Adult General Genetics Flashcards

Question

What are the characteristics of arrhythmogenic cardiomyopathy

Answer 1

Fibrosis/fatty infiltration of right ventricle BUT frequently involves the left ventricle May present with DCM phenotype 1st symptom is commonly sudden death on exercise Later presentation with Cardiac failure

Answer 2

Desmosome proteins, which adhere cardiac cells together, and allows messaging between the cells Faulty messaging can lead to fibrosis Lamin A/C - supports the nuclear membrane Mutations in these genes causes nucleus to collapse causing cell death Desmin - protein that fixes the sarcomere to other structures in the cardiac cell

Answer 3

Implantable devices (pacemaker) treats rhythm while implantable defibrillator protects and only acts when needed

Answer 4

Autosomal dominant with reduced penetrance - MYH7 in HCM Age related penetrance - MYBPC3 May present from foetal - old age MYH7 Autosomal recessive - Pompe’s X-linked recessive Fabry’s GLA X-linked Dominant with male lethality X-linked Dominant - Danon LAMP2 Oligogenic

Answer 5

Primary rhythm disturbances Long QT Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Answer 6

Q = when the heart is full while T = when the heart contracts/empties

Answer 7

LQTS1 - K - loss of function - 30-35% - easily treated with beta blockers LQTS2 - K - loss of function - 25-30% - mutation in KCNH2 LQTS3 - Na - gain of function - 5-10% - mutation in SCNA, worrying as it is triggered by sleep

Answer 8

Abnormal ECG - identified in A&E when individual is sick Sodium channel blocker may trigger the abnormal pattern for investigation Beta blockers don't work, so may need ICD (implantable cardioverter-defibrillator)

Answer 9

Rare but highly malignant, 30% with mutation in RYR2 Calcium channel for contraction, mutation may cause leakage of calcium especially under adrenaline Recurrent attacks upon exercise Resting ECG is normal, with a bidirectional alternating VT Can be treated partially with beta blockers, but ICD can be fatal due to shock causing adrenalin

Answer 10

Obvious ones - epilepsies, neurodegenerative disease, movement disorders, neurofibromatoses Less obvious - mitochondrial disease, channelopathies, Diseases - Charcot-Marie Tooth Disease, Muscular Dystrophies, ALS/MND

Answer 11

To provide an explanation To allow screening/monitoring for other symptoms Guide treatments E.g. whether a person with epilepsy should have sodium valproate or not (mitochondrial disease?) There may be implications for other family members

Answer 12

Consider non-genetic and genetic causes - family history, are there other associated features etc. Diagnostic Testing Single Gene Testing Panel Testing Whole Exome/Genome Sequencing

Answer 13

Myotonic dystrophy

Answer 14

Type 1 4 different subtypes - mild, classical, juvenile, congenital CTG Triplet repeat disorder in DMPK gene Type 2 Typically proximal muscle weakness, variable myotonia, no congenital form CCTG repeat in CNBP gene

Answer 15

Cognitive function - intelligence, behaviour, psychological disorders, excessive daytime sleepiness Vision - cataracts, retinal damage Endocrine system - diabetes, low thyroid hormone levels Respiratory system - breathing difficulties, aspiration, sleep apnoea, high risk for pneumonia Reproductive system Men - low testosterone, ED, testicular failure, gonadal atrophy Women - weakened uterine muscle, pregnancy complications and gynaecological problems Cardiovascular system - heart condition abnormalities, arrythmias, cardiomyopathy GI tract - swallowing issues, abdominal pain, IBS, constipation/diarrhoea, poor nutrition, weight loss Muscle - weakness, wasting/atrophy, myotonia, pain Also - skin bone and immune anomalies

Answer 16

Poor motivation, concentration, ADHD, ASD, mental retardation or delays, speech problems Swallowing and feeding difficulties, bowel and bladder delays Possible club feet, tight heel cords, AFO or braces Poor head control, ear infections, facial weakness Respiratory distress, may have breathing problems at birth, mechanical ventilation Floppy baby, poor muscle tone

Answer 17

CTG expansion in non-coding region of DMPK Imperfect double stranded hairpin RNA structure ``` Toxic RNA gain of function Gene missplicing Transcriptional dysregulation Abnormal protein translation Activation of cellular stress pathways - mitochondrial and metabolic ```

Answer 18

PCR detects alleles containing 5 and 125 CTG repeats and can be accurately sized TP-PCR uses 3 primers and creates products of differing lengths with large repeats being detectable but not sizeable Southern blotting used for accurately sizing DNA fragments

