Prevention of Alport Syndrome in the Next Generation

Pre-implantation Genetic Diagnosis IVF

By Dr Alison Blatt


I was 34 years old in 2007 when I discovered my brother had Alport Syndrome and I was a carrier.  We were devastated to say the least.  I had one daughter, Matilda, and was unaware of her status.  But I knew I wanted more children so my husband and I consulted a geneticist at Sydney IVF and requested Pre-implantation Genetic Diagnosis (PGD).  Sydney IVF PGD website

This technology had only been available in the last 10 years and only one other person with Alport Syndrome had gone through this process in NSW.  I knew Sydney IVF was one of the few places in Australia with the expertise and experience in this technology.  PGD would enable us to exclude Alport-affected embryos during the in-vitro fertilisation (IVF) process and potentially have an Alport-free baby.

Finding the Genetic Defect

First the genetic defect needed to be confirmed.  My brother and I had our blood sent to the UK and it took many months to get a result.  It eventually confirmed that the defect was on our X chromosome.  This was supported by our family tree which strongly suggested X-linked inheritance in our family.

Designing the Probe for screening my embryos

Rather than design a test to find the tiny defect on the chromosome, the test was designed simply to identify my faulty X as it was passed on to embryos.  Blood was collected from my husband, my brother and me.  My X chromosomes were identified and matched with my brother so that it was clear which the normal X was and which had the faulty gene.  (see figure 1)  Then my husband’s X chromosome was identified.  A probe was designed to mark these three Xs.  This took the scientists about 6 months to design and create.




Figure 1: Designing a probe involved identifying the X chromosome containing the defective gene (in red) by matching my chromosomes with my brother’s chromosomes.  The embryos were each biopsied and their X chromosomes were labelled to identify Alport-affected embryos. My normal X chromosome is purple, my husband’s normal X chromosome is green.  There are four possible outcomes of combining our chromosomes which include (from left to right) one female carrier, one normal female, one affected male and one normal male.





The IVF-PGD Process

Once the probe had been designed my husband and I started the IVF process.  I started a series of medications which manipulated my hormones and resulted in the ovaries going into overdrive.  Where the ovaries would usually produce one egg per month, multiple eggs matured.  I was bloated and uncomfortable and it made me feel tired and crabby (like PMS only worse!).  Every second day or so I had to have my bloods taken to monitor my hormones, then as the eggs were “ripening” I was having 2nd to 3rd daily ultrasounds.  When the eggs were ready I went into hospital for the “egg retrieval”.  This was a minor procedure done under local anaesthetic with the doctor using a long needle to collect eggs through the vaginal wall.  The same day my husband had to provide a sperm sample which was used immediately to fertilise the eggs.  After the procedure I had to have bedrest.  We went home and waited.

Over a 5-6 day period the fertilised embryos were closely observed and I got a call every morning to give me an update on how many embryos were thriving.  I had an excellent result with nine embryos eventually reaching the biopsy stage.  The biopsy itself is a miracle of modern technology and involved microsurgery on the embryo.  Have a look at the SIVF website to see footage of a biopsy.  A single cell was taken from the outer shell of the embryo (at this stage called a “blastocyst”) which is a non-essential part of the blastocyst.  This cell was then tested for the genetic abnormality.  I had five embryos which were Alport free.  This was more than I’d dreamed of!  The best embryo was chosen and the rest were frozen.

The embryo transfer required no analgesia (like having a pap smear) and used ultrasound guidance to deliver the embryo to the centre of the uterus.  Then it was back to waiting…  After two weeks a blood test was performed.  I got a phone call with the results after lunch.  I was not pregnant and even though I knew my chances were poor (I’d been given a 30% chance of success with each transfer) I had still lived in hope.  After many tears we picked ourselves up and tried again.  Every month, with the help of medication and blood tests, I underwent an embryo transfer until all five of my precious embryos were gone.  Then we started again.

By this stage you can imagine I was doing everything I could to improve my chances.  I hadn’t drunk any alcohol for 6 months and was barely drinking any caffeine.  I was avoiding any food additives and a long list of potential ingredients that were vaguely rumoured to decrease one’s fertility.  Despite my medical background the hard scientific evidence was not necessary to scare me off even the mildest potential offenders.  We had been living on a rollercoaster of emotions and it was hard to focus on outside commitments and goals.  I was fortunate to have a busting two year old to keep a smile on my face and remind me of how lucky I was every day.

So, the next round of drugs and blood tests and ultrasounds started.  Everything went smoothly but only two embryos made it to the end of the line.  I went into the IVF hospital for my embryo transfer.  For the next two weeks I did everything I could to forget about IVF and get on with things.  So I ignored the tender breasts and slight constipation and told myself the bloated feeling was premenstrual tension.  When my specialist called me with the good news I almost cried , “I know”.

Success


My second daughter was born in April 2010.  She’s an absolute delight and her big sister is the proudest three year old in town.  It’s a great relief to me to know that although the IVF process was difficult I’m extremely fortunate to have had PGD available to me.  In choosing to have a family I didn’t just “roll the dice” as many people do with genetic diseases when PGD is unavailable. 


I highly recommend the Genea (formerly Sydney IVF) website for more information.


Dr Alison Blatt and her baby daughter.

 
MY STORY