Genetic Development - Final Exam Flashcards
Four main stages of prenatal development
- Preimplantation embryonic stage
- Germ layer formation
- Early organogenesis
- Definitive organogenesis
Preimplantation stage
First cleavage of zygote and blastocyst formation
Morula (16 cells, day 4)
Blastocyst (day 5)
Trophoblast (dedicated to placenta and extraembryonic tissue)
Germ layer formation
Embryo implants in endometrial wall of uterus
Gastrulation occurs after implantation, cells arrange into 3 cellular compartments
Axes of final body plan form
Germ layers
- Ectoderm
- Mesoderm
- Endoderm
Late organogenesis
Anatomical and funcitonal maturation of organs occur (4-8w)
Position and basic structures of all organs are now established and cellular components necessary for full development are not in place
Neural tube defects form at this stage
Causes of neural tube defects (3)
- Geographical
- Folic acid deficiency (very early on)
- MTHFR involved in genetic component of neural tube defects
Congenital defects
Present at birth Organs or other structures Significant cause of infant death (20%) Major cause of long term morbidity, intellectual disability, and other dysfunction Major impact on public health
Congenital defect causes (5)
- 75% - unknown
- 20% - genetic
- 2% - chromosomal
- 2% - infectious
- 1% - chemical
What point of organogenesis is most susceptible to developmental defects?
First trimester
Developmental malformation causes (6)
Disturbances in development resulting in development malformations - morphological defect of an organ or larger part of body results from intrinsically abnormal developmental process
- Genetic factors
- Exogenous teratogens
- Chromosomal abnormalities
- Single-gene disorders
- Prenatal diagnosis
- Prematurity, birth injury, SIDS
Cleft lip
Incidence increased in some families
Inherited as multifactorial trait
Achondroplastic dwarfism
Cause by single gene defect
Mendelian trait
Exogenous teratogens (3)
- Physical (X-rays, corpuscular radiation)
- Chemical (industrial, drugs, alcohol)
- Microbial (viruses, bacteria, protozoal parasites)
Fetal alcohol syndrome
Caused by prenatal exposure to alcohol
Intellectual and behaviour disabilities
Impairment of internal organs
TORCH syndrome
Toxoplasma
Others
Rubella
Cytomegalovirus
Herpes
Can stress mother and lead to low fetal weight
Marked by involvement of several organ systems
Other (TORCH)
Less common infectious agents
EBV, varicella virus, listeria monocytogenes, leptospira, etc
Brain (TORCH)
Most often affected
Small (microcephaly), mental retardation usually combined with neurological symptoms
Eyes (TORCH)
Small (micropthamlia), inflammation of inside layer of eyes, lens clouding
Heart (TORCH)
Development defect
Liver/lung (TORCH)
Inflammation, reactive enlargement of lymph nodes and spleen
Skin lesions (TORCH)
Petechial hemorrhages and vesicles
Especially after herpes virus infection
Congenital Rubella Syndrome
Now prevented by maternal immunization Marked by triad: 1. Microcephaly 2. Microphthalmia 3. CHD
Chromosome disorders
Clinical condition caused by abnormal chromosome constitution in which there is duplication, loss or rearrangement of chromosomal material
Structural or numerical
What is a chromosome?
1/3 DNA 1/3 RNA 1/3 Protein Coloured body Threadlike structures seen in cell nucleus containing chromatin Single molecular DNA in interphase state
What do chromosomes do?
Carry genetic information in a defined structure
Somatic cell division
Gamete formation
How do we study chromosomes?
Stained to give regular lines
Aneuploidy
Any chromosome number that is not an exact multiple of haploid number
Gain or loss of entire chromosome
Hyperdiploidy
2n+
Hypodiploidy
2n-
Monosomy
Loss of a single chromosome
Trisomy
Gain of a single chromosome
Trisomy 21 (Down’s Syndrome)
Non-disjunction in M1 Mental retardarion Unique facial features Eye abnormalities Gaping mouth and large tongue Heart diseases Intestinal defects Hand abnormalities (shortened fingers, curved) Abnormalities of toes (wide gap)
Pathogenesis of sex chromosome abnormalities
More common in clinical practice
Less lethal and cause less fetal wastage
Turner’s syndrome
Usually diagnosed at puberty, or at infancy with excessive webbing
Short stature, heart-shaped face, webbing of neck, heart disease, broad chest, cubitus valgus, streak ovaries, hypoplastic uterus, amenorrhea
Klinefelter Syndrome
Groups of chromosomal disorders where there is at least one extra X in male karyotype OR translocation of SRY to XX Tall, long arms and legs Lack of beard, body hair and pubic hair Gynecomastia (breasts) Female-like hips Testicular atrophy, infertility
WAGR syndrome
11p12-p14 deletions - deletion of short arm
Wilms tumour of kidney
Aniridia
Genital malformations
Mental retardation
Results in loss of important genes, such as WT1 - deletion of chromosome 13 causing retinoblastoma (RB1)
Reciprocal translocation
Transfer of one segment of one chromosome to another chromosome (two non-homologous chromosomes)
1/500 newborns
Balanced reciprocal translocations
Generally no loss or gain of genetic information
Position change but no phenotypic consequences
Reproductive consequences
Down’s Syndrome - Translocation form
4% have 46 chromosomes
Reciprocal translocation between chromosome 21 and another acrocentric chromosome (14 or 22)
No maternal age effect, but may be the result of familial translocation
Parental karyotypes required for follow up
Robertsonian translocations
