Birth Defects Flashcards
1
Q
Birth defects
A
- congenital malformation
- structural, functional or behavioral disorder present at birth
- structural malformations due occur in 3 % of live births (1 in 33 babies)
- account for 25% of infant deaths
2
Q
Causes of birth defects
A
- there are several known causes of birth defects:
- genetic problems (chromosome abnormalities or gene mutations) cause 28% of birth defects
- environmental factors cause 3-4%
- a combination of gene and environment (called multifactorial inheritance) accounts for 20-25%
- twinning causes 1%
- however for many defects (40-45%) the cause is unknown
3
Q
Genetics of birth defects
A
- can be due to a single gene mutations
- can be due to chromosomal abnormalities
- often sporadic
- can be inherited as dominant, recessive or X-linked
4
Q
Chromosome defects alter embryonic development
A
- aneuploidy (altered chromosome number)
- structural defects: deletion, duplication, translocation
- chromosome abnormalities can be inherited or occur de novo
5
Q
Mutations in single genes can alter the development of multiple systems
A
- Axenfeld-Rieger syndrome is primarily an eye disorder, but it can also affect other parts of the body
- many affected individuals have distinctive facial features such as widely spaced eyes (hypertelorism)
- a flattened mid-face with a broad, flat nasal bridge and prominent forehead
- the condition is also associated with dental abnormalities including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia)
- some people with Axenfeld-Rieger syndrome have extra folds of skin around their belly button (redundant periumbilical skin)
- estimated prevalence of 1 in 200,000 people. This condition is inherited in an autosomal dominant pattern
6
Q
Gene gene and gene-environment interactions
A
- a single rare mutation can fully account for a disease, but clinical variablilty can be observed even for determined monogenic disease, and this variability may itself involve genetic factors, the so-called modifier genes
- in contrast to monogenic traits, complex traits have many contributing genes and non-genetic influences
7
Q
Holoprosencephaly
A
- chromosome abnormalities: number and structure (trisomy 13, or 18, )
- environmental conditions: maternal diabetes, also retinoic acid and alcohol
- single gene mutations
- common malformation of the forebrain in humans
- failed or incomplete forebrain division in the third to fourth weeks of gestation: the forebrain (prosencephalon) incompletely cleaves into right and left hemispheres
- when the embryos forebrain does not divide, it causes defects in the development of the face and in brain structure and function
8
Q
Genes have been implicated in holoprosencephaly
A
- many genes have been implicated in HPE
- many of these operate in the hedgehog signaling pathway
- heterozygous deletions and nonsense, frameshift, and missense mutations in SHH predict a loss-of-function mechanism
- SHH encodes a secreted protein that functions as a morphogen and is involved in establishing cell fates at several points during development
- it is expressed in the Hensen node, the floor plate of the neural tube, the early gut endoderm, the posterior of the limb buds, and throughout the notochord
- it has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites
9
Q
Infectious agents and birth defects
A
- rubella viral infections (German measles) during pregnancy were linked to specific birth defects: congenital cataracts, deafness and congenital heart malformations
- Coxsackie (B- spontanesous abortion)
- Cytomegalovirus
- Herpes simplex
- Parvovirus
- Toxoplasmosis- found in animal feces and under cooked meats can lead to cerebral calcifications and head defects.
- Syphilis
- another complicating factor is that many infections cause fevers (hyperthermia), which can disrupt neurulation and result in neural tube defects
10
Q
Pharmacological agents can cause birth defects
A
- limb defects to the sedative thalidomide
- thalidomide was widely used in the 1950s and 1960s to treat nausea in pregnant women (morning sickness)
- was taken off the market in 1961
- mechanism of action unclear: inducing oxidative stress or disrupting angiogenesis
11
Q
Environmental factors can cause birth defects
A
- teratology is the study of birth defects
- teratogen-agents that cause birth defects
- addition to infectious agents, drugs can cross the placenta, enter the baby and impact development
12
Q
Specific environmental factors that cause birth defects
A
- infectious agents, physical agents, chemical agents and maternal conditions such as autoimmune disease or diabetes, maternal obesity
- alcohol, cortison, heroin, lead, tetracycline, warfarin
- ionizing radiation, hyperthermia
13
Q
Susceptibility to teratogens
A
- genotype of the embryo (or mom); gene-environment interactions. The maternal genome is also important in determining drug metabolism, resistance to infection and potentially other influences
- developmental stage at the time of exposure (most sensitive weeks 3-8)
- birth defect severity can depend on the dose and duration of exposure
14
Q
Fetal Alcohol Syndrome
A
- FASD refers to all alcohol-related defects
- alcohol is the leading cause of congenital mental retardation
- not clear how much alcohol is necessary to cause defects, but there is probably no safe level
- amount of alcohol, timing and genetics all contribute to FASD severity
- effects: learning and remembering, understanding and following directions, controlling emotions, communicating and socializing, daily life skills such as feeding and bathing
- fetal alcohol syndrome is the most serious type of FASD and includes structural defects, growth deficiency and intellectual disability
- FAS is characterized by small head size (microcephaly),indistinct philtrum, narrow upper lip, low nose bridge and flat midface
15
Q
How does alcohol interfere with embryo development
A
- interfere with cell migration, proliferation, adhesion, survival and signaling
- several genes are misregulated in the embryo following maternal alcohol exposure
