Cystic Fibrosis Flashcards by sita clark

New born screening process

Heel prick at 1-2 days of age
20+ metabolic disorders tested
45 babies per year have a disorder

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Your new born baby’s blood test

-The New Born Metabolic Screening Programme

Given to every mother before testing

Abbreviated facts about the disorders looked for
frequency of disorder
www. nsu.govt.nz

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Cystic Fibrosis

Genetic Disorder
Gene codes for protein which forms CL channel
(Gene –> Protein –> Chloride Transport Channel)
Cl cannot be pumped out of cell - Na+ stays with the Cl- –> water stays with both (due to high osmolarity)
So all secretions in the airways of ducts are thick and sticky

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Cystic Fibrosis the Abnormality

Gene --> Protein --> Cl Transport Channel
CFTR gene (DNA) --Transcription--> mRNA message --Translation--> Chain of 1480 a/acids --Protein folding + transport to membrane --> CFTR protein in cell membrane allowing Cl flow Intra --> Extra cellular space

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Functioning CFTR channel

Cl pumped out
Na+ triples across (balanced)
Water also balanced across cell membrane
-Thin Watery mucus
-Hydrated enviro to allow Cilia to work
-Bugs and dust settle on this flow, going up the respiratory tract and is cleared

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Abnormal CFTR channel

Cl cannot be pumped out of cell - Na+ stays with the Cl- –> water stays with both (due to high osmolarity)
So all secretions in the airways of ducts are thick and sticky
-dehydrated

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Newborn Screen for CF

Thick secretions block the 
fine pancreatic duct – enzymes cannot move into GI tract
-but continues to make enzymes, arent secreted naturally into the duck = overflow/ -->
Enzymes are then absorbed 
into the bloodstream
The screening measures:
1. Blood trypsin (pancreatic enzyme)
2. If high → 3 common CF genes

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The Family

Christine and Rob have their first child Zak – things have been going well
Lead Maternity Carer gets a notification letter
The screening test for cystic
fibrosis on this baby was POSITIVE.

The positive test means baby either
has CF or is a carrier for CF.
We suggest referral to the regional
CF paediatrician.

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What do you think the family want to know?

What information would you like to be able to give them?

Does Zak have CF Cystic Fibrosis or is he a carrier?
What does a positive screen mean?
What is his chance of having CF ?
How will he show if he has got CF ?
Has there been a mistake?

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Cystic Fibrosis From Book

Caused by: a defective gene and its protein product, leading to thick, sticky mucous
Can lead to: poor growth, chest infections and shortened life
Treated by: high calorie diet, medicines and physiotherapy to keep the lungs healthy
Occurs in: about 8 babies every year

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What would the family want to know if Zak does have CF Cystic Fibrosis?

What is CF?
What will happen to him?
Can it be treated?
What can they do to help him?
Will he die? How long will he live?
Can he have children?
What about other family members?

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Steps after being Positive on the New born Screen Test to see if Zak has CF or is a carrier

Sweat Test
- Sodium and Chloride production in sweat
Genetics from Zak
- to check for mistakes
- test for 31 mutations
Stool samples for (pancreatic) enzymes
- look for trypsin in gut
- if not present, would start enzymes regardless for waiting or other tests, as baby wont be able to grow if cannot break down food

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What does it mean for Zak : Most common

Recurrent pneumonias → progressive lung disease
Failure to thrive/poor growth
-inability of pancreatic enzymes to functioning normally breaking down food
Normal Neurology, Normal Development

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Other Possible issues for Zac over time

-all essentially re thick sticky secretions blocking something
 Nasal polyps
 Sinusitis
 Diabetes
-enzymes still made, damage pancreas becuase arent released, enough Islet cells damaged to cause diabetes
 Liver disease
 Gallstones
 Portal hypertension
 Distal intestinal obstructive syndrome, 	constipation
 Vitamin deficiencies
-absorbption
 Bone disease
 Fertility concerns

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Management of CF: Regular Review

History
Growth (height, weight)
Physical signs
-Finger clubbing (swollen)
-chest deformity
-Cough
-Auscultation
-Abdominal examination
(seen more in late teens and early adults, due to management being more intensive)

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Investigations of CF (Respiratory Testing)

Check for infection
- Cough swabs (tonsils)
- Sputum
- Bronchoscopy &amp; lavage (thick secretions plug the airways- free this)
Oxygen Saturation monitoring
Lung function tests (when children older)
X-rays
Radiology: CXRs, CT scans, Ultrasounds
-regularily reviewed

