Biochemical and Genetic Bases of Diseases Flashcards
Four Major Classes of Treatment Strategies For Genetic Disorder:
Class 1
(1) replace the missing product or
(2) minimize the substrate
Four Major Classes of Treatment Strategies For Genetic Disorder:
Class 1 treatment for familial goiter
administration of levothyroxine
Four Major Classes of Treatment Strategies For Genetic Disorder:
Class 1 treatment for PKU
Diet low in phenylalanine
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 2
(1) replace the defective/mutant enzyme or protein
(2) increase activity of enzyme
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 2 treatment for Gaucher disease
Injections of beta-glucosidase
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 2 treatment for hemophilia
Injections of Factor VIII
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 3
Remove excess of a stored compound
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 3 treatment for methylmalonic aciduria
injections of vitamin B12
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 3 treatment of Criglernajjar syndrome
Administration of Phenobarbital
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 4
attempt to correct the basic genetic abnormally
Four Major Classes of Treatment Strategies For Genetic Disorder
Class 4 treatment of galactosemia
Liver transplantation
Points to note when diseases are considered at a biochemical standpoint
Almost every cell organelle has been involved in the genesis of various diseases
Points to note when diseases are considered at a biochemical standpoint
Different biochemical mechanisms can produce similar pathologic, clinical, and laboratory findings
Points to note when diseases are considered at a biochemical standpoint
Diseases can be caused by deficiency or excess or certain biomolecules
Points to note when diseases are considered at a biochemical standpoint
1) many diseases are determined genetically
2) all classes of biomolecules found in cells are affected in structure, function or amount involved or in another disease
3) Biochemical alterations that cause disease may occur rapidly or slowly (massive coronary thrombosis, cyanide poisoning, Niemann-Pick disease
4) Diseases can be caused by deficiency or excess or certain biomolecules
5) almost every cell organelle has been involved in the genesis of various diseases
6) Different biochemical mechanisms can produce similar pathologic clinical and laboratory findings
Human Genome Project (HGP)
- October 1990 to 2003
- discovered all the estimated 20,000 to 25,000 human genes
the study of large groups or populations with complex, multifactorial conditions aiming to molecularly substratify them
Genomics
Focused on families with rare inherited conditions
Human Genetics
Provides more individualized care and may also benefit population health through improved screening interventions and disease prevention for healthy propulations
Precision Medicine
Types of Genetic Testing
1) target a single variant
2) single-gene testing
3) gene panel
4) whole exome sequencing/whole genome sequencing (WES/WGS)
Types of Genetic Testing
Looks for a specific variant in one gene
Used to test family members known to have a particular variant to determine whether they have a familial condition
Target single variant
Types of Genetic Testing
Looks for genetic changes in one gene to confirm - rule in or rule out a specific diagnosis
Single-gene testing
Types of Genetic Testing
Looks for variants in more than one gene
Pinpoints a diagnosis when a person has symptoms that may fit a wide array of conditions
Disease can be caused by variants in many genes
Gene panel
Types of Genetic Testing
Analyze the bulk of an individual’s DNA when the suspected condition or genetic cause is unclear
Whole exome sequencing/ whole genome sequencing (WES/WGS)
Types of Genetic Testing
Most cost- and time-effective
WES/WGS
Reflects the proximity of genes in chromosomes
Genetic linkage
Two genes on different chromosomes show independent assortment at meisosis and are ()
NOT LINKED
Two genes are adjacent to each other unlikely to be separated at meiosis and are ()
TIGHTLY LINKED
Genetic Likage Principle
Genes separated but on the same chromosome will probably be inherited together unless recombination occurs during meiosis
The more distant they are from each other in the same chromosome, the greater chance of recombination occuring
Ex. if A is the disease gene and B and C are genetic markers, recombination is likely to occur much more frequently between A and C than it is between A and B
The genetic length of a chromosome over which one recombination event occurs per meiosis
Unit of measure
morgan (M)
Statistical estimate of whether two loci are likely to lie near each other on a chromosome and are therefore likely to be inherited together is called a ()
LOD score
a LOD score that indicates that the two loci are linked and are close to one another
3 or more
The crossing over of DNA strands between the paired chromoses
Recombination
Applications of Precision Medicine
1) preconceptual and prenatal screening
2) pediatrics
3) Risk assessment and Family Health History
4) Oncology
5) Cardiovascular Diseases
6) Pharmacogenetic Testing
Precision Drug Development
Trastuzumab target for breast cancer
HER2/Neu-positive
Applications of Precision Medicine
Imatinib mesylate target for chronic myelois leukemia (CML)
BCR-ABL-positive
Applications of Precision Medicine
Olaparib first poly(ADP)ribose polymerase (PARP) inhibitor targets what mutation of breast cancer
BRCA mutation
Phenotype resulting from visible alteration in the number structure of the chromosome
