Case 7 Flashcards
Revision
1
Q
What are the traits of an autosomal dominant disorder and how would you spot it on a family tree
A
man and woman equally affected. Male to male transmission. Risk to child is 1/2 x penetrance.
2
Q
What are incomplete penetrance (a) and variable expression (b)
A
a. have the gene but not the disease
b. have the gene but different expression to somebody else in the family.
3
Q
What are the traits of an autosomal recessive disorder and what increases the risk to the child ?
A
both parents are asymptomatic carriers. If parents blood relatives (consanguineous). Risk to child = mum x dad x 1/4.
4
Q
What are the traits of an X linked recessive disorder
A
Usually only men affected. Females asymptomatic carriers with 50% of sons affected.
5
Q
What is uniparental disomy and how does it occur?
A
2 chromosomes come from 1 parent and 0 from the other. Meiosis 1 - 2 non identical chromosomes are inherited from one parent (heterodisomy, benign).
Meiosis 2 - error in meiosis 2 as chromosome copies itself (isodisomy, lethal)
6
Q
What is trisomy rescue ?
A
fertilised ovum with 3 copies of DNA loses one of its copies. May lead to UPD if the unique copy is lost.
7
Q
List the two HW equations and give some required conditions of the theory
A
p+q=1 , p^2+2pq+q^2=1.
Random mating and reproductive success, large population, no mutation, no net immigration/emigration.
8
Q
What is the difference between penetrance and expressivity?
A
Penetrance is wether a specific gene is expressed or not. Expressivity is the form it takes when the gene is shown.
9
Q
Where is the normal site of fertilisation
A
Ant or post wall of the body of the uterus. Ejac deposits 2-6 mill sperm around external os. Originally ampulla of uterine tubes.
10
Q
What proportion of sperm is fertile and how motile is it ?
A
20-50% , 40% motile after 2 hours. some still motile after 24.
11
Q
What is the point of capacitation?
A
sperm undergoes functional change allowing it to pass through corona radiata cells. Lasts around 7 hours in female tract, removes proteins from plasma membrane overlying acromial region.
12
Q
What are the consequences of fertilisation ?
A
Restoration of diploid number (2n) , induction of cleavage and sex determination.
13
Q
What to do the ICM and trophoblast cells give rise to ?
A
ICM/embryoblasts –> embryo
Trophoblasts –> placenta.
14
Q
Can cells be lost at any point without it having a detrimental affect to the unborn child ?
A
Once completed morula forms it needs all cells to be a full human. Lost cells = lost child.
15
Q
What are the 3 abnormal sites of implantation and what are the ratios of each ?
A
Uterine tube 95%
Mesentery of interstitial loop
Pouch of Douglas
16
Q
What is ovarian implantation and what are the consequences ?
A
Placenta previa, implantation in the region of internal os. Placenta grows in lowest part of womb (uterus) and covers the cervix. Out of control bleeding leads to caesarean no matter the gestation.
17
Q
What is the cause of the ‘spotting period’ ?
A
Trophoblasts invade spiral arteries, giving the appearance of period when there’s a 2 week embryo.
18
Q
What are the common indicators of FAS ?
A
lack of adipocytes (bony), no septum or philtrum. Low set ears.
19
Q
What type of cells line the internal aspect of the heart?
A
Squamous endothelium (same as rest of vascular system)
20
Q
Are freshly ejaculated sperm able to fertilise the egg ?
A
No they’re not capacitated.
21
Q
What are the common names of (a) trisomy 13 and (b) trisomy 18?
A
a. Patau’s
b. Edward’s
22
Q
What is the NT test, when is it performed and what is it testing for ?
A
Nucheal translucency, 11-13.6, Down’s
23
Q
What are the indicators of pre-eclampsia ?
A
Proteinuria and hypertension
24
Q
What is the cause of conjoined twins ?
