Mechanisms of Birth Defects Flashcards
Prevalence of birth defects
- 5-7% of the total population
- 2% of infants are born with potentially life threatening birth defects
Teratology
the study of birth defects and the mechanisms responsible for them
- has moved from studying the timing of birth defects and “critical periods” of developmental susceptibility to more experimental approach (molecular genetics, genomics, advances in cell biology)
- Now: systems biology: look at cells and gene expression/protein gradients
Cardiac development pathway
Hierarchy of genetic expression
- one pathway regulating muscular differentiation and positioning of the heart (Shh, Nodal)
- one pathway regulated by the expression of genes in neural crest cells that migrate into the developing aortic arches (truncus arteriosus)
Organs form within developmental fields (examples of different fields)
[Organogenesis involves hierarchies of gene expression]
Tissues sharing gene expression - e.g. Hedgehog signaling pathways
Tissues related to each other through location – e.g. branchial arches
Tissues sharing developmental timing – e.g. embryonic inner cell mass
Tissues affected by interacting processes – e.g. cell proliferation and apoptosis
VACTERL (developmental field defect example)
Vertebral anomalies Anal atresia Cardiac anomalies TE= esophageal atresia, tracheal esophageal fistula Renal Limb anomalies
Birth defects associating with each other more frequently than can be accounted for by chance alone
Developmental field may include early events such as implantation and inner cell mass formation that are known to be affected by twinning (more frequent in monozygotic twins)
Phenocopies
similar birth defects resulting from predominantly genetic or predominantly environmental factors
Theoretically, anything produced by genetic mutations can also be produced by environmental manipulations
Multifactorial Threshold model
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.
Ex. neural tube defects (myelomeningocele) and folic acid levels (deficiency increases risk for spina bifida especially in areas like western England and northern Ireland where genetic predisposition is high.)
Most common genetic mutations associated with Tetralogy of Fallot and environmental exposure that can cause the same problem
(40%): deletion 22q11
- associated Shprintzen and diGeorge syndromes
- 3 genes (TBX1, CRKL, ERK2) have been identified whose haploinsufficiency (presence of only one allele) causes dysfunction of the neural crest cell and anterior heart field and anomalies of 22q11.2 deletion syndrome.
(20%): Mutations in gene associated with Alagille syndrome: JAG1
Environmental:
(ie Phenocopy of diGeorge syndrome + TOF):
-exposure to isotretinoin (Accutane) a vitamin A analogue
ToF
- Right ventricular hypertrophy
- Pulmonary stenosis
- overriding aorta
- Ventricular septal defect
Teratogens
exogenous agents (physical or chemical) that disrupt developmental pathways causing birth defects
Thalidomide (need right gestational age and right dose to see most severe defects) Vit A analogues Cholesterol synthesis inhibitors Anticonvulsants (esp Valproic acid) Ethyl alcohol ACE Inhibitors
New teratogens:
- Maternal cortisol
- Organophosphate pesticide
Xenobiotics
compounds foreign to nature
Fetal alcohol syndrome
- FAS produces essentially a phenocopy of chromosomal disorders (each results in growth retardation, dysmorphic features and cognitive deficiencies).
- High doses: cell death and microcephaly, asymmetric eyes, etc.
Major Causes of Birth defects
Unknown 40% Multifactorial 25% Environmental 10% Monogenic 10% Chromosomal 15%
