Biochemical and Genetic Bases of Diseases Flashcards by AFD Alvarez

Four Major Classes of Treatment Strategies For Genetic Disorder:

Class 1

(1) replace the missing product or
(2) minimize the substrate

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Four Major Classes of Treatment Strategies For Genetic Disorder:

Class 1 treatment for familial goiter

administration of levothyroxine

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Four Major Classes of Treatment Strategies For Genetic Disorder:

Class 1 treatment for PKU

Diet low in phenylalanine

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 2

(1) replace the defective/mutant enzyme or protein
(2) increase activity of enzyme

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 2 treatment for Gaucher disease

Injections of beta-glucosidase

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 2 treatment for hemophilia

Injections of Factor VIII

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 3

Remove excess of a stored compound

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 3 treatment for methylmalonic aciduria

injections of vitamin B12

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 3 treatment of Criglernajjar syndrome

Administration of Phenobarbital

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 4

attempt to correct the basic genetic abnormally

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Four Major Classes of Treatment Strategies For Genetic Disorder

Class 4 treatment of galactosemia

Liver transplantation

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Points to note when diseases are considered at a biochemical standpoint

Almost every cell organelle has been involved in the genesis of various diseases

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Points to note when diseases are considered at a biochemical standpoint

Different biochemical mechanisms can produce similar pathologic, clinical, and laboratory findings

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Points to note when diseases are considered at a biochemical standpoint

Diseases can be caused by deficiency or excess or certain biomolecules

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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

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Human Genome Project (HGP)

October 1990 to 2003
discovered all the estimated 20,000 to 25,000 human genes

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the study of large groups or populations with complex, multifactorial conditions aiming to molecularly substratify them

Genomics

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Focused on families with rare inherited conditions

Human Genetics

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Provides more individualized care and may also benefit population health through improved screening interventions and disease prevention for healthy propulations

Precision Medicine

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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)

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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

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Types of Genetic Testing

Looks for genetic changes in one gene to confirm - rule in or rule out a specific diagnosis

Single-gene testing

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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

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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)

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# 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** ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote 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 ## Footnote

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 ## Footnote 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 ## Footnote pattern of deterioration is dominated by a single class of insults

Positively skewed ## Footnote ex. Duchenne muscular dystrophy

When the disease is late - the survivorship curve is ## Footnote 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 ## Footnote 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 ## Footnote 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

Biochemical and Genetic Bases of Diseases Flashcards

(80 cards)