So the time has come for me to finally put pen to papering write Alice’s story. I have tried on many occasions over the past three years to do so but as you know dealing with every day to day life with a loved one that has a death sentence hanging over them is really hard. Life is like living on a roller coaster at the moment and not an enjoyable one at that.
Lets start at the beginning, as a child Alice was a perfectly happy, healthy little girl. She just had the usual childhood aliments asthma, eczema etc all of which weren’t a problem. She reached all of her developmental milestones and had done well at school and college. However, at the age of 17 Alice hadn’t started menstruating. After having a scan and blood tests Alice was diagnosed with ovarian auto immune failure. We were told that she would never be able to conceive or carry a baby, we were devastated as you can imagine. Little did we know that worse was still to come.
They started Alice on 2mg of Ethinylestradiol for for 6 months then increasing the dose each 6 months until April 2014 when Alice started on the full dose. This they explained was to force Alice’s body to go through puberty. However, with each increase Alice became increasingly lethargic, from early early 2014 she started to suffer with pains throughout her body and would have random bouts of vomiting. The endocrine doctors tested Alice’s thyroid, ACTH, cortisol, renin and adrenal antibody levels, all came back normal. Their conclusion was that Alice’s body was now in “teenage mode and teenagers need more sleep” If only this was the case and it wasn’t anything more sinister.
As 2014 passed Alice’s gait worsened as did her moods and lethargy. In August whilst at work Alice broke her finger, this was the last time she went to work. Her body was wracked with pain, she was unable to stand up straight leaning towards her left side. Our GP was at a loss and kept referring her to physio sessions and to a foot specialist. He did make a referral with a neurologist but this would take at least 3 months or more. When Alice saw the doctor at the foot clinic he took one look at Alice trying to walk and referred her to the neurologist that day.
The poor young doctor( he only looked 12) seemed to be quite flustered with the symptoms that Alice presented with. He preformed various neurological tests and ordered a nerve conduction velocity test, MRI and bloods to be taken. We told him about Alice’s ovarian failure and asked if there could be a link at all. He just shook his head and said ‘I don’t think so” November 3rd Alice had the MRI, we were called back that afternoon to see the senior neurologist Dr Pinto for the results. He told us that he thought Alice has leukodystrophy. We had already found out that cerebella ataxia often manifests at puberty and is often associated with Leukodystrophy. Because of Alice’s delayed puberty we considered this to be a strong potential link.
We again asked the Drs about the link with the hormones and HRT. They said they would look into it with the endocrine department . Alice could no longer walk and it was becoming increasingly harder to support her with transfers onto her wheelchair and stair lift. Alice was becoming weaker as each week went by. On December 9th, 2014 — Alice had her first and only seizure. Panic and fear descended around us as nothing like this had happened to us before. Alice was taken to the hospital and the next morning Dr Pinto confirmed by handing us an A4 print out that Alice had vanishing white matter disease (VWM).
Our world fell down around us as i glanced at the paper I was just handed and through tears I read the prognosis of seizures, coma then death. How could this be? Surely he had got it wrong, it was what I was silently screaming to myself. He had no answers for us. We handed him research papers on Hashimotos etc and the correspondence we had undertaken with professor Goldman in USA. He told us he would look into it and our concerns regarding the hormone treatment. We were left alone in our own bubble of turmoil as we watched Alice deteriorate even further over Christmas and New Year.
For the next few weeks Alice was projectile vomiting daily, unable to keep fluids, food or even her meds down, it felt like Alice’s body was shutting down, her life slipping away. I contacted the endocrine clinic again and asked them about the hormone link and VWM. I was told it was ‘a coincidence’. We weren’t prepared to accept this, they had to be wrong all the research that we had found said so, so why wouldn’t they listen to us.
On 3rd February 2015, Alice was finally admitted to hospital, by this time Alice could only move her head and her hand slightly. Every part of her body was in pain. It felt like we had very little time left with Alice, family and friends come to say their good byes, our lives were full of despair. Everyday we asked the Drs about the hormone treatment and it seemed that we were now begging them to investigate themselves. However, we were told that if Alice stopped taking the hormones she would be at a high risk of osteoporosis and the withdrawal would cause an early menopause.
Despite our protesting that osteoporosis would be years off and that our research indicated that withdrawing the hormones could return Alice to the pre-hormone induced state the endocrinologists and neurologists, who some months later agreed their position of ‘coincidence’ had been incorrect, continued to advise the hormone dosing.
We continued our research the outline of which is that within EIF2b1 (effectively a controller of the EIF2b function) there is an estrogen receptor which research had already proven that when activated displaces part of a heat response function of EIF2b. It had also been demonstrated in separate research that there was a link between estrogen receptors and phosphorylation, whilst this is not demonstrated to be generally negative, it did demonstrate a link between Estrogen and myelin which has been known about since at least 2004. It was also known that alterations in the phosphorylation process can lead to oligodendrocyte failure/death.
Whilst there were at that time to our knowledge, no other cases where withdrawal of estrogen had demonstrated a reversal specifically within VWM, we were importantly also not aware of anyone other than Alice suffering such a prolonged and rapid decline following the external dosing of estrogen and a consequently late onset puberty. The fact that nobody else had experienced this was confirmed in correspondence with Dr Orna Elroy-Stein. Our hypothesis, which she did not consider conclusive (but did not rule out) was that Alice had a very unusual form of this extremely rare disease which was, possibly unique in being initiated by hormones. It was our further conclusion that Alice’s autoimmune ovarian failure had not as such been her immune system failing her, but instead had protected her by inhibiting the natural source of estrogen in her system.
