inherited cardiac coditiosn in clinical genetics Flashcards

Question

asessing aortic root dilatation?

Answer 1

Transthoracic echocardiography used for assessment of aortic root Enlargement can occur from in utero to adulthood Early onset correlates with greater risk of dissection/AR Diameter naturally increases with growth, therefore must be corrected for body surface area and age Dilation can, but rarely proceeds beyond innominate artery. However desending thoracic and AAA can occur Aortic measurements made at: Sinuses of Valsalva, the supraaortic ridge and proximal aorta Dilation often begins at SoV and progresses distally

Answer 2

Spontaneous Pneumothorax Cor pulmonale following chest wall deformity Poor muscular development Lack of adipose tissue Varicose veins Degenerative arthritis Uterine prolapse ADHD Body image

Answer 3

AD, Chromosome 15q. Penetrance 100%. 3p locus in French family. Missense and nonsense mutations described 25% new mutation (gonadal mosaicism described) Paternal age effect (39yrs vs 26yrs) Several hundred mutations known. Most private Probable dominant negative mechanism, but some evidence for haploinsufficiency Genotype-phenotype correlation limited to neonatal MFS ## Footnote

Answer 4

Life expectancy in MFS has increased greatly in last 30yrs Life expectancy is primarily determined by the extent and severity of cardiovascular involvement Improvement has followed improved surgical and medical management in conjunction with improved surveillance However social, lifestyle e.g. sports, employment and insurance issues are also important

Answer 5

Hypertrophic [HCM] Dilated [DCM] Restrictive [RCM] Arrhythmogenic right ventricular cardiomyopathy [ARVC] Left ventricular non-compaction [LVNC] Skeletal myopathies [DMD; DM…] Other forms [Danon, WPW.]

Answer 6

Hypertrophy Hypercontractility Diastolic dysfunction Fibrosis and disarray ## Footnote ~15 genes/ \>200 mutations Sarcomeric/cytoskeletal proteins No unifying “sarcomeric” hypothesis of pathogenesis Clinical studies suggest 50% familial Penetrance is incomplete and age dependant Molecular analysis shows \>90% of cases are familial - AD 15 disease genes \>100 known mutations many “private” mutations disease genes encode sarcomeric or cytoskeletal proteins proteins part of both thick and thin filaments

Answer 7

Clinical history- clinical examination 12 lead ECG Risk stratification: 24 hour tape, exercise tolerance test, echocardiogram 60% low risk 30% mod risk 10% high risk

Answer 8

1/5000-10000, idiopathic 30% “genetic” AD, XL(dystrophin), AR Penetrance age related \>15 disease loci sarcomeric protein genes lamin A/C cytoskeletal proteins dystrophin, taffazin (Barth’s) EYA4 phosphlamban Linked loci

Answer 9

1/5000 Myocyte necrosis apoptosis with fibrofatty replacement RV +/- LV (76%) AD AR (Naxos disease) clinical features? Variability of age of onset, penetrance and clinical features Ventricular/supraventricular arrhythmia SCD 2.5%/year, CCF in late disease

Answer 10

10 disease loci 6 known genes- most common 4 genes: - plakophilin 2 - plakoglobin (Naxos) - desmoplakin - demsoglein ? Diverse pathophysiolog

Answer 11

Familial Arrhythmic Syndromes - Long QT [Romano-Ward syndrome - Long QT with deafness [Jervel-Lange-Nielson] - Short QT - Brugada [SCN5A and others] - Catecholaminergic polymorphic VT [CPVT] - Familial Conduction disease e.g. Fam BBB - Atrial Fibrillation - Wolfe-Parkinson-White syndrome - Familial Junctional Tachycardia

Answer 12

romano-ward syndrome ``` Autosomal dominant (mostly) or autosomal recessive (with deafness) Many different “channelopathies” cause prolonged ventricular repolarisation ```

Answer 13

``` 10 loci (LQT1-10) most genes now cloned AR variant (Jervell and Lange-Nielsen) results from mutations at LQT1 or LQT5. Parents  heterozygous! Most genes encode K+ channels, except LQT3 (SCN5A) Mutation of KCNQ1(LQT1) or KCNE1(LQT5) disrupt slow inward K+ current (Iks). Mutations of HERG(LQT2) or KCNE2 (LQT6) disrupt the rapidly activating delayed rectifier K+ channel, IKr ``` MUTATIONS IN HERG GENE (LQT2) AND KCNE2 (LQT6) RESULT IN Ikr BLOCKADE RESULTING IN POTASSIUM ION EFFLUX BLOCK TOWARDS THE END OF VENTRICULAR ACTION POTENTIAL signs? Variable 50% have first cardiac event before 12yrs 90% by age 40yrs SCD risk factors: deafness, QT length, previous history of syncope, female sex, documented TdP or VF, young age at first event and what gene is affected. Age and Sex: females more often symptomatic, in males risk of cardiac event decreases after puberty with a natural decline in QTc Pregnancy: increased risk in post-partum period. PROLONGED QT MAY LEAD TO FATAL TORSADES DE POINTES AND VENTRICULAR FIBRILLATION- THE MOST COMMON SEQUENCE OF EVENTS IN SUDDEN CARDIAC DEATH

Answer 14

signs if asymptomatic? ECG: (QTc=QT/RR) LQT = QTc\>440-460 But 40% of LQT1/2 carriers have QTc 410-470. Overlap with normal QTc\>460 provides positive predictive accuracy of 96% in women and 91% in men With QTc in this range, phenotypic studies become imprecise and molecular genetic analysis may be of increased utility. Other Features: QT dispersion, T wave structure (biphasic?, alternans?), bradycardia with exersise, sinus pauses. Symptomatic individuals require treatment including lifestyle and drug advice (avoid those that increase LQT) Avoid competitive sports Care around electrolyte losses e.g. diarrhoea Beta-blockade decreases mortality from 50% to 5% in probands and affected family members. Permanent pacemakers (esp with SCN5A) have been advocated. If “breakthrough” events ICD has been shown to prevent death in LQT in conjunction with beta-blockers.

Answer 15

Na+ blockers (e.g. mexilitine) for LQT3? Modification of K+ in LQT1/2 e.g. oral K+ therapy, nicorandil ? Avoid beta-blockers for LQT3, pacemaker? LQT1 avoid competitive exersise LQT1 avoid diving and swimming LQT2 remove sources of loud noise e.g. alarm clocks

Answer 16

Not uncommon ? Prevalence unknown Common among Oriental peoples May only present with unexplained death Genetic and clinical heterogeneity Autosomal dominant inheritance Mainly a sodium ion channelopathy (SCN5A) Typical and atypical ECG changes Unmasking by azmeline/flecainide challenge No drug treatment- ICD only choice! ecg changes? Short PR RBBB ST elevation V1-V3

inherited cardiac coditiosn in clinical genetics Flashcards

(43 cards)