Clinical Consequences Flashcards
Describe Tay Sachs Disease
Failure of lysosomes (specifically hydrolytic Hexosaminidase enzyme) to degrade lipids.
Lipids (gangliosides) accumulate in neurons
Neurodegeneration, blindness, seizures, usually death
Autosomal Recessive
Describe Kartagener’s Syndrome
Mutation in Dynein motor protein in microtubules
Causes problems with cilia and flagella movement
Result: recurrent resp. infection, infertility (males)
Autosomal Recessive
Describe Vohwinkel Syndrome
Thick honeycomb calluses (palmoplantar hyperkeratosis), and build-up of fibrous tissue on hands and feet, can also present as deafness
Caused by gene mutations impacting Connexin-26, results in GAP junction dysfunction.
Describe Epidermolysis Bullosa Simplex
Hemidesmosome Dysfunction
Causes severe blistering of skin and epidermal-dermal junction is not functioning properly.
Describe Taupathy related disorders
Neurodegeneration caused by hyperpolarization of protein tau. Hyperpolarization causes tau to dissociate from microtubules of neuronal axons, and aggregate into tangles, causing microtubule destabilization.
Includes diseases such as Alzheimer’s and Parkinson’s.
Describe Lymphoedema
If lymphatic vessels are damaged, they are very poor at regeneration therefore lymph drainage back to nodes is impaired, and can result in oedema caused by excess lymph.
Can also be caused by Lymphatic Filariases
Describe Rheumatoid Arthritis
Example of autoimmune disease
Extensive inflammation caused by immune system mounting response to synovial membrane of joints.
Describe Septic Shock, and the processes that lead to it.
Hypoperfusion occurs when heart has increased pumping due to immune response to blood-borne infection.
Infection -> Vasodilation
Vasodilation -> reduced blood pressure
Reduced BP = Organ hypoperfusion
Hypoperfusion -> Tachycardia (increased heart rate)
Tachycardia is used to increase BP and restore perfusion so organs receive appropriate amounts of blood
Extended Tachycardia -> Heart failure/death
Autosomal mutations in Toll-Like Receptors can result in what?
Recurrent infection
Innate cells wont produce cytokine release when TLR recognizes a pathogen
Describe the RAS mutation and its implications
Mutation in the key regulatory codon resulting in change in protein function, causes hyperactivation of RAS, and excessive 2nd messenger activation and over-transcription of key genes, and cancer
Discuss the mutations leading to sickle cell anaemia.
GAG gene is mutation to GTG which changes the tertiary folding of the polypeptide, it is flatter, and the haemoglobin doesn’t fold correctly leading to a moon shaped RBC.
If heterozygous for mutation, some blood cells will still fold correctly
Describe how the understanding of proteins in Chronic Myeloid Leukaemia is useful in drug design.
Chronic Myeloid Leukaemia occurs due to translocation of the the BCR gene (chrom 22) and ABL gene (chrom 9) bind, forming a fusion protein with strong kinase activity.
Knowing this aided in the development of a drug that would block the binding of this
Describe Li-Fraumeni Syndrome
Inherited familial predisposition to a wide range of certain, often rare, cancers. This is due to a change (mutation) in the TP53 gene.
Describe Ehlor-Danlos Syndrome
Group of inherited (or more rarely random mutation) syndromes that typically involves defects in collagen 1 resulting in hyper-flexibility, stretchy-velvety skin, joint pain and abnormal scar formation.
Describe Psoriasis
Epidermal Hyperplasia, skin regeneration is so quick (up to 7 days), that keratohyalin and tonofibrils cannot develop completely in the stratum spinosum, this results in granular layer not developing properly
What is zika virus, and how is it transmitted?
Mosquito Borne virus
Can be passed vertically to unborn child causing microcephaly
What is ebola, and how is it transmitted?
Virus transmitted through blood and body fluids.
• symptoms typically start between two days and three weeks after contracting the virus
• fever, sore throat, muscular pain, and headaches
• Vomiting, diarrhoea, decreased liver/kidney function
• Internal/external bleeding
~50% mortality rate
What is malaria and how is it transmitted?
Mosquito Borne parasite
• Disease of poverty
• Parasite (sporozoites ) travels to liver to reproduce asexually, then releases (by wrapping self in liver cell membrane) merozoites into blood where they reproduce in erythrocytes, break out, and resume the cycle.
Cycles (waves) of fever and flu like symptoms
What is lymphatic filariases and how is it transmitted?
Mosquito Borne- highly infectious parasitic disease
Parasite lives in lymph system and causes lymph oedema
Disfiguring
What is yellow fever and how is it transmitted?
Viral Mosquito Borne
Haemorrhagic disease
Causes fever, headache, jaundice, muscle pain, nausea, vomiting and fatigue
What is African trypanosomiasis and how is it transmitted?