A
Zygote splits and stays connected but with both new cells thinking they’re dominant so grow independantly
25
Name the fluid that surrounds developing baby? what is it's origin
Amniotic fluid. Amniotic cells and maternal blood.
26
What stage of cell cycle is the ovum suspended in prior to fertilisation ?
Metaphase 2
27
What is placenta accreta?
Placenta invades the end and myometrium. Causes mum to haemorrhage and often need a hysterectomy
28
What is the bilaminar embryo?
composed of the epiblast and hypoblast
29
What are the 3 germ layers ?
Ectoderm (outside cavity) , mesoderm and endoderm (inner tubing)
30
What does the amniotic cavity develop from ?
Develops between the hypoblast and epiblast
31
What effect does pregnancy have on stroma cells?
Causes stroma cells of endometrial wall to change shape (store glycogen needed for growth)
32
Where and when does Hensen's node form ?
The primitive streak forms on surface of embryonic epiblast between 16-18 days.
33
List the main derivates of the Germ layers ...
Ectoderm: CNS nerves epidermis glands
Mesoderm: muscles, CT, heart
Endoderm: lower organs, GI, pancreas
34
When and how does the notochord form ?
after 17 days, midline/mesoderm cells break off and differentiate. This instructs ectoderm to start from neural tissue.
35
What is the primary inductive effect?
notochord formation on the overlying ectoderm. Ectoderm responds by lengthening and folding. Folds then hinge and tilt.
36
What is Spina bifida occulta?
mild form of SB, failure of the neural plate to fuse dorsally. No pain or neurological disorder, only sign is a dimple or hair tuft.
37
What are the 4 domains of the neural crest?
Cranial, Trunk, Vagal/sacral and cardiac.
38
What are somites ?
Paired blocks of mesoderm either side of neural crest. Specificed by Homeotic genes.
39
What do somites differentiate to form?
Cartilage --> bone of axial skeleton, muscles of rib cage.
40
What are the regions of somite ?
Sclerotome (bone and cartilage) , myotome (muscle and dermatome (skin).
41
What is meant by 'birth defect'
Congenital malformation that gives either a structural/functional or metabolic disorder at birth
42
What is meant by 'malformation'
Mis formation occurs during organogenesis when structures are being formed. Mostly in weeks 3-8.
43
Why does deformation occur ?
Occurs due to mechanical factors such as low amniotic fluid causing mum's organs to press on baby --> clubfoot.
44
What is 'disruption'
Altering already formed structures through destructive forces eg. amniotic band syndrome
45
What are 'syndromes'
Malformations occurring together that have a common cause. Requires diagnosis of the associating factors eg. FAS
46
What is a 'teratogen'
anything that disrupts development producing birth defects/malformations
47
What are the 3 principles of teratogenesis ?
Dosage (amount) , time/length of exposure and Genotype (some more susceptible than others)
48
What are the major causes of birth defects ?
Chromosomal abnormalities, single gene defects (mutant genes) , environmental
49
How do chromosomal abnormalities cause birth defects ?
50% of abortions are due to CA. Disruption of apparatus that separates chromosomes during meiotic divisions. Increased risk with age.
50
What are micro deletions are what are the common sites of damage ?
Deletion spanning only a few contiguous genes. Common at fragile sites eg. CGG repeats.
51
Which trimester should drugs be avoided ?
First, crucial development of the limbs
52
What is the effect of tobacco on pregnancy ?
doubles risk of premature birth. Infant weighs less. Nicotine restricts BVs of placenta so less blood to infant.
53
What is a Giemsa stain? what does a lighter area show?
Differential stain to show G banding in chromosomes. Light = less dense, more GC (guanine/cytosine) and more transcriptionally active.
54
What is a telomere?
DNA and protein cap, prevents damage to DNA end and helps stabilise. Tethered to the nuclear membrane
55
What is a centromere?
Repeating DNA connects 2 sister chromatids.
56
What is nondisjunction and what does it cause ?
Gamete produced with 2 copies of the same chromosome. Cause of mosaicism.
