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MS 1 Unit 7 MCP > Birth Defects > Flashcards

Flashcards in Birth Defects Deck (24):

Birth defects

-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


Causes of birth defects

-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


Genetics of birth defects

-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


Chromosome defects alter embryonic development

-aneuploidy (altered chromosome number)
-structural defects: deletion, duplication, translocation
-chromosome abnormalities can be inherited or occur de novo


Mutations in single genes can alter the development of multiple systems

-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


Gene gene and gene-environment interactions

-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



-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


Genes have been implicated in holoprosencephaly

-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


Infectious agents and birth defects

-rubella viral infections (German measles) during pregnancy were linked to specific birth defects: congenital cataracts, deafness and congenital heart malformations
-Coxsackie (B- spontanesous abortion)
-Herpes simplex
-Toxoplasmosis- found in animal feces and under cooked meats can lead to cerebral calcifications and head defects.
-another complicating factor is that many infections cause fevers (hyperthermia), which can disrupt neurulation and result in neural tube defects


Pharmacological agents can cause birth defects

-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


Environmental factors can cause birth defects

-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


Specific environmental factors that cause birth defects

-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


Susceptibility to teratogens

-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


Fetal Alcohol Syndrome

-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


How does alcohol interfere with embryo development

-interfere with cell migration, proliferation, adhesion, survival and signaling
-several genes are misregulated in the embryo following maternal alcohol exposure


Congenital heart defects-

-malformation of the heart is the most common birth defect found in 1% of live births and an estimated 10% of all fetuses
-heart defects have a broad range of severity
-heart development can be altered by teratogens and chromosomal abnormalities, but most cases are thought to be due to multifactorial causes
-the same malformation can result from disrupting several different developmental events


Septal defects

-hole in the heart
-atrial septal defect is an opening in the wall that serparates the left and right atria, oxygen rich blood is pumped back into the lungs
-ventricular septal defect- separates the ventricles, O2 rich blood to flow from the left to right ventricle instead of the aorta, 20% of defects



-the heart is positioned on the right side of the thorax instead of the left
-reversal of heart laterality is often caused by defects in establishing the left-right body axis during embryongenesis
-heterotaxy can result in several congenital heart malformations including septal defects, double outlet right ventricle and transposition of the great arteries


Identification of congenital heart defects

-rapid breathing
-poor blood circulation


Heart defects in 22q11.2 deletion syndrome

-heterogeneous multisystem syndrome
-3 million base pair deletion on chromosome 22 (30-40 genes)
-5-10% of cases are inherited (autosomal dominant)
-congenital heart disease in 80% of patients
-heart malformations include tetralogy of Fallot and truncus arteriosus


Rise of the great arteries

-the outflow tract of the embryonic heart gives rise to the greater arteries
-during heart development the outflow tract remodels to form the aorta and pulmonary artery


Truncus arteriosus

-persistent truncus arteriosus
-single common blood vessel comes out the heart, instead of the usual two vessels (the main pulmonary artery and aorta)
-it occurs when the blood vessel coming out of the heart in the developing baby fails to separate completely during development, leaving a conection between the aorta and pulmonary artery
-O2 poor and O2 rich blood are mixed together as blood flows to the lungs and the rest of the body
-truncal valve is often abnormal, the valve can be thickened and narrowed which can block the blood as it leaves the heart


Tetralogy of Fallot

-ventricular septal defect
-pulmonary stenosis (narrowing of pulmonary valve and artery)
-overriding aorta *increases flow)
-ventricular hypertrophy


Cardiac Neural Crest Cells

-cardiac neural crest cells migrating from the dorsal neural tube into the arterial pole participate in separation of the outflow tract
-genes located in the 22q11.2 deletion region (specifically TBX1) are thought to regulate cardiac neural crest cell development