Rare form of chromosomal rearrangement that, in humans, generally occurs in the five acrocentric chromosome pairs, namely 13, 14, 15, 21 and 22
Autosomal dominant disorders
Apparent in heterozygotes
Trait is expressed in every generation that carries dominant trait
Unaffected offspring of symptomatic carrier do not transmit trait
Marfan’s syndrome
Autosomal dominant disease affecting connective tissue
Structural defect in fibrillin, causing connective tissue to be loose and disjointed
Elongated head, eye abnormalities, aortic aneurysm with dissection and exsanguination, floppy mitral valve, vertebral deformity, long fingers
Familial hypercholesterolemia
Autosomal dominant disease affecting CVS
1/500
Mutation in LDL receptor
Lipid deposits in tissues, especially arteries
Accelerated atherosclerosis and coronary artery disease
Nodules in hands, not curable but manageable with strict, low fat diet
Statins can help
Adult polycystic kidney disease
Autosomal dominant disease affecting kidney
Wilm’s tumour
Autosomal dominant disease affecting kidney
Huntington’s disease
Autosomal dominant disease affecting nervous system
Neurofibromatosis
Autosomal dominant disease affecting nervous system
Familial polyposis coli
Autosomal dominant disease affecting GI tract
Autosomal recessive disorders
Gene is apparent only in homozygotes
Cystic fibrosis
Autosomal recessive disorder
Disorder in Cl ion transport channel
Positive sweat chloride test and DNA testing
Many fluid in body are highly viscous
Affects pancreas, affecting absorption - failure to thrive
Fetal intestines
Can be detected by ultrasound
Lungs start to fill up with viscous fluid, increased chance of bronchitis and pneumonia
Anemias
Sickle cell anemia, thalassemia
Autosomal recessive disorder
Lipodoses
Tay-Sachs disease, Niemman-Pick disease
Autosomal recessive disorder
Mucopolusaccharidoses
Hurler’s syndrome
Hunter’s syndrome
Autosomal recessive disorder
Amino acid disorders
Phenylketonuria
Albinism
Autosomal recessive disorder
Lysosomal storage diseases
Autosomal recessive disorder
Deficiencies in enzymes in intermediate metabolism
things accumulate in cells
Phenylketonuria
Autosomal recessive disorder
Phenylpyruvic acid accumulation as phenylalanine does not get converted into tyrosine
Can only detect when children start eating phenylalanine
Slow, progressive, irreversible mental retardation
Tay Sachs Disease
Autosomal recessive disorder
Increased substrates in vacuoles
Affects brain and eyes
X-linked recessives
Gene effected is usually evident only in males, rarely in females
Gene is transmitted from asymptomatic, heterozygous mother
Son of female has 50% chance of being affected
>100 genes on X chromosome, many linked to important diseases
Hemophilia A and B
Hereditory bleeding disorders
Mutations in genes involved in coagulation
Factor 8: 1/5000 males larger, more room for mutation),
Factor 9: 1/30000 males
50% inherited, 50% new mutations
X-linked muscular dystrophy (2)
- Duchenne’s
2. Becker’s
X-linked congenital immunodeficiencies (4)
- Agammaglobulinemia
- Wiskott-Aldrich syndrome
- X-linked immunodeficiency
- Lymphoproliferative disorders
Fragile X syndrome
X-linked recessive disorder CGG triple nucleotide repeat Most common mental retardation in males 1/1250 males 1/1200 female (carrier) Normal number of repeats is 5-44 200 greater repeats is pathologic
Multifactorial inheritance
Trait or disease is product of several genes
Inheritance cannot be explained in terms of Mendelian single-gene inheritance
Exogenous and endogenous factors influence expression of the trait and determine severity of the disease
Genes encoding trait or disease have dose effect
More severe form: more likely to transmit to offspring
Ancephaly and Craniorachischisis
Multifactorial inheritance
Failure of neural tube to close
Complete absence of brain
Folic acid deficiency
Diabetes type II
Multifactorial inheritance
50% of affected persons have relatives with diabetes
High incidence in populations with high rate of intermarriage
High concordance among monozygotic twins
Not entirely environmental
Prenatal diagnosis
Many genetic diseases and chromosomal abnormalities can be diagnosed prenatally
Usually for highrisk pregnancies
Techniques for prenatal diagnosis (4)
- Utrasonographic examination
- Chorionic villus biopsy (10-15w)
- Amniotic fluid analysis
- Maternal blood analysis
Prematurity
<30w
<2500g
Immaturity <1500g
Immaturity
<1500g
Anatomical and functionally immature - more noticeable in brain and lungs
Cannot survive without medical assistance
NICU
Causes of prematurity (3)
5-10% pregnancies terminate prematurely
- Maternal factors
- Fetal factors
- Placental factors
Maternal factors of prematurity (2)
- Malnutrition, smoking, substance abuse
2. Infection
Fetal factors of prematurity (3)
- Infections
- Fetal malformations
- Genetic diseases
Placental factors of prematurity
Placental insufficiency
Neonatal respiratory distress syndrome
Immature Type II pneumocytes
Surfactant deficiency
Atelectasis, alveolar, endothelial injury of lungs
Hypoxia of the hyaline membrane
Hypoxia of hyaline membrane
Can cause cerebral intraventricular hemorrhage
Hemorrhagic intestinal necrosis
Birth injury
Various lesions caused by mechanical trauma
Skull fractures, intracranial hemorrhage, peripheral nerve injury, fractures of long bones
Sudden infant death syndrome
Sudden, unexpected death of infants Cause unknown Maternal risk factors Fetal risk factors Most common cause of death beyond immediate neonatal period 2mo