57
What is anaphase lag and what can It cause?
Chromosome is slow to move to one side of the cell so is trapped with another copy of itself (mosaicism).
58
What is germline mosaicism ?
Mutated cells only present in testes/ovaries therefore person asymptomatic but offspring affected.
59
What is the cause of Down's syndrome and how is it tested?
Trisomy 21 (most common autosomal triploidy). Increased nuchal translucency at 12 weeks.
60
Apart from Down's, what are the two most common triploidies ?
Edward's (18). IUGR, severe developmental delay, Arthrogryposis (multiple joint contractors).
Patau (13) 20% survive first year. Microcephaly, holoprosencephaly.
61
What is the difference between diandry and digny?
Diandry, one egg fertilised by 2 sperm. large placenta, small fetus. Increased choriocarcinma risk.
Digny, diploid egg fertilised by 1 sperm. small fetus + placenta. miscarriage premature birth IUGR.
62
Why is sex aneuploidy milder than autosomal aneuploidy?
Y chromosome is small so few genes. One X chromosome gets suppressed in females into Barr body (deep spot on periphery of cell).
63
What is a major cause of Klinefelter syndrome?
Primary hypogonadism (FSH/LH increase, testosterone decreases).
64
What is balanced reciprocal translation ?
Part of chromosome swaps/attaches to another. Can cause spontaneous abortion.
65
What are the common sites of Robertsonian translocations and why ?
13/14, 14/21 because centromere is to the pole of chromosome.
66
What are 'Cri du chat' , 'Wolf hirschhorn' examples of and what chromosome is affected?
Terminal deletions
a = 5p
b = 4p.
67
Why might DiGeorge syndrome cause additional problems ?
interstitial 22q11.2 deletion that is too small to detect in routine karyotypes so FISH has to be used. Means missed diagnosis is common
68
What conditions relate to interstitial deletions of:
a) Prader will/Anglemen syndrome
b) Williams syndrome
a) 15q11-q13
| b) 7p11
69
During a blood sample what are the uses of phytohemagglutinin and colcemid ?
phytohemagglutinin stimulates mitosis
| Colcemid disrupts spindle fibres allowing harvest to take place.
70
What is a normal result for a FISH?
probe binds twice to missing antigen.
71
What are the indicators of deletion and duplication during a microarray ?
Check ratios of amounts:
less than reference = deletion
More than reference = duplication.
72
What chromosomes correspond to Huntington's, CF and sickle cell anaemia during cytogenetic testing ?
Huntington's = 4
CF = 7
Sickle cell anaemia = 11
73
In what stage of meiosis do the sister chromatids become non identical ?
Meiosis 2 during crossing over.
74
What is screening ?
Testing for people who aren't affected by a disease or at risk of one. Identifies those who can be helped.
75
What are the factors that influence whether or not you can have screening (8)
religion, social background, partner, fam/friends, prior knowledge, personal experience, professional bias and age.
76
What are the conditions for a new newborn screening test? (6)
important health problem and epidemiology
Natural history that is understood
Cost effective
Safe and precise
Must have procedures if positive result
Early detection must lead to positive outcome.
77
What does the quadruple test measure and when is it carried out?
hCG, uE3, AFP and Inhibin A.
| Between 15 and 20 weeks.
78
What does the integrated screening test measure for? (5) and when does it have to be carried out by?
NT plus : PAPP-A , hCG, uE3 and AFP.
| 14 weeks
79
Why is the quadruple test still used if the integrated has better success for a lower risk?
Integrated can't be used on obese foetuses.
80
At what CRL would you measure head circumference and referral ?
above 84 mm.
81
What gestational age do the dating and anomaly scan take place ?
```
Dating = 10-13 weeks
Anomly = 20 weeks.
```
82
What do blood tests screen for ? (9)
Syphilis, Hep B (can be passed down, incurable) , HIV, rhesus antibodies, Down's, sickle cell, thalassaemia, FBC and blood group.
