9.1, 9.2, 10. Genetic disorders, SARS-CoV-2, Seminars.

9.1 Genetics & Developmental disorders
1. Definitions
1. Multiplicative – Increase in cell number by mitosis
2. Auxetic – Increase in cell size
3. Accretionary – Increase in intercellular tissue components
4. Differentiation – Cell develops functions different to parent cell
5. Morphogenesis – Development of organ shape & function
6. Induction – Control of differentiation of one type of cell by another
2. Establishment of phenotype
1. Gene expression controlled by ‘control genes’
2. Control genes encode protein
3. Control genes regulated by master control genes
4. Homeobox genes are proteins influencing morphogenesis
5. Epigenetic alteration in DNA structure, DNA methylation, Histone proteins
3. Factors affecting maintenance of a differentiated state
Differentiated state affected by:
1. Local alterations in positional information by control gene products
2. Migration ofcells mediated by paracrine/endocrine factors
Maintenance of differentated state by:
1. Interacting with extracellular environment
2. Epigenetic modification
4. Anomalies of organogenesis
1. Agenesis – organ failed to develop
2. Aplasia – Incomplete development
3. Atresia – Lumen failed to develop
4. Hypoplasia – Failure of organ size development
5. Ecopia – Small mature tissue area present in another tissue area
6. Choristoma – A mass of one or more tissues at an iappropriate site
7. Hamartoma – Mass of tissue derived from all 3 germ layers found at inappropriate site
5. Cleft palate & lip
1. Failure of 1st branchial arches to complete fusion
2. Normally in week 5, maxillary processes fuse w frontonasal process to form upper lip
3. Normally in week 9, maxillary processes form palatal processes which fuse w nasal septum
4. Failed fusion of palatal shelves = Small palatal process & failed midline epithelium seam formation
Associated defects – 1. Absent/malformed teeth, 2. Spinal/mental congenital defects
Dental aspects – Malocclusion
2. Hypodontia
3. Hypoplasia
4. Supernumeraries
5. High caries & gingivitis
Management – Prevent movement of 2 maxillary halves + feeding, speech & cosmetic management
5. Genetic disorders
-Single gene defects
1. By mutations – Point mutation, mutationsin coding sequence, frameshift mutation, trinucleotide repeat mutation
2. Mendelian disorders – Enzyme defects, Defects in receptors/cell transport (cystic fibrosis), Non-enzyme protein defects
-Chromosomal defects
1. Trisomy 21 (Down’s syndrome)
General signs – Flattened facial profile, Prominent epicanthic folds, short hands w transvers palmar crease
Dental implications – Class III malocclusions, Hypoplastic midface, Rapid + early onset periodontal disease
2. Trisomy 18, Trisomy 13, Klinefelter’s syndrome
-Complex multigenic disorders
6. Congenital anomalies
1. Derformation – Extrinsic physical force
2. Malformation – Intrinsic disturbance
3. Disruption – Extrinsic disturbance resulting in destruction of normally formed tissue
4. Syndrome – Combination of anomalies not explained by 1 change
5. Sequence – Combination of anomalies caused by 1 change
e.g. Fetal alcohol syndrome, Teratogen exposure
7. Genetic testing indications
Prenatal: mother old, ultrasound fetal anomaly, Family history
Older: Neurodegenerative disease, inherited cancer, disorder manifesting in older age

9.2 SARS-COV-2
1. Pathogenesis
1. SARS-CoV-2 S-protein binds to ACE2 receptor
2. TMPRSS2 on host cell cleaves ACE2 receptor which allows virus to bind to cell membrane
3. Virus binds, enters cell via endocytosis
4. Virus releases RNA & hijacks cell machinery to replicate
Early stage
1. Bronchial epithelial cells, pneumocytes, capillary endothelial cells infected
2. Inflamatory signalling molcules released (TNF-alpha, IL1, IL6)
3. Recruitment of macrophages, T-lymphocytes, neutrophils
Late stage
1. Continued inflammatory response = Alveolar interstitital thickening, vascular permeability
3 Features of SARS-CoV-2 pathogenesis
1. Severe endothelial injury
2. Widespread vascular thrombosis w microangiopathy
3. New vessel growth by existing vessels splitting into 2
2. Why do only 20% of hosts develop severe symptoms
1. Exacerbated inflammatory response from transition innate -> adaptive immunity
2. Autoantibodies for type I interferons
3. Comorbidities (diabetes, cardio)
4. Maturity of ACE2 receptors (age)
3. Histiologic features of fatal covid infection
1. Diffuse alveolar damage
2. Mononuclear inflammatory by lymphocytes
3. Exudative & proliferative phase of alveolar damage
4. Atypical pneumocytes w/ large/multiple nuclei
4. Fatal outcomes + Oral manifestations
1. Pulmonary hypertension
2. Activation of coagulation facors
3. Microthrombi formation
4. Thrombotic arterial complications (ischaemic stroke)
5. Viral sepsis
Oral manifestations
1. Mucosal ulcerations
2. Vesicles
3. Petechiae
4. Erythematous plaques

Path seminars
1. COPD + Asthma
Aetiology
– COPD – Pollution/cigarette smoke + host factors
-Asthma – Triggers (exercise, inhaled) + host factors
Pathogenesis
– COPD – Direct/indirect effects of pollution/smoke on respiratory tract
-Asthma – Tpe I hypersensitivity reaction (allergen reacts w IgE bound to mast cells)
Clinical features
-COPD – Chronic cough, dyspnea, sputum production
-Asthma – Wheeze, cough, chest tightening
2. Diabetes mellitus
Aetiology
-Type I – Genetic + Environmental (social mixing, viral infection)
-Type II – Age, obesity, diet, lack of exercise
pathogenesis
-Type I – Autoimmune destruction of beta cells in pancreas (which secrete insulin)
-Type II – Failed feedback loops between insulin action & secretion
Clinical features
-Fatigue, neuropathy, delayed wound healing
3. Atherosclerosis
Aetiology
-Elevated LDLs, diabetes, obesity
Pathogenesis
-1. Fatty streak formation, 2. Atheroma formation, 3. Atheroma disruption
Clinical features
-Depends on artery affected
(coronary artery) arrhythmias, transient ischaemic symptoms
(Carotid artery) dizziness, stroke
4. Hypertension
Aetiology
-Genetic, environmental, behavioural
-Secondary hypertension caused by underlying systemic condition
Pathogenesis
-Sympathetic nervous system
-Renin-angiotensin-aldosterone actiation
-Endothelial dysfunction
Clinical presentaiton
-High BP, but usually asymptomatic
(If severe) Vision problems, headaches, shortness of breath
5. Stroke
Aetiology
-Hypertension, old age, family history
Pathogenesis
-Infarction -> ischaemic stroke
(Lumen close from atheroscloersis, thrombosis, embolus)
-or Haemorrhagic pathogensis
(From hypertension, aneurysms)
Clinical presentation
-Facial drooping, arm weakness, speech difficulty

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