Sleeping sickness, arthropod transmission via tsetse fly
Parasite causes disturbed sleep, fever, severe headaches, irritability, extreme fatigue, swollen lymph nodes, and aching muscles and joints
Can be treated with pentamidine which crosses BBB
What is leishmaniasis and how is it transmitted?
Parasite transmitted via sand-flies
Causes immune system to break down mucosal membrane
Presents as ulcers, fever, erythropenia, enlarged spleen/liver
What is American trypanosomiasis and how is it transmitted?
Chagas disease, or kissing bug disease
Caused by arthropod, the reduviid parasite faeces.
Live as carrier for 20-30 years
Parasite is transmitted by defecating into blood, and travel to live on intestines and heart.
Causes inflammation, flu-like symptoms, rash, loss of appeptite.
What is salmonella and how is it transmitted?
Gram-negative rod-shaped bacterial infection transmitted via water and food
Causes fever, stomach pain, diarrhoea, cramping
What is cholera and how is it transmitted?
Gram-negative rod shaped bacterium transmitted through water.
Causes gut leakage leading to severe diarrhoea and dehydration, can be fatal.
What is E. coli and how is it transmitted?
Gram-negative, rod shaped bacterium transmitted via water and food
Some types can cause food poisoning and serious infection
What is shigella and how is it transmitted?
Gram-negative rod shaped bacterium transmitted via water
Causes diarrhoea, fever, and stomach cramps.
Typically passes without antibiotics within 7 days
What is schistosomiasis and how is it transmitted?
Parasitic worm that lives in blood stream, transmitted via water.
Causes abdominal pain, diarrhoea, bloody stool, blood in the urine, and anaemia.
What is chikungunya and how is it transmitted?
Virus spread by mosquitos
Symptoms set in 4-8 days after contraction, causing fever, joint pain, headache, nausea.
Can be acute, subacute or chronic, rarely life threatening.
What is plague, and how is it transmitted?
Caused by Yersinia pestis, gram-negative, rod-shaped, zoonotic bacteria, transmitted via ticks on rodents.
Causes fever, weakness, and headache.
What is Adenosine deaminase deficiency?
A primary severe combined immunodeficiency with no syndromic features
Adenosine deaminase enzyme is not present, and is needed in high quantities for thymocytes to produce B, T and NK immune cells.
Recurrent bacterial, viral, and fungal infections.
Can use ex vivo viral manipulation to genetically introduce correct gene.
What is X-Linked SCID?
An x-linked primary severe combined immunodeficiency with no syndromic features.
Caused by mutations in cytokine receptors, IL-2R gamma (IL-2 Common Gamma Chain) which is needed to bind IL-2,4,7,9,15, 21.
Therefore, don’t respond to cytokines, you cant make T cells or NK cells, cant produce sufficient antibody responses, although you can make B cells.
Recurrent bacterial, viral, fungal infections
What is hyper IgM Syndrome?
A primary severe combined immunodeficiency with no syndromic features CD40L deficiency on T cells means unable to bind and activate B cells, meaning class switching from IgM to other Abs fails. No germinal centres in lymph nodes, recurrent bacterial and fungal infections.
What is Foxn1 deficiency syndrome?
A primary sever combined immunodeficiency with syndromic features.
FoxN1 encodes for thymic epithelium (athymic), therefore no T cell maturation, and no resulting B cell activation.
Thymic cells needed for hair growth, syndromic feature is alopecia.
What is X-Linked Agammaglobulinemia?
A x-linked primary immunodeficiency
Mutation of Bruton’s Tyrosine Kinase (btk) Gene which prevents B cells development from pro-B cell to pre-B cell stage.
Results in few follicles in lymph nodes and low serum Ig.
What is IgA deficiency?
Most common primary immunodeficiency.
Cytokines are needed to help convert b lymphocytes into mature IgA-secreting plasma cells, but this doesn’t happen. Therefore no or low IgA levels.
Recurrent bacterial/fungal infection- especially in eye, mouth, and urinary tract.
What is chronic granulomatous disease?
Primary immunodeficiency
Defects in NADPH that produce superoxide burst, therefore phagocytes inefficient at eliminating bacteria, granulomas build up.
What is familial Mediterranean fever?
Primary immunodeficiency
Inflammasomes are needed to convert Pro-IL-1 to IL-1.
Inflammasome regulators, FMF, are mutated, causing increased conversion and presence of IL-1
Causes recurrent inflammation of GI and resp. tract, fever, swollen joint, ankle rash
What is chronic mucocutaneous candidiasis?
IL-17RA/IL-17F/CARD9 Deficiency
Primary immunodeficiency impacting innate immunity.
Anti-cytokine Ab will bind and inhibit IL-17A/F pathway resulting in no activation of target cells which causes lack of response to pathogens via no antimicrobial peptide/neutrophil recruitment/pro-inflammatory cytokines.
What is a secondary immunodeficiency?
An acquired immunodeficiency resulting due to a treatment or illness.
I.e. chemotherapy/radiation, HIV infection, protein/calorie malnutrition, cancer metastasis, spleen removal.
