Mechanisms of Birth Defects Flashcards
Principal causes of human birth defects and their relative distribution
- A birth defect is an abnormality of structure, function or metabolism (body chemistry) present at birth that results in physical or mental disabilities or death.
- 2008 Data:
Hierarchical pathways in human development + examples
- Organogenesis involves hierarchies of gene expression.
- For example, the sex determination pathway depends on the expression of SRY.
- A similar setup occurs in the heart. You can go down one of two or three genetic pathways to get to the end result.
- different molecular pathways can lead to a left or right bend in the heart, namely whether or not sonic hedgehog is active or inhibited.
Describe concept of “phenocopies”.
- All phenotypes = interactions between environmental and genetic factors
- ==> phenocopies = similar birth defects resulting from predominantly genetic or predominantly environmental factors.
- Genetic and environmental interactions producing birth defects can be described by a threshold model that divides populations by genetic risks that are modified by the environment in a “dose” dependent fashion.
Congenital heart disease and NTDs as “phenocopies”
- Congenital heart disease and neural tube closure abnormalities (anencephaly and spina bifida) are birth defects that comply with multifactorial threshold risk models
- For neural tube defects, an environmentally determined threshold is associated with folic acid levels.
- Folic acid supplementation dropped the incidence of meningomyelocele 2-3%, and was statistically significant.
- Taking too much folic acid, however, will mask pernicious anemia.
Characteristics Tetralogy of Fallot
- Tetralogy of Fallot
- Supravalvular pulmonic stenosis
- Overriding aorta
- Ventricular septal defect
- Right ventricular hypertrophy
- Mutations affecting the expression of genes in neural crest cells contributing to further development beyond the truncus arteriosus will contribute Tetralogy of Fallot (TOF)
- e.g deletion on chromosome 22, del 22q11, associated Shprintzen and diGeorge syndromes
- associated with 40% of cases of TOF.
- Mutations @ gene associated with Alagille syndrome, JAG1 account for another 20%.
- A phenocopy of the diGeorge syndrome that often includes TOF results from exposure to isotretinoin (Accutane) a vitamin A analogue.
- Vitamin A is a morphogen (a factor that stimulates the development of a structure) that regulates migration of neural crest cells in the region of the developing branchial crests and arches.
Take home message regarding phenocopies
Take home message: whenever you are looking at a phenotype, you are looking through the glasses of selection. Not all conceptions that are exposed to a certain thing will make it to birth. In other words we only see the tip of the iceberg.
Descriptive approach to teratology
- Clinical teratology has in the past has largely been a descriptive exercise focusing on the timing of birth defects and so called critical periods of developmental susceptibility.
- based on experimental observations in animals and the epidemiology of Thalidomide, a potent teratogen that caused a specific pattern of limb defects called phocomelia. It was clear that exposure to the agent after 5 weeks was no longer associated with phocomelia.
Systems approach to teratology
- Embryology has now moved from a primarily descriptive to a much more experimental science with the advent of molecular genetics, genomics and advances in cell biology.
- Using the tools of molecular biology embryologists are now dissecting hierarchical pathways of development and developmental fields that determine organogenesis and mechanisms of birth defects.
Four major classifications of birth defects
- Malformation: can be detected on ultrasound-like DiGeorge
- Disruption: pregnancy is occurring normally and suddenly an event occurs to knock it off course
- High dose of accutane for example
- Tetralogy of Fallot is a good example of a birth defect that can be either a malformation or a disruption.
- Deformation: Pulmonary hypoplasia results when physical restraint, as caused by oligohydramnios, a diaphragmatic hernia, or other physical limitation that prevents alveolar expansion.
- Dysplasia: Point mutations of Fibroblast Growth Factor Receptor genes lead to skeletal dysplasias (abnormal formation of bone) such as achondroplasia.
Isolated vs. syndromic birth defects
The first and most important endpoint of an evaluation of an infant presenting with a birth defect is to determine whether he or she has an isolated anomaly (most likely multifactorial + ↓ chance of recurrence) or a multiple malformation syndrome (most likely chromosomal, monogenic or teratogenic)
Characteristics of human susceptibility to teratogens
- Teratogens = exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects.
- Teratogens gain access to the embryo/fetus across the placenta because the chemical properties (i.e. size, lipid solubility, pH, etc) that allow them to be absorbed into the maternal circulation also allow them to cross the placenta.
- Mechanisms of drug/xenobiotic induced birth defects include deleterious interactions with surface and intracellular signaling proteins and cytotoxicity that “kills” cells, usually by inducing apoptosis (programmed cell death).
Examples of teratogens
- Teratogens include but are not limited to:
- Thalidomide
- Vitamin A analogues
- Cholesterol synthesis inhibitors
- Anticonvulsants
- ACE inhibitors
- ethyl alcohol
Describe the threshold theory of environmental/genetic interactions in the etiology of human birth defects.
you can be genetically predisposed to a condition, but a certain level of environmental interaction may be needed to push you over the edge into developing it.