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Ausculation

Normal: Inspiratory longer
Asthma
- hyperinflated X-ray
- prolonged expiration
- very tight and wheezy
Crackles
- Hyperinflated + Patchy consolidation throughout (areas of fibrosis and bronchixis)
- air going through mucus or popping open of alveoli
Wides spread changes with Atelectasis, bronchial wall thickening, bronchieclasis, fibrosis

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Prevalance of Respiratory Microorganisms by Age Cohort

Infection changes with time
Common early: Staphylococcus Aureus + H influenza.
Older: Pseudomonas Aeruginosa increase (sensitive and drug resistance.)
-use different antibodies

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Treatment for CF

Respiratory
Nutrition
Other

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Respiratory aspect of CF Treatment

Chest physiotherapy
-daily (multiple), percussion, devises to increase resistnace so huff and sputum up, vibrational vest
-children get very tired of it, so switch around
Exercise
-enjoyable way to clear lungs
Antibiotics
-oral (mainly)
-nebulised (allows high levels in lung and systemic absorption)
-intravenous (porton for child having repeated pneumonia)

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Nutrition aspect of Treatment

Enzyme replacement
-immediate
-in apple purree as cannot swallow capsules until 5/6yrs
Vitamin supplementation
-mainly fat soluble (they struggle to absorb)
High calorie diet
Supplemental feeding via gastrostomy
-cannot eat enough. Additional feeding via tube going straight into stomach overnight
-regular weekly tablets (14yrs spend 2 hrs a day doing treatment)

Lung function over time

With each decade –
lung function over time
decreasing more slowly
-Other complications now evolving:

How long will Zak live?

In 2014 – current life expectancy - 39.3 years

improving, so expect life expectancy to increase
but requires a lot of input from family

2012 National Data registry

shows relative data in NZ and internationally
and improvements/how things are changing over time

The future for the family

The family would like to have more children
- can it happen again?
- can it be prevented?
Their own siblings are also having children
- What advice should be give to the wider family members?

False Positives

20%

-if child cannot gain weight = very high likelihood

CF Inheritance

Autosomal Recessive
-has to come from both parents
-both parents carriers generally
Both grandparents 1/2 risk of being carrier. atleast 1 is a carrier, sometimes both.
-Risk for next child: 1/4

Things to consider as a Clinical geneticist

Genetic Testing
-May inadvertently reveal family relationships (non-paternity) (dad isnt dad)
-see which mutation is coming from which side
-“De Novo” mutation that happened within egg/sperm - extremely rare
-Ability to give consent for testing
a) Informed
b) For children need to demonstrate a direct benefit
c) Who can have access to results (informed and confirmation)
Distress with new diagnosis/loss of “perfect” child
-not known in the family
Feelings of guilt
Options for the future
-when is the right time to discuss these things

GC Appointment

Reviewing diagnosis
-typically know that both parents are autosomal recessive, but checking
Answering questions
Can it happen again?
-Parents would like to have more children.
What about the rest of the family?
-Both have siblings wanting to have families.
Arrange testing
Checking to see how they are managing
-come back later? family positions change over time
Referrals

Family Planning

Can be difficult and distressing decisions
(guilt. importance of having to take care of CF child, tension would be more spread, potential for cross infection)
Options
-Not having further children
-Having children with no testing (3/4 chances not going to have another CF child)
-Sperm donor
-Prenatal testing for information or TOP
-Pre-implantation genetic diagnosis with IVF
Decisions influenced by ethical, religious beliefs, views on sickness and disability, treatment availability and efficacy, availability of social and financial support for the family

Prenatal testing CVS

11-13 wks
Testing placental tissue
-Only done at MFM units
-Need for maternal sample
-Placental placement
-Placental mosaicism
Results 1-2 wks	
1/500 risk of miscarriage
Reveals karyotype and gender

Prenatal testing Amnio

15 wks on
Testing amniotic fluid
Results in ~2 wks
1/1000 risk for miscarriage 
Reveals karyotype and gender

Preimplantation Genetic Diagnosis

Couples who are eligible can access up to 2 publically funded cycles
-has to be SEVERE
Eligibility criteria
-female partner under 40y
-non-smoker
-BMI under 32.
Privately funded PGD costs approximately $20,000 (if dont want to wait on waitlist or if dont meet the criteria)

