases===

====[[Rett Syndrome]]====

====[[Lesch-Nyhan syndrome]]====

====[[Inherited Muscular Dystrophies]]====

===Newborn Screening===
*The following criteria for newborn screening assure that our screening has ''analytic validity'', ''clinical validity'', and ''clinical utility'':
**The disorder must be '''well defined'''.
**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).
**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).
**The disorder must be '''significant in morbidity / mortality if left untreated''' (otherwise we might start treating things that have little consequence).
**The disorder must be '''treatable such that there is an improved condition''' (lest we start adding anxiety to insult).
**The test must be '''rapid, inexpensive, specific AND sensitive over an entire population'''.
**The test must be '''acceptable and cost-effective'''.
**The test must be '''appropriately administered'''.


*Newborn screening is required by law on all infants
**A second test is required if the first screen is done prior to 48 hours


*In Indiana we screen for:
**Metabolic disorders:
***[[Phenylketonuria]]
***[[Galactosemia]]
***[[Maple Syrup Urine Disease]]
***[[Homocysteinuria]]
***[[Biotinidase Deficiency]]
**Endocrine disorders:
***Hypothyroidism
***Congenital Adrenal Hyperplasia
**Hemoglobinopathies:
***Sickle Cell Disease
**[[Cystic Fibrosis]]
*Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem mass spectrometry

====Pitfalls of Screening====
*False positives cause unecessary stress / anxiety and investigation / treatment.
*False negatives cause false security.
*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.
*Medical procedures initiated because of screen results may be uncomfortable and unnecessary.

===General Molecular / Biochemical Pathogenesis Principles===
*Dominant diseases usually result from:
**Gain of abnormal function
**Haploinsufficiency
**Dominant-negative effects (think multi-subunit proteins)
**Combinations of these reasons
*Recall that dominant disease can be "incomplete" and thus have more severe phenotypes when presented as homozygous conditions.
*Recessive diseases usually result from:
**Loss of normal function
*Heterozygotes of recessive diseases (carriers) usually have enough wild-type gene product to function properly