Principles

of Human disease – Causes and mechanisms of human disease (Lec 2)

1. What three major factors determine the Etiology of disease?
2. Describe and give examples (4 of each) of intrinsic and extrinsic causes of disease
3. What is the relationship between causative agents and probability of disease in the
following scenarios
a. Physical agents, b. Allergens c. Infectious agents d. Alcohol consumption
4. With regards to manifestation, familial incidence, remission, incidence and linkage
to inherited factors; what are the comparisons between environmental and genetic
disease?
5. What are the major causes for birth defects in humans?
6. What are the major causes of non-genetic congenital diseases?
7. Where is genetic material packaged, and how does a mutation come about?
8. What are the types of mutations? What are the types of DNA damage that lead to
mutations?
9. What is a chromosomal abnormality, how do they occur and what are the different
types?
10. What are examples of diseases that are caused by one gene or more than one gene?
11. What is the role of mutations in disease?
12. What is a karyotype, and what are the different types of chromosomal
arrangement?
13. Define gene, allele, homozygous and heterozygous
14. What is an autosomal dominant disease, and how is it manifested?
a. Give 4 examples and their corresponding gene defects
15. What is autosomal recessive and what are the examples?
16. What is X-linked recessive, note example
17. What does multifactorial inheritance mean, give examples
18. What are some of the diseases caused if there are sex chromosome abnormalities?
19. For Down’s syndrome, on which chromosome is there an extra chromosome
a. What is this called?
b. What is the major disability that sufferers of Down’s Syndrome acquire?
c. What must occur for Down’s syndrome to manifest?
d. What is the average IQ of a child suffering from DS
20. What are the clinical features of a DS sufferer?
21. What increases the chances of developing Down’s syndrome, and how can DS be
prevented?
22. What are MHC genes responsible for, and what is the role of HLA in disease?
23. What is infectious disease?
a. Example of gram negative LPS component
24. What steps are taken for bacteria to cause disease?
25. Describe one method used by bacteria to enter the body
26. Once bacteria have entered the body, how do they cause disease (toxins/enzymes)?
27. Describe the differences between endotoxin and exotoxin products
28. What is a virus, how does a virus function?
29. What are the mechanisms of viral pathogenesis
30. What are prions, what diseases do they cause, and how are the diseases spread?
31. How do prions multiply, what is mechanism that prions undergo?

 1. The Etiology of disease is how the disease comes about, this can be:
a. Genetic - The disease is inherited from parents, examples include sickle cell
anaemia or haemophilia
b. Environmental – The disease is caused by various factors including infectious
agents, trauma, consumption regimes etc
c. Both – The disease is caused by a combination of a. and b. For example, the
onset of diabetes is dependent on family as well as current environmental
factors. If the patient fails to maintain a control over their weight and
unhealthy diet, it is likely they will develop the disease at a younger age.
2. Intrinsic factors are naturally belonging/inherited factors and include the following
a. Genetic – Most common
b. Metabolic
c. Cellular
d. Structural
Extrinsic factors are environmental and include the following
a. Physical
b. Chemical
c. Biological (infectious agents)
d. Nutritional (onset of diabetes as a result of repeated unhealthy food intake)
3. A varied relationship is present depending on what is causing the disease. Graphs
below show the distinction between these causes
a. Relationship between physical agent (CA) and POD
b. Relationship between allergen (CA) and POD
c. Relationship between infectious agents (CA) and POD
d. Relationship between alcohol intake (CA) and POD

4. The causes of disease affect various factors
Genetic causes of disease Environmental causes of
disease
Manifestations Likely to be manifested Can manifest at any stage,
during childhood provided the PA is available
Familial incidence Common, especially if first Uncommon, unless the PA is
cousin marriages are around the family and in
common close proximity to them
Remission (Symptom free Unlikely, unless treatment As soon as environmental
period) such as gene therapy given agent is not around, the
disease will not manifest
incidence Rare, usually occurs once Common, as infectious
and remains agents for example may
cause disease numerous
times
Linkage to inheritance Highly common in genetic, Unlikely
for example, HLA protein is
known for rejecting certain
organs from the body. The
protein is also known for
causing other disease