On February 13th, 2015 — Alice was moved to the neurologist-rehab hospital. Alice was just about ticking along sleeping most of the time. She was being PEG fed by now for all her nutritional and meds intake.
Alice was still vomiting on a regular basis and we were still asking for Alice to be taken off the HRT, whilst continuing to provide the research above to the neurologists. It was becoming increasingly clear we now knew more about this condition than Alice’s doctors.
As Alice’s condition continued to deteriorate to the point where she had only very minor movement of her left hand and the evidence that estrogen does have a link to myelin became more evident with our research, Alice’s turning point came on the 13th of March 2015, when we decided with her that she would stop taking the estrogen. On the March 17th, 2015 — Alice had to go back to the General for an endocrine clinic they were so shocked by Alice’s condition as if they knew nothing of her deterioration. But after scanning through the notes, they suggested Alice “taking a break from HRT”. In a calm restrained manner I told them we had already done this the week before and that we had been asking them to do this for months because we felt it was slowly killing her. They decided to discharge Alice from their ‘care’ as there wasn’t anything more they could do for her, in other words they were washing their hands of her.
Five days after Alice stopped taking HRT the nurses were already remarking how much more alert Alice seemed and she was awake for a little longer each day. I really knew Alice was at a turning point when she asked for some potato crisps.
Although with a lot of ‘hunting’ she was able three times to pick up a crisp and unaided put it in her mouth and eat it. She was exhausted afterwards but this was so amazing, I could not stop smiling and crying for the rest of the day.
With each day Alice’s strength and stamina was increasing her body was coming back to life. The physiotherapists worked hard with Alice and although she still had bouts of sickness and mood swings.
Over the following weeks everyone could see a marked improvement in her. Through intensive and often exhausting physio sessions Alice was learning how to sit up, brush her hair and teeth and to feed herself. All those small daily tasks that we take for granted Alice was having to relearn how to do them. By late April 2015, she was even strong enough to wheel herself a few meters in her wheelchair. Progress was slow but steady. At the end of May 2015 with the help of a stand aid Alice pulled herself up into a standing position for 70 seconds.
Through this period Alice’s infectious personality was returning and she was surprising all that met her. Alice was very popular with patients and staff at the hospital.
At last we reached the day in June 2015 when feeling very positive but apprehensive we were able to take Alice home.
With renewed vigor and a real positive attitude to life, over the past 18 months Alice’s very hard work has allowed her to go from strength to strength. She continues to exercise everyday and attend hydrotherapy every week. With the aid of her walking sticks Alice can now walk at least 50 meters. She has regained full mobility in her upper body and right leg, her left leg is still weak but slowly it is improving. Her hand control now allows her to write as neatly as she could before and she can use normal cutlery, glasses etc., without any real issues.
She is now able to again apply her own make-up and style her hair. Alice has many hobbies and throughout her illness had continued to support her local football team. She is now able to attend home games and recently managed to attend a cup match at Wembley where she had also managed to see Beyonce in 2016.
Returning to the diagnosis we finally received the results of Alice’s genetic tests in September 2015, which concluded the diagnosis is ovario-leukodystrophy caused by mutations in EIF2B1. From what we understand there are approximately 250 VWM suffers in the world of which only 1% are EIF2B1. Trust Alice to have the rarest of the rare! Within EIF2B one of the mutations is at C252+1G>A of which there are a number of occurrences (though typically not in EIF2B1) the other is at C824+1A>G. There are well over 100 mutations that have been identified as causing EIF2B myelin disorders, it appears this one was discovered through gene research as we have seen no evidence that anyone else suffering symptoms has C824+1A>G and we conclude that as sufferers having C252 from both parents appear to have early onset VWM it is therefore the C.824 mutation that is influenced by estrogen, carriers of C.252 (i.e. inherited from only one parent) such as myself have been studied and found to have only limited decrease in myelin thickness. We believe that our hypothesis of March 2015 was correct that removal of estrogen could return her to effectively having no more symptoms than a C.252 carrier. The evidence of Alice’s continued improvement seems to support this.
We had in 2015 and following initial improvements attempted to discuss Alice potentially taking tamoxifen or a variant of it. This is usually associated with inhibiting estrogen receptors in the treatment of breast cancer the doctors were unengaged in this suggestion. It has been shown by studies published in August 2016 that tamoxifen has been shown to improve re-myelination. Perhaps they should have listened to us again.
At this point Alice has not had any tamoxifen, or anything else curative, simply the withdrawal of estrogen and a great deal of very hard work. In October 2016 we engaged with a Group of Doctors at London Hospital who are extremely interested and positive about Alice’s progress and what they can learn from it for the assistance of others. What a very pleasant and different experience!
Who knows what the future holds for Alice, but then we can say that about each of us, life can change in the blink of an eye. But what I do know is that as it stands, today Alice’s future is a lot brighter than it was on that terrible day in December 2014.
Written by Alice’s mom.
Small amounts of money can have outsize impact in the world of#VanishingWhiteMatterDisease (VWM). Because #leukodystrophies are so rare, therefore research relies heavily on private donations. Even if it’s a small amount, please consider donating. Your gift can save a child’s life!