Kogi State University Pathophysiology of Diseases Discussion

“The main terms used in this course like what is mean Pathophysiology and What is a disease in your own words?

Introduction

Diseases as manifestations of disordered functions
Proper knowledge of body’s normal structure and function (and how they can become disordered) gives us ability to design rational and effective treatment
Although phenotypes of genetic diseases are diverse, their causes are not
Primary cause of any genetic disease is a change in the sequence or cellular content of DNA that ultimately deranges gene expression.
Most genetic diseases are caused by an alteration in DNA sequence that alters the synthesis of a single gene product.

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Genetic Disease Terminology

Gamete: egg or sperm cell that represents a potential reproductive contribution to the next generation
Mosaicism: situation in which a genetic alteration is present in some but not all of the cells of a single individual
Gene: short stretch of DNA responsible for a measurable trait
Locus: the place where a particular gene lies on its chromosome
Alleles: variant sequences of DNA
Mutation: biochemical event such as a nucleotide change, deletion, or insertion that has produced a new allele
Homozygous: having two alleles at the same locus that are the same
Heterozygous: having two alleles at the same locus that are different
Phenotype: any characteristic that can be measured

Penetrance & Expressivity

Two individuals with same mutated gene may have different phenotypes
Penetrance refers to whether or not the variant genotype can be inferred based on defined phenotypic criteria
Penetrance may vary with age and according to the set of criteria being used
Same mutated gene can give rise to different spectrum of phenotypes, called variable expressivity
Type 1 osteogenesis results in short stature for one sibling and confinement to wheelchair for another
Both have penetrance of the mutation, but the expression is variable

Mechanisms of Mutation & Inheritance Patterns

Mutations can be characterized by their molecular nature and effects on gene activity
Dominant inheritance: disease state or trait is apparent when one copy each of the mutated allele and the normal allele are present
Recessive inheritance: two copies of the mutated allele must be present for the disease state or trait to be apparent
Hemizygosity: the presence of one allele at a locus because the other allele is deleted or because it is normally not present (eg, X-linked genes in males)

Recessive Inheritance & Loss-of-Function Mutations

Two general principles when considering loss-of-function mutations:

Expression from the non-mutant allele usually does not change, gene expression in a heterozygous carrier of a loss-of-function allele is reduced to 50% of normal
For most biochemical pathways, a 50% reduction in enzyme concentration is not sufficient to produce a disease state
Most diseases resulting from enzyme deficiencies (such as phenylketonuria) are inherited in a recessive fashion

Dominant Inheritance & Loss-of-function Mutations

Most dominantly inherited phenotypes are actually semidominant, meaning an individual that carries two copies of the mutant allele is affected more severely than someone who carries one mutant and one normal allele
Two general principles to keep in mind when considering loss-of-function mutations
First, because expression from the nonmutant allele usually does not change (i.e., there is no dosage compensation), gene expression in a heterozygous carrier of a loss-of-function allele is reduced to 50% of normal.
Second, for most biochemical pathways, a 50% reduction in enzyme concentration is not sufficient to produce a disease state.