 5. There are multiple reasons as to why birth defects are caused in humans
a. Unknown causes (70%)
b. Hereditary
c. Cytogenic disease
d. Drugs, chemicals and radiation
e. Maternal infection
f. Birth trauma and uterine issues
g. Maternal metabolic disorders
6. Multiple diseases are caused at birth and still referred to as congenital
a. Non-genetic causes usually occur when the mother is exposed to an
infection and include the following
i. Toxoplasma – a parasitic disease caused by Toxoplasma Gondi
ii. Rubella virus – If infected during the first trimester of pregnancy, it is
able to cause heart problems
iii. If parents (mother) are infected with CMV (Cytomegalovirus) or
Herpes simplex virus, the child can still cause congenital effects in the
child
1. This is even if the child is fine genetically
2. This happens in the womb as the mother is environmentally
exposed to infection (70-80%of the world’s population suffers
from CMV)
b. Non-genetic causes can also be iatrogenic, this is where some sort of
treatment of therapy is causing the disease
i. Foetal alcoholic syndrome – If the mother is taking excessive
amounts of alcohol
ii. Thalidomide – Drug which was otherwise used (thought to be) for
hallucinations but ended up causing deformities in children
7. Genetic material is packed within the nucleus in chromosomes
a. 3 DNA bases eventually code for one protein
b. A change in one of the DNA sequences is called a mutation
8. Mutations can be caused by various DNA damages
a. Acquired factors include
i. Radiation
ii. Alkylating agents
iii. Genetic Events such as recombination via telomeres
9. Chromosomal abnormalities occur when changes happen within the entire
chromosome
a. Deletion – One chromosome ends up being smaller than another, as some
DNA is lost
b. Inversion – Two cuts in the current chromosome and then a swap around
c. Translocation – Happens between two different chromosomes
d. Nondisjunction – Failure of chromosome separation during cell division
(gametogenesis)
i. For example, Down’s Syndrome
e. Some tumours can also be caused by genetic factors (Neoplasms)




10. Genetic diseases can be caused either by a defect in one gene or multiple genes
a. Monogenic (by ONE gene)
i. Cystic fibrosis
ii. Sickle cell anaemia
b. Polygenic (MULTIPLE genes)
i. Diabetes
ii. Bronchial asthma
11. Mutations can also cause disease
a. Sickle Cell Anaemia
i. Caused by a defect in the haemoglobin gene
1. Haemoglobin consists of 2 alpha chains, 2 beta chains and the
globin protein
ii. The Globin protein has a defective single base pair change – also
known as a single nucleotide polymorphism
iii. The DNA sequence GAG is changed to GTG
1. GAG codes for glutamic acid
2. GTG codes for valine
iv. This change from glutamic acid to valine makes changes adult
haemoglobin to haemoglobin S
v. Haemoglobin S is characterised by precipitation in the red blood cells
vi. The precipitation makes it form the sickle shape (rod shaped)
vii. When the RBC’s are passing through the blood vessel, surrounding
tissue is damaged
viii. Haemoglobin S is NOT produced is the third codon is changed to G
b. Radiation
i. Cancer occurs when a mutation caused by radiation makes cells grow
in an uncontrollable way
12. Karyotyping is a chromosome arrangement method which pairs them
a. More or less chromosomes allow problems and defects to be detected
b. A haploid cell has 23 chromosomes (sperm and ovum)
c. A diploid has 46 chromosomes (most somatic cells)
 d. Polyploidy is when there is 3 or more times the number of chromosomes
(69) which are multiples of 23
i. Pregnancies where these are detected are usually aborted since the
child has a very low survival level and are rarely compatible with life.
e. Aneuploidy is having extra chromosomes which are NOT a multiple of 23
i. For example, Down’s syndrome, where there is one extra
chromosomes is an example of a disease caused by aneuploidy
13. Definitions
a. A gene is part of genomic DNA sequence, corresponding to a unit of
inheritance
b. A allele is a alternative form of a gene, which is located at a specific location,
on a specific chromosome
c. Homozygous means that both genes are the same (homozygous alleles)
d. Heterozygous means that both genes are different, usually presenting a
defect on one copy

14. Autosomal dominance – defects in SOMATIC chromosomes
a. Only one abnormal copy is required for the disease to manifest
b. Examples include
i. Neurofibromatosis – nerve sheath tumours, caused by an autosomal
dominant gene defect on chromosome 17
ii. Polycystic kidney disease – characterised by cysts on the kidney
iii. Family hypercholestremia
iv. Marfan syndrome
15. Autosomal recessive – defects in SOMATIC chromosomes
a. Both copies of the paired genes, from both parents are required for the
disease to manifest
b. If one copy of the gene is normal and the other one is a defect, the child will
be a carrier, but will not manifest the disease
c. Example includes:
i. Cystic fibrosis, defect on the CFTR gene on chromosome 7 (gene that
is responsible for chloride transportation)
1. Condition involves the phenotype having excessive sweat and
tears and a thick mucus viscosity













 16. X Linked recessive is where one copy of the X chromosome has a defect
a. More common in males since they have only one X chromosome, and since it
is recessive, both copies of the defective gene are necessary
b. Males are twice as likely to get the disease
c. Disease can only be acquired from diseased females, not males
d. For example
i. Haemophilia A (defective clotting factor VIII deficiency Xq28)
17. Multifactorial inheritances are where there are multiple genetic effects lead to the
outcome of the disease (also known as polygenic inheritance)
a. There is usually a combination of lifestyle and environmental factors, both of
which play a role in causing the disease
b. Examples include
i. Diabetes
ii. Hypertension
iii. Atherosclerosis
iv. Asthma
v. Autoimmune diseases
vi. Cleft lip and Cleft palate
18. Chromosomal abnormalities (different number of chromosomes)
a. Sex chromosomes missing (such as 45X, instead of 46)
i. These females usually go ahead to have less breast development and
possible fertility problems (turners syndrome)
b. Additional sex chromosomes (47XXY instead of 46)
i. Such males go ahead to have breast development, poor facial hair and
a underdeveloped penis and testes size (Klinefleter’s syndrome)
19. Downs syndrome is where there is an extra chromosome (chromosome 21)
a. The syndrome is a major causes of intellectual disability in children, and the
commonest disease is numerical autosomal abnormality
b. For downs syndrome to occur, nondisjunction cell division must occur
c. most individuals have an extra chromosome 21, known as trisomy 21
d. The IQ of the child is likely to be between 25-70