Chromosomal disorders
Trisomy 21
Down Syndrome
Trisomy 18
Edward syndrome
Trisomy 13
Patau syndrome
Result of variation in one or both alleles of a gene on an autosome or sex chromosome or in a mitochondrial gene
Single gene disorders
Single-gene disorder classification:
7.0 in 1000 live births
Autosomal Dominant
Single-gene disorder classification:
2.5 in 1000 live births
Autosomal recessive
Single-gene disorder classification:
0.5 in 1000 live births
X-linked
Examples of single gene disorders
- familial hypercholesterolemia
- polycystic kidney disease
- Huntington disease
Metabolic defects in the respiratory chain
mutations in autosomal or X-linked genes or mutations in the genes encoded by the mitochondrial chromosome (mtDNA)
mitochondrial disorder
Homoplasmy
If all of the mother’s mtDNA carries the mutation - all of the offspring will as well
Heteroplasmy
Only a fraction of female mtDNA carries the mutation - offspring will inherited variable proportions of mutant mtDNA and their clinical features will vary in severity
Interaction of one or more genes with one or more environmental factors
Multifactorial disorders
Genetic contribution predispoded the individual to the actions of environmental agents
Account for one-half of all congenital malformations and to common chronic disorders of adulthood
Ex. hypertension, rheumatiod arthritis, psychoses, and atherosclerosis
Multifactorial disorders
Genetic alteration acquired by a cell that can be passed to the progeny of the mutates cell in the course of cell division
Differ from germline mutations, which are inherited gene alterations that occur in germ cells
Somatic cell genetic disorders
Is involved in autoimmune disorders, aging process
Somatic cell genetic disorders
Morbidity and mortality due to genetic disease on conception and pregnancy is caused by
numerical chromosomal abnormalities
Morbidity and mortality due to genetic disease on childhood
- 22.1% - multifactorial disease
- 3.9% - single gene disorder
- 0.6% - chromosomal disorder
Morbidity and mortality due to genetic disease on adulthood
Multifactorial - cancer and cardiovascular disease
Study of the causes of a phenomenon/disease
Etiology
The properties of the genetic causal factors of disease and how they behave
Genetic Etiology
Study of the mechanisms by which the etiologic factors are convertes into disease states
Pathogenesis
A condensation of “genetic pathogenesis” study of how anomalies in the genome are converted into the phenotypes of disorders
Pathogenetics
Not applicable to multifactorial and somatic cell disorders
Galton-Fischer Theory
Origination and development of an organism usually from the time of fertilizationof the egg to adult
prenatal > birth > infancy > childhood > adolescence > adulthood > death
Ontogeny (ontogenesis)
Natural tendency of a living organism to continue its evolving development - property of dynamical systems to converge to a (possibly new) stable trajectory after being perturbed
Homeorhesis
Discrepancies between the current and the ideal states of ontogeny are discerned and correcte
angular homeostasis
Where the genetic disorder manifest early - the survivorship curve is
pattern of deterioration is dominated by a single class of insults
Positively skewed
ex. Duchenne muscular dystrophy
When the disease is late - the survivorship curve is
Patient shows characteristic multiplex pathology - often difficult to say the final cuase of death and survivorship
negatively skewed
Pathways and multiple-stage processes
What are the 3 potential toxicity of simple pathways
synthesis of B from A by enzyme ab
1.) precursor toxicity - substrate accummulates
2.) product deficit
3.) combined product deficit and precursor excess
Pathways and multiple-stage processes
If A is absent then B is lacking and C cannot be synthesized
Epistasis
gene governing the first step is epistatic to that governing the second
Pathways and multiple-stage processes
In Branched pathway - what competes for the substrate
Open type
Pathways and multiple-stage processes
In Branch pathway - what path rejoins and results in parastasis
Closed type
Two or more pathways run in parallel, which accelerates the entire process and acts as a failsafe device should any of them fail
Refers to multiple, even seemingly unrelated, aspects of the same syndrome
Pleiotropy
several clinical properties “running together”
Syndrome
The disease symptoms outwardly bear no connection to each other but are all rootes in mutations of gene FBN1
Marfan Syndrome
Protein functions that involve interactions with small molecules
enzymes, receptors, transporters
Proteins that perform regulatory roles
transcription factors & hormones
Proteins that function in complex system
structural proteins
Consequences of mutation
Can be due to a regulatory mutation
Ex. loss of sensitivity to inhibition - cancer;
affects active site of and enzyme (Vmax increased, km lowered)
Quantitative increase in function
Consequences of mutation
Decrease function or loss of function
Ex. inborn error of metabolic pathways
Quantitative decrease in fuction
Consequences of mutation
Due to a variant in or around the locus encoding that enzyme, resulting in a qualitative or quantitative defect
- abnormal post translational processing of the nascent enzyme
- abnormal subcellular localization or extracellular traffickin
- altered affinities for substrates or cofactors
- altered responsiveness to allosteric regulators of activity
Qualitative gain of function
Consequences of mutation
- Familial hypercholesterolemia - due to defects in the LDL receptor
- Neoplasisa - due to defects in the tumor suppressor genes
Qualitative loss of funtion