83
What is AFP and what can it indicate ?
Alpha fetoprotein.
Open neural tube defect eg. spina bifida.
Folic acid can help reduce incidence.
84
What biochemical markers change during Downs?
Increase : Inhibin A and hCG
| Decrease: uE3 and MSAFP (maternal serum alpha fetoprotein )
85
What condition is indicated by a decrease of all biochemical markers being screened ?
Edwards syndrome (trisomy 18)
86
What is ventriculomegaly?
Hydrocephalus
| CSF ventricular structures enlarge and put pressure of the brain hindering growth.
87
What is echogenic bowel and what can it indicate?
Fetal bowel appears brighter than usual on an US.
| Soft signal for trisomy 21.
88
What is NIPD? and what is the process
Non invase prenatal diagnosis (NIFTY)
| maternal blood/cervical secretion contain some DNA, extracted -> amplified -> diagnosis of abnormalities/sex.
89
How much blood is required in a NIPD?
10 ml
90
What is the time period for a NIPD?
after 10 weeks gestation, can also be done on twins.
91
What is this test : eggs collected, fertilised, developed. one blastomere removed after 6-8 days and DNA is extracted to be tested.
PGD
| preimplantation genetic diagnosis
92
After diagnosis in PGD what is the next step? how many genetic disorders are screened for ?
Embryo without genetic disorder implanted into mum
| Over 400
93
What is CVS and how quickly are results given ?
chorionic villi sampling, aspirated through abdomen under US. results in 3 days with a full karyotype in 14.
94
What is the time frame for amniocentesis ?
Any point until a couple of weeks before term.
95
What is variable expression?
Same mutation expressed as different disease phenotypes
96
What is reduced penetrance
A false negative, can be age related eg. Huntington's
97
What is sex limitation ?
Mutation predisposes to a disease in one sex but not the other
98
What is phenocopy ?
A false positive, disease in family unrelated to familial mutation (more relevant to common disease phenotypes). Has gene but a different disease.
99
At which stage is one X chromosome silenced in females ?
The blastocyst stage
100
What would females present with if carriers of an X linked recessive disease ?
'mild features'. Often late onset phenotype (Duchenne's)
101
What is mosaicism ?
When only a certain proportion of cells have a particular mutation.
102
What is chimerism ?
Organism composed of 2+ populations of genetically distinct cells that organise from different zygotes.
103
What is somatic mosaicism?
Some cells lack mutation -> milder phenotype. Child at risk of inheriting change as a constitutional mutation.
104
What is confined placental mosaicism ?
Only in placental cells, relatively common. Complicates prenatal testing. It's absent in baby (different group of cells).
105
What is gremlin (gonadal) mosaicism ?
Person is asymptomatic, no mutation/blood testing. Presence of mutation in testes/ovaries --> children affected.
106
What is the concept of imprinting ?
Gene expression is dependant on who it's inherited from. Affects 1% of human genes (clusters).
107
Which chromosomes have clusters of imprinted genes?
6, 7, 11, 14, 15
108
What proportion of mother and father mitochondria is passed onto the child ?
100% mother
109
Why is there no passing on of paternal mitochondria to offspring ?
body of sperm doesn't pierce the egg. So only maternal mitochondria are present in cytoplasm of zygote.
110
What is heteroplasmy ?
Proportion of mitochondria (mutated) varies between tissues. Affects which organs show symptoms (variable expression).
111
Why can heteroplasmy complicate blood testing ?
Variation in load between tissues eg. blood levels differ from key tissues (brain/muscles)
112
What is the genetic difference between Angelman syndrome and Prader Willi syndrome ?
```
AngelMAN = Maternal chromosome 15 deletion.
PWS = Paternal chromosome 15 deletion.
```
113
What is epigenetics and when is it stable/not stable ?
Modification of chromosomes without altering DNA sequence.
| Stable in mitosis, reset in germ cells.