20. Clinical features include
a. Slanted eyes
b. Congenital; heart disease
c. Mega colon
d. Wrinkled tongue
e. Short, broad hands
f. Wide gap between the 1st and 2nd toes
g. Prone to leukaemia
21. The chances of getting a child with down’s syndrome are greater as the age of the
mother increases
a. Namely around 30+, is when the chances are quite high
b. In order to prevent Downs syndrome, women are able to undergo tests that
present the risk of downs syndrome in week 12
i. It is then up to the mother whether or not she wants to keep or abort
the child
 c. The best prevention method is to give birth at an earlier age
22. MHC genes are responsible for the recognition of foreign substances
a. MHC = Major histocompatibility complex
b. In humans, MHC is known as HLA
i. HLA does not cause disease, but is prevalent in numerous diseases
1. E.g., Ankylosing spondylitis, when 100 people were tested,
89% had HLA b27. Similar proportions shown with other
diseases
23. Infectious diseases are caused by infectious agents
a. 25% of deaths accountable by infectious disease
b. Gram. Negative Bacteria, e.g., which have a LPS (Lipo-poly-saccharide)
component are liable to causing blood infections (septicaemia) which will
result in death
24. Bacteria take a number of steps to cause disease
a. Attachment via Pilli
b. Colonisation using host nutrition
c. Invasion via specific elements (usually enzymes, e.g. Proteases (Neisseria
meningitis produces IgA proteases), Hyaluronidase, Collagenase)
d. Escaping the immune system, via components such as a carbohydrate
capsule that prevents the bacteria from being engulfed
e. Immune mediated change, taking advantage of the immune system, auto
immunity as in the case of rheumatic fever
25. The hyaluronidase enzyme penetrates between epithelium to enter the body. The
enzyme is secreted, eventually allowing the bacteria itself to enter the host
26. Once within the host, bacteria can cause illness via toxin production
a. Toxins form pores in cell membranes, and allow the bacteria deeper into
tissues
b. Coagulase is formed by Staph. Aureus that clots blood and is a method of
immune escape
i. Immune cells are unable to enter the “blood clot” wall
c. Streptokinase is a bacterial enzyme that dissolves blood clots, and will allow
the bacteria to spread
i. NB – SK is used for Heart attack treatment, since it dissolves clots in
the coronary arteries
27.
Exotoxin Endotoxin
Source Gram + Gram -
Metabolic product Secreted by growing cells Present in LPS of outer
membrane, the toxins
are realised when the cell
dies
Chemistry Protein Lipids
Fever NO fever Yes
Neutralization by Yes No
antitoxins?


 28. Viruses use the machinery of the host to reproduce
a. The typical morphology includes a capsid which encompasses the genetic
material within. An envelope is acquired from the host cell which have
proteins encoded by the genetic material within the virus
b. The genome consists of RNA, DNA (single or double stranded)
i. Among single stranded, there can be negative or positive
ii. The positive stranded RNA viruses can code the protein if they bind to
the RNA of the host cell
iii. Negative stranded RNA viruses must be converted to positive RNA SS
29. Viral pathogenesis occurs after the virus enters the cell
a. Cytocidal and cytopathic – The virus will have to bind with a receptor
i. E.g. HIV – CD4
ii. Once the virus is within the cell, it will multiply
iii. The virus will then burst, and the cell dies by bursting
b. Immune lysis
i. Once the virus enters the cell, a part of the protein will be expressed
on its surface
ii. These cells will be killed by antibody mediated antigens, which are
coded by the virus
iii. The immune system is killing target cells, and hence kills the virus
inside
c. Cell fusion
i. Cells fuse together and do not become very stable
d. Transformation
i. Malignancy is produced when a virus multiples the host cell, making it
cancerous
30. Prions are proteins which DO NOT have DNA
a. Prions continue to multiply within the host
b. Pathology includes spongiform encephalopathy, small cysts (empty spaces)
in the gray matter of CNS
c. Symptoms include ataxia, tremor, insomnia and dementia
d. In humans = CJD, Kuru and cCJD (variant)
31. Prion protein mechanisms
a. The normal proteins have alpha helices
b. The change from normal to disease causing makes the proteins have beta
plated sheets (conformational change)
c. The change to beta plated sheets allows the protein to replicate on its own