Answer 19

Unstable/dynamic expansions therefore can increase in size in next generation Anticipation This occurs in repeat expansion disorders, as the repeat region grows Symptoms can present earlier and earlier in subsequent expansion Instability may depend on parent of origin - maternal in MD, paternal in huntington's General correlation between size of expansion and severity of the disorder

Answer 20

Maternally

Answer 21

Paternally

Answer 22

Adult onset neurodegenerative disease, dominantly inherited C-A-G triplet repeat expansion Main features are chorea, dementia and neuropsychiatric disease Antisense oligonucleotides can target RNA and prevent protein transcription - also used in spinal muscular atrophy

Answer 23

Recessive CNV in SMN1 - loss of protein production The SMN2 gene only produces a small amount of functional protein, genetic artefact, oligonucleotides can help stimulate the 90% that usually does not get translated into protein Causes problems with muscles in neonatal period, can lead to muscular weakness and death

Answer 24

Approximately 25% of all AD is familial (i.e., ≥2 persons in a family) Of which 95% is late onset ( >60-65 years), 5% is early onset (<65 years)

Answer 25

Slowly progressive memory difficulties Confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism

Answer 26

Clinical signs - slowly progressive dementia Neuroimaging Gross cerebral cortical atrophy on CT or MRI Diffuse cerebral hypometabolism on PET Cerebrospinal fluid (CSF) - decreased Aβ amyloid 42 and increased tau Neuropathological Findings at postmortem – 80-90% concurrence with clinical diagnosis

Answer 27

Mean Onset <65 years, Autosomal Dominant ``` Chance of finding a mutation in a simplex case is LOW <6% APP (10-15%) 1.4% PSEN1 (30-70%) 4% PSEN2 (<5%)1% Other loci ```

Answer 28

ApoE encodes a polymorphic glycoprotein expressed in liver, brain, macrophages, and monocytes ApoE participates in transport of cholesterol and other lipids Involved in neuronal growth, repair response to tissue injury, nerve regeneration, immunoregulation, and activation of lipolytic enzymes

Answer 29

The APOE gene contains three major allelic variants at a single gene locus (ɛ2, ɛ3, and ɛ4) Encodes different isoforms (ApoE2/3/4) that differ in two sites of the amino acid sequence.

Answer 30

The APOE ɛ4 allele increases risk in familial and sporadic early-onset and late-onset AD ○ x3 risk for APOE ɛ34, x15 for APOE ɛ44, 40–65% of AD patients are ɛ4 carriers The effect of APOE ɛ4 accounts for 27.3% of the estimated disease heritability of up to 80% The APOE ɛ2 allele is thought to have a protective effect 20–25% of the general population carries one or more ɛ4 alleles

Answer 31

Up to 75% of individuals heterogeneous for APOE ɛ4 do not develop AD during life Up to 50% of people with AD do not carry the high-risk ɛ4 allele The case for testing and the risks associated with other genes is even weaker

Answer 32

Insight into pathogenic mechanisms Druggable targets Risk stratification in clinical trials There is limited clinical utility in the context of the individual patient

Answer 33

Main blood vessel/artery leading out of the heart, exiting the left ventricle and loops out into an arch The arch leads upwards to supply the head, neck and arms The descending aortas becomes the abdominal aorta once it passes the diaphragm and innovates everything else including the kidneys and legs Descending aorta can be divided into the thoracic and abdominal

Answer 34

Aortic aneurysm Aortic dissection Aortic regurgitation

Answer 35

The aorta is pretty smooth, slightly dilateds it leads out of the heart Aneurysm = pathological dilatation Most common site being in the abdominal aorta, mainly due to environment Burst can be fatal - treated by implanting a graft/mechanical valve/tube

Answer 36

A partial tear in the wall of the aorta The aorta has two layers, blood accumulates into the second layer forming a 'false lumen' At this point an aneurysm can become symptomatic E.g. compression on nerve, push on oesophagus

Answer 37

Aortic value fails to close, allowing blood to leak backwards Blood re-enters into the left ventricle Can be due to primary pathology in the valve itself Or due to aneurysms, because of the dilatation pulling the valves apart

Answer 38

Marfan syndrome Loeys-Dietz syndrome Collagenopathies Non-syndromic thoracic aortic aneurysm - harder to identify as there are no obvious external features

Answer 39

Connective tissue disorder

Answer 40

Incidence is same | Men have shorter life expectancy

Answer 41

AD, with variable expressivity

Answer 42

Fibrillin-1 (FBN1) - a microfibril glycoprotein in elastic/non-elastic tissues, part of extracellular matrix ~25% de novo mutations / ~75% inherited and > 97 different mutations Diagnostic yield 66-91% of cases