114
What are DNA methylation and histone medication examples of ?
Covalent modification
| methylation, citrullination, acetylation and phosphorylation.
115
How does epigenetics alter DNA ?
varies tightness, this affects binding of transcription factors, altering transcriptional potential of genes (silencing)
116
How can you have a UPD but still be healthy ?
uniparental disomy
| As long as there are imprinted genes on chromosomes.
117
What is LHON ?
Leber heridatary optic neuropathy
| sudden painless permanent loss of vision (optic atrophy). onset as adult/teens. Male predominance (50% m, 15% females).
118
Cytostatic factor arrests the oocyte in fertilisation. At what stage does it arrest the cell?
2nd metaphase
119
How is cytostatic factor broken down to allow for oocyte growth?
Broken down by Calcium rise from the fertilising sperm
120
What is one reason for female infertility increasing with age ?
As time increases, the cell is more likely to cleave and separate incorrectly. This forms an incorrect karyotype which is fatal for any development.
121
What are the normal measurements for CRL at 10, 12 and 13 weeks ?
```
10 = 3cm
12 = 5cm
13 = 7cm
```
122
What is the risk point of Down's syndrome ?
1/150
123
Why might a Down's syndrome screening be done earlier ?
If prevalent in previous pregnancies. If miscarriage or foetal bleeding.
124
In a urine test, what might increased levels of protein and albumin indicate?
Infection or pre eclampsia.
125
What is the pathway of an amniocentesis through US guidance ?
Abdo wall, uterus, sac
126
What are the 3 major causes of Down's and their probabilities ?
Nondisjunction (95%)
Robertonsian translocation (4%)
Mosaic (1%)
127
At what division does nondisjunction occur that can lead to Down's ?
First meiotic division, 2 chromosomes 21 go to same pole. Meiosis arrests in metaphase 2 and held in utero until used. The longer arrested , the more likely nondisjunction is to occur.
128
Spina bifida is incomplete closure of the embryonic tube. The spinal cord protrudes like a sac. What are the 3 types ?
Occulta, mild small opening often asymptomatic.
Meningocele, meninges go into the spine. Pain
Myeloschisis, most severe. Protrudes with coverage causing paralysis.
129
What common vitamin supplement can prevent neural tube defects from occurring ?
B9 , Folic acid. Advised to have 400mg/day whilst trying to conceive and until 12 weeks pregnant.
130
What is the function of the yolk sac before intestinal circulation begins ?
It acts as the developmental circulatory system of the human embryo. Lined by extra embryonic endoderm.
131
What region of the uterine tubes does fertilisation occur ?
Ampulla, what are the other regions ?
132
Sperm undergo capacitation at the isthmus making them less motile. What reaction allows fertilisation of the egg ?
Acrosome reaction.
133
Capacitation takes 7 hours. Seminal plasma proteins and glycoproteins are removed from the acrosomal region of the spermatozoa. When does the acrosome reaction occur ?
initiated when binding to Zona pellucida , allows fusion of gametes.
134
What is the function of Oestrogen in the menstrual cycle (broad)
Increases size of endometrium
135
What is the function of progesterone in menstrual cycle (broad)
Maintains the endometrium
136
What is the function of GnRH during the menstrual cycle ?
Secreted from the hypothalamus, acts on APG to stimulate LH/FSH release.
137
What effect do prostaglandins have on SM ? What do they cause during labour
Increase SM contraction. Cause pain and inflammation during labour
138
Briefly outline Follicular phase...
FSH ^, follicles grow, O ^, causes all follicles to degrade Barr the Graafian follicle. This then produces more O which inhibits FSH but stimulates LH.
139
What does an old corpus luteum become and what might be seen histologically ?
Corpus albicans, white scarring.
140
What gene is mutated in sickle cell anaemia ?
B globin gene on chromosome 11.
141
What is the cause of fragile X syndrome ?
Short arm deletion of chromosome 5. Biggest cause of autism.
