Genetics Flashcards
What does genetic risk increase with
Number of affected fam members
Frequency in population
Big 5 genetic defects
Congenital heart disease NTDs Hemoglobin disorders Down's syndrome G6PD deficiency
Types of genes affected in NTDs
Folate metabolism ( not SA) Other metabolic genes Genes related to neural tube development (planar cell polarization pathway) Neural plate bending (SHH) Epigenetic
‘Syndromic’ NTD conditions
Downs
Triploidy
Meckel gruber (AR) Curriano syndrome (AD)
Environmental factors in NTDs
Seasonal variation Geographic variation Nutritional Twins Teratogens (alcohol, anticonvulsant, hyperthermia)
Prenatal diagnosis of NTD
U/S AFP Maternal serum screen Second trimester aneuploidy screening Amnio = very rare
Congenital defect in platelet function
Von Willebrand disease (AD)
X linked recessive bleeding disorder
Haemophillia A or B
Why may females bleed in haemophilia
One X eg Turners syndrome
Both copies of gene
Skewered X inactivation pattern
Other X abnormalities
Congenital thrombosing disorders
Antithrombin 3 deficiency
Protein C and S def
Factor V Leiden
Prothrombin mutation
All autosomal dominant but reduced penetrance
Aetiology of NTDs
Isolated (familiality + environmental factors)
Spectrum of disorders (commonly meningomyelocoele and anencephaly)
Teratogens in NTD
Maternal IDDM
Anticonvulsants (valproate/ carbamazepine)
Alcohol
Hyperthermia
Outcome in prenatal diagnosis of NTD depends on..
Type and level of lesion
Associated findings
Post natal course (hydrocephalus / shunt complications)
Primary prevention of NTDs
Improve health, nutrition Family planning Rx chronic diseases eg DM, epilepsy Avoid teratogens Genetic counseling PRECONSEPTUAL FOLATE
Folic acid doses
1 month before preg to 3 months after birth
400ug ‘‘normal risk’’
4mg previous NTD, affected parent, 2nd degree relative
Secondary prevention of NTDs
Identify woman at risk U/S Genetic counseling Voluntary antenatal testing (if appropriate) Access to voluntary TOP
Tertiary prevention of NTDs
Early/ accurate diagnosis Intervention to avoid/ minimize complications Medical/ surgical Rx Rehab therapy Psychosocial support
Congenital bleeding disorders
Rare AR deficiencies (eg factor Xl def - Ashkenazi Jews)(prothrombin/fibrinogen defs)
X linked recessive - Haemophilia
Congenital platelet defects - Von Willebrand Disease
Clinical presentation of haemophilia
Spontaneous bleeds into joints/muscles
Excessive bleeding after trauma or surgery
Management of haemophilia
Factor replacement (acute vs prophylactic)
Monitor for inhibitors
Supportive therapy eg physio
Genetic counseling
Problems with gene based therapy
Getting to target Site of insertion Effects of vector NB immune Expression (how much, when, how long, control) Timing of replacement
Why is gene therapy for haemophilia possibly possible
Small gene Single target organ (liver) Only small amount of clotting factor needed Continuous production of factor No effects on development
Haemophilia A is a def in..
Factor Vlll
Haemophilia B is a def in
Factor lX
Clinical presentation of thrombosing disorders
Venous thrombosis/ embolism
Pregnancy loss
When is a genetic disorder more likely in thrombosis
Young No precipitant Unusual site Recurrent Family history
Management of thrombosis
Anticoagulation
Avoid risk factors eg COC
Genetic counseling
What is Factor V Leiden
Substitution of amino acid (from A/G sub)
Abnormal factor V. Resistance to activated protein C. Less control over thrombin production.
Who do we test for low penetrance common mutations causing thrombosis
First unprovoked VTE Recurrent VTE Thrombosis in unusual sites (cerebral, mesenteric, portal, hepatic) VTE in pregnancy VTE associated with COC and HRT FDR with VTE under 50yrs
Things to take into consideration in genetic counseling
- age
- parity
- social/cultural background
- religion
- support
- finances
- previous experience with disability
Genetic disorders that increase risk of intracranial haemorrhage
- haemophilia A (x linked recessive)
- haemophilia B (x linked recessive)
- Von willebrands disease (AR)
4 aspects of secondary prevention of ntds
- maternal AFP
- 2nd trimester fetal anomaly ultrasound
- genetic counseling
- access to voluntary top
Factors that influence recurrence risk of ntds
- population incidence
- family history of ntds
- syndromic features
- teratogen exposure
- maternal diabetes
- use of preconceptual folate