Answer 43

Long limbs/fingers, downslant eyes, flattened cheek bones, lower jaw pushed back, deep set eyes

Answer 44

Cardiac - mitral valve prolapse, aortic root dilation Head/neck - myopia (nearsightedness), lens dislocation (ectopia lentis), high palate and crowded dentition Chest - spontaneous pneumothorax Neurologic - dural ectasia Skin - stretch marks Musculoskeletal - tall, along arm spam, long digits, scoliosis, hypermobility and more

Answer 45

Used to diagnose Marfan syndrome in absence of family history

Answer 46

Aortic root Z-score ≥ 2 AND ectopia lentis Aortic root Z-score ≥ 2 AND FBN1 mutation Aortic root Z-score ≥ 2 AND systemic score ≥ 7 Ectopia lentis AND FBN1 mutation associated with aortic aneurysm

Answer 47

Either of the following Ectopia lentis Systemic score ≥ 7 Aortic root Z-score ≥ 2

Answer 48

Statistical term to normalise the aortic size to the standard for a person of that age and size This is because aortic diameter varies depending on various factors Aortic score >2 meaning above 2 SD from the normal

Answer 49

Most common cause of morbidity/mortality (~80%) Aortic root disease > aneurysms, AR, dissection 50% of children, 80% of adults May lead to neurovascular complications Mitral valve prolapse (minor criterion Most common valve defect 60-80% Worsens with time, complicated by rupture Arrhythmias

Answer 50

Prognosis can be poor if diagnosed in infancy/childhood Severe Marfan can include deforming skeletal anomalies • Later-onset symptoms: ○ Cataracts, retinal detachment, easy bruising (but normal wound healing), stretching of the spinal dura with neck/abdominal pain, osteoporosis, risks in pregnancy (e.g. vascular)

Answer 51

Early manifestations: Heart: abnormal echo (96%), aortic root enlargement (84%), mitral valve prolapse (58%) Eyes: ectopia lentis (70%), myopia (60%) Skeletal: pectus deformities (68%), scoliosis (44%), flat feet (44%) Height >95th centile (56%), arachnodactyly (88%), striae (24%)

Answer 52

Cataracts, retinal detachment, easy bruising (but normal wound healing), stretching of the spinal dura with neck/abdominal pain, osteoporosis, risks in pregnancy (e.g. vascular)

Answer 53

At least annual evaluation Clinical history Examination Echocardiography Consider aortic root surgery when the aortic diameter at the sinus of Valsalva exceeds 5 cm Enhanced monitoring in pregnancy (risk of aortic dissection if the aortic diameter exceeds 4 cm)

Answer 54

Beta blockade Calcium channel blockers ARB's (Angiotensin II receptor blockers)

Answer 55

Autosomal dominant inherited connective tissue disorder

Answer 56

TGFBR1~20%-25%, TGFBR2~55%-60%, SMAD3~5%-10%, TGFB2~5%-10%5.TGFB3~1%-5%, SMAD2~1%-5% Differential diagnosis to Marfan - rarer, exact prevalence unknown and ocular features absent

Answer 57

Cardiovascular - arterial tortuosity, congenital heart defects (ASD, PDS, BaV) • Eyes, Head and Neck ○ Widely-spaced eyes (hypertelorism), blue-gray sclerae, wide or split uvula, cleft palate, cervical spine instability or malformation Skin - easy bruising, wide scars, soft skin texture, translucent skin Bones - club foot (talipes equinovarus), osteoporosis Gastrointestinal problems - malabsorption, diarrhoea, abdominal pain, bleeding, inflammation, other Other - allergies (food/environmental), spleen/bowel rupture, uterine rupture during pregnancy

Answer 58

Aortic dissection occurs at smaller diameters than in Marfan Vascular disease not limited to the aortic root, requires MRI scan to look at other vessels

Answer 59

Beta-adrenergic blockers or other medications are used to reduce hemodynamic stress Aneurysms are amenable to early and aggressive surgical intervention Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage Standard treatment for club feet and severe pes planus Craniofacial management for cleft palate and craniosynostosis

Answer 60

Genetic conditions which affect the collagen genes Includes Ehlers-Danlos syndrome and other connective tissue disorders

Answer 61

Can be syndromic or non-syndromic There is a wide range of genes - some involved can overlap with those seen in syndromic diseases TGFBR1/2, MYH11, FBN1, SMAD3, MYLK, ACTA2

Answer 62

Muscle contraction - problems = more prone to be stretched, causing aneurysm ECM - provide structural support = more prone to being stretched TGFB - interacts with some of the ECM, and affects activation of transcription

Adult General Genetics Flashcards

(87 cards)