What is Broca’s Aphasia?
Damage to the Broca’s area of the frontal cortex of left hemisphere resulting in impaired production of speech.
What is Wernicke’s Aphasia?
Damage to the Wernicke’s Area of the left temporal lobe, resulting in impaired comprehension of speech.
What is Gullain-Barre Syndrome?
Autoimmune disease which breaks down gangliosides causing problems with motor functioning.
What is Multiple Sclerosis?
Autoimmune disease in which myelin sheath of brain are broken down causing problems with neural action potential firing.
Can cause visual problems, muscle stiffness/spasms, problems walking, thinking, planning, coordination.
What is Parkinson’s Disease?
Loss of dopamine-secreting cells within the substantia nigra.
Catecholamine plays large role in behaviour and reward pathways, as well as motor functioning.
It causes problems like shaking and stiffness that get worse over time.
What is Myasthenia Gravis?
Muscle weakness caused by auto-immune cells attacking nicotinic acetylcholine receptors at neuromuscular junctions, preventing receptor-ligand binding and opening of chlorine ion channels, allowing depolarization and action potential of muscles
Treated with acetylcholinesterase inhibitors
How does meningitis present clinically, and what are common causes?
Streptococcus pneumonia, Neisseria meningitides, Listeria monocytogenes, Haemophilia B
Presents as fever, stiff neck, and sometimes altered mental status.
Bacterial meningitis typically invades via nasopharyngeal injury into vasculature, then into subarachnoid space. Resulting cytokine release causes increased BBB permeability, which can block arachnoid granules, disallowing evacuation of CSF, causing build up of fluid, pressure, and can lead to brain damage.
What is thalassaemia?
Severe anaemia caused by mutation in gene promoter, TATA box of B-globin gene promoter, which results in less b-globin production, and therefore less haemoglobin being made
What mutation can alter the progression of HIV to Aids?
CCR5 promoter gene mutation affects the rate at which HIV progresses to Aids
If less CCR5 are being produced, it will be harder to the virus to bind to T cells as these are the receptors used by HIV to bind and enter, therefore slowing progression.
What is a promoter mutation causing haemophilia b?
Factor 9 promoter can cause Haemophilia B
Inherited or spontaneous mutation of promoter can result in inability to form factor 9, impacting bloods ability to clot?
What causes familial hypercholesterolemia?
Mutations in LDL receptor promoter lead to reduced production of LDLR, and an elevation of cholesterol.
Starts at birth, causes early heart attacks
Inherited
How are promoters/repressors in Myc important, clincally?
Mutations in SNPs (single nucleotide polymorphisms) found in enhancers and silencers of Myc can alter transcription of this gene, and may alter replication of cells.
Several mutations are linked to clinical disease.
What causes Hispanic Thalassaemia?
Mutation in locus control region up-stream of globin gene
Transcription factors wont be able to bind, and transcription of globin wont happen, resulting in severe anaemia
What is hereditary persistence of foetal haemoglobin?
Mutations in enhancers of foetal gamma globin gene increase the amount of expression, so it doesn’t reduce after birth.
Asymptomatic, makes sickle cell disease less severe.
Typically gamma globin and beta globin expression are inverted after birth
How can alternative splicing result in clinical disease?
Can lead to Thalassemia, change severity of Cystic Fibrosis, Duchenne’s Muscular Dystrophy, Frontotemporal Dementia with Parkinsonism
All related to splicing of mRNA
How do benign prostatic hyperplasia and prostatic cancer differ in terms of their transcriptome?
Can look at levels of mRNA expression in cells
BPH has a low expression and then high, whereas prostatic cancer has high than low, mRNA gene expression allows you to determine the disease.
Can do this in breast cancer too.
What is critical limb ischemia?
Lack of circulation to limbs, causing necrosis
What is Raynauds?
Poor circulation causes whitening of extremities
No known cause
In relation to blood flow, what factor impacting the veins can lead to tissue oedema?
Build up of blood in vein causes backflow to capillaries which can cause tissue oedema
What is Barrett’s Oesophogus?
Oesophageal epithelium is damaged by acid reflux, resulting in metaplasia
What is Goodpasture Syndrome?
Autoantibodies to collagen 4 destroy basement membrane in glomerulus and lung.
Leads to kidney failure, bleeding in lungs, and glomerulonephritis.
What is Alport Syndrome?
Inherited, degenerative, abnormality with Collagen 4 leading to kidney disease, hearing loss, and eye abnormalities.
What is Marfan Syndrome?
Inherited condition impacting fibrillin-1 (therefore elastin organization), causing problems with skeleton, cardiovascular system, and eyes.
Symptoms: tall/slender build, protruding sternum, near-sightedness
What is osteogenesis imperfecta?
Mutation impacting Collagen Type 1 formation, results in low collagen levels in bone and elsewhere, resulting in brittle bones that are easily fractured.
Can also cause blueing of sclera, short height, loose joints, hearing problems