ICSI

After IVF
when sperm is injected into the egg’s nucleus
-couples followed closely

Embryo biopsy

3-5 days of growth
extract 1-2 cells and send off for testing
embryos frozen during testing (so not growing too fast during testing)
Test takes couple of weeks, done through feasibility study, take samples from parents and grandparents, to make a really good quality test so require only 1-2 cells

Blastocyst

Once found cells that are -ve for condition
=will unfreeze embryos
= whichever ones survive they will implant back

Pregnancy guarrentee

Pregnancy is NOT guaranteed (20-30% pregnancy chance if young and healthy)
No eggs are recovered at the time of egg collection.
No viable embryos for transfer
-Some or even all eggs may fail to fertilise.
-Not every embryo will be suitable for biopsy.
-There may not be a genetic result from every embryo, or the result may be inconclusive (i.e. the test might fail on some embryos). These embryos are generally not transferred.
-There may not be any unaffected embryos.
-Some embryos may not survive the freeze/thaw process
The result is not 100% accurate, prenatal diagnosis is recommended (testing during pregnancy)
Risk of miscarriage, as for any pregnancy.
Does not rule out chromosome abnormalities- e.g downsyndrome

Referrals

If the couple want PGD
- referral to Northern Regional fertility service
- waitlist (2 yrs)
If the couple gets pregnant naturally
- referral to Maternal Fetal Medicine team
- liaise with molecular genetics laboratory to ensure they are aware of PND
- -maternal DNA sample for MCC studies
- -information about what mutations the parents carry

Its not just the procedure

Indication – referral-check woman is clear
Counselling- test and procedure
Prerequisites-patient and procedural
Follow up results- who will do this?
Final outcomes- care and support

Why might we be doing this today?

Previously affected pregnancy
Family history-parental carriers
Abnormality seen on a pregnancy scan
Possibly parental concern

Why might we be doing this tomorrow?

Non Invasive Prenatal Testing
• parents will know their genotypes or be screened
•**will test in pregnancy, non invasively
• Will there be gene-stem cell therapy for affected fetuses?

Antenatal scan

Meconium Pseudocyst

Secretions thicken in bowel,
Meconium becomes thick in the bowel -is ecogenic (bright)
comes up on the US –> marker/sign for CF

Prenatal Diagnosis allows reproductive choice

For the patients
– Impact on parents and family (95%parents want to have info so know what to do (but only 45% would act upon this info))
– Prevent suffering of baby-child
– Reassurance if baby unaffected
– Options not to continue if baby affected
– Preparations for the new baby
• We can not preempt what the parents will choose to do
• Most parents want to know

Need for DNA

Options
• DNA from tissue- INVASIVE TESTS
Trophoblast – early placenta
Fetal cells- fibroblasts in amniotic fluid
• DNA from maternal plasma NIPT-NIPD
Can get DNA from the embryo at IVF and PGD and maybe media fluid

Trophoblast

• Can extract DNA from chorionic villi obtained by
Chorionic Villus Sampling-CVS
• Advantages
Earlier in pregnancy
Direct DNA extraction (as placental tissue is dividing rapidly)
• Disadvantages:
Technically more difficult than amniocentesis
Maternal cell contamination ~1% of samples
Mosaicism can also occur (placental cells not recognised by mother)

Fetal cells in amniotic fluid

• Obtain these by amniocentesis, culture then DNA extraction
• Advantages
Technically easier
• Disadvantages
Later in pregnancy >14 weeks longer processing time
All invasive procedures have a loss rate ~ 0.4%
Syncytial knots Or
Syncytial nuclear aggregates

Non Invasive Prenatal Testing

Presence of fetal DNA in maternal plasma and serum
10% of DNA in mothers blood is fetal
• Sequencing 10 commonest mutations
• If paternal ≠ maternal - fetus not affected
• If paternal=maternal
• Offer invasive prenatal testing

New Diagnostic approaches

Whether mother carries paternal mutation, and if not she can be reassured
Benefits of NIPT
• No miscarriage risk
• Simpler, less stressful
• Informed TOP decision • Preparation for affected • Earlier result
• (preferred blood test)

How do you date a pregnancy?

Crown Rump Length

measure from head to tail of baby
will predict delivery +- 5 days for 40 weeks
most reliable estimate

An ethical question

Should health care resources be spent on a very expensive way of providing information only, which does not alter care or outcomes?
-95% want to know even though 45% wouldnt act

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Cystic Fibrosis Flashcards

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