It is said that anyone who thinks they are too small to make a difference, hasn’t spent the night with a mosquito in the room.
Of a human size but still small, (Game of Thrones spoiler alert) who wasn’t impressed when tiny Lyanna (Lady) Mormont felled a zombie giant, or that the Night King was killed by Arya Stark, the smallest but most lethal member of her family?
And from insects to TV fantasy to very real life. What’s known for sure is that we FAers have low levels of Frataxin; apart from that nothing’s actually known for certain. Something’s awry with iron-sulphur clusters; it’s suspected there’s too little iron in one part of our cells and possibly too much iron in another part. And the reason nobody’s certain yet is what’s being measured is microscopically small. This is about deduction rather than observation.
Consider it this way: each of us has more individual cells in our body than there are stars in the known universe. An average-sized man (175cms) of average weight (78kg or 78,000gms) has just 4gms of iron in his body in total. As our American cousins say, “You do the math!” Whenever you wonder why faster progress isn’t being made on finding a cure for FA and you’re told “it’s complicated”? That’s what they’re talking about.
small things of major importance, a tiny quantity of flu vaccine avoids a huge
problem for you and for those who care for you. Get vaccinated now.
Bigger isn’t always better (but its a good way to start)
If you don’t use it, you’ll lose it.
I’m a FARA Ambassador so I was invited to attend the full day of presentations at FARA’s Scientific Symposium. It was an honour of course as I’m just a regular FAer rather than a scientist. As a result though, much of what was presented was beyond me. I did understand enough to be able to say that there’s a fantastic amount of research going on in FA, not just quantity but also range of aspects being studied. The day was packed with presentations and rather than try to summarise everything I’ll expand on five points that struck very powerfully.
The first and possibly most important point for us FAers wasn’t in the scientific presentations but in a presentation made at the end of the day by Jen Farmer and Ron Bartek, guests from FARA North America. It was this: every FAer can make a direct contribution to finding treatments and eventually a cure by joining the FA Global Registry.
When researchers or drug companies need a group of FAers to test a hypothesis or conduct a trial, the Registry lets them check where there are groups of FAers they can access and salient details about those in the group. If they’re confident they can get enough FAers for their test or trial, its more likely to go ahead, and sooner.
There’s one FA Patient Registry for the whole world which is managed by FARA North America. It’s much more efficient that there’s just one Registry and it includes details from FAers throughout the world. If you’re an FAer and not yet registered, or not sure if your details are up to date, please go to: https://fara.org.au/patient-zone/ and register. It’ll benefit you, benefit me, benefit all FAers.
The keynote scientific presentation on the day was given by Professor Robert Wilson who has been doing research in FA for more than 20 years. With that much experience comes wisdom as well as knowledge and when he described some of his current work, I was reminded of a quote from one of the most underrated movies of all time:
Now, a few words on looking for things: when you go looking for something specific, your chances of finding it are very bad, because of all the things in the world you’re only looking for one of them. When you go looking for anything at all, your chances of finding it are very good, because of all the things in the world you’re sure to find some of them. (Daryl Zero, The Zero Effect 1998)
Here’s what I took from his presentation: inside a cell is very small indeed so although it looks like different things that do different jobs are separate when scientists represent them visually as diamonds, ovals etc. in a presentation, things are a bit more mixed up in reality, and seeking to affect just one tiny thing often has “off-target effects” when you approach it head-on.
(By the way, checking for “off-target effects” and avoiding them when necessary is a huge part of why the drug development process and trials in particular, seem to go so slowly).
One of the approaches Professor Wilson’s team is working on is as follows: Frataxin is needed to make things called iron-sulphur clusters, which are important for many cellular proteins to function correctly. FAers have reduced Frataxin as we know but that means we also have a low level of these iron-sulphur clusters. There are complicated steps from there but the end result is that iron accumulates inside the mitochondria and causes lots of damage.
Professor Wilson’s team is looking at ways to help mop up that excess iron so this damage is avoided and the cells survive. To use an AFL analogy, if FA means your midfield is weak (lack of Frataxin, poorly-performing mitochondria, the power-packs in your cells), Professor Wilson’s team is looking for a way to effect some strategic recruitment (like St Kilda picking up Dan Hannebery) to improve the midfield (overcome the iron overload), so the team (cells) get to do what they’re meant to do.
As usual, there were a number of presentations looking at changes in FAers over time in the search for reliable biomarkers. If something can be identified that changes at a constant rate, or for which rate of change can be attributed to specific variables, then it’ll make the job of researchers a million times easier than it is today. If they can be certain that with normal FA progression a particular parameter would change from A to B, then to prove efficacy of a treatment or drug they’d need to show only that instead of B it has now changed to C. It would make running tests and trials cheaper, faster and easier. Sadly, while results (white matter volume in our brains, dentate nucleus volume in the cerebellum, speed and accuracy of eye movement, dysarthria severity and more) can be shown to change over time with FA progression, in each case the rate of change was different in each individual.
If as an FAer you’re hesitant to hang out with other FAers, when you look at someone whose condition is more advanced if you sometimes think that’s what my future looks like., or when you see someone whose FA isn’t as aggressive as yours and you wonder why; well the answer is that you’re special. You’re an individual and while we help one another by all joining the FA Patient Registry and participating in trials if we get the chance, none of us is directly comparable in our FA with anyone else. Its up to each one of us to make the most of whatever opportunities were given.
Ian Harding (whose name and accent would almost guarantee him an audition as a James Bond baddie) outlined a group known (more Bond baddie inspiration?) as ENIGMA. While most research sites in the world have access to relatively few FAers because FA is rare, what ENIGMA hopes to do is standardise procedures for how certain imaging data are collected and reported up to and including MRI scans; so they can be combined and evaluated in aggregate.
For any study that starts with data, the bigger the sample, the better. Major themes can be identified more reliably. It’s easier to identify patterns, things that are the same. Then, to study changes, things that aren’t the same, the ENIGMA group can explore further with smaller groups or even individuals at particular locations.
Findings from a study presented by Phillip Ward brought to my mind a paper written a while ago by Geneieve Tai based on a study of patients at the Melbourne FA Clinic across many years. Phillip studied changes in iron concentration in the cerebellum over time via MRI. Iron concentration is important because it’s associated with brain atrophy over time. What he found was that iron levels increased over time in FAers, but that atrophy seems to plateau. What struck me is Gen’s finding that measures on the FARS, ICARS and all the other scales seem to do the same – increase over time and then plateau.
How that was explained to me then, and makes sense to interpret these results too, isn’t that FA progression reaches a plateau, but that as FA progresses and an FAer becomes less active and less mobile, there’s less for the brain to control, so less controlling brain to lose.
In Norman Doidge’s amazing book The Brain that Changes Itself he talks of the brain being such busy real estate that when a limb or even a finger is lost, relatively soon the area of the brain that used to process movement instructions for that limb or finger is retasked to do other work. Similar finding I think.
There is a mind-boggling array of research going on in FA, all focused on determining promising therapies. Some projects are local, some global. It works in our favour that FA is so rare because the researchers tend to know each other and coordinate their work better. Although it hasn’t reached us yet, progress is definitely being made. In the meantime, what has been established beyond a doubt is that physiotherapy slows progression; regular activity, even just variety of movement is good.
Make sure you’re in the Patient Registry and stay as active as you can so when the first treatments come, you’re in the best condition to benefit from them!
I heard an Olympic champion proclaim the other day that her success was proof that anything’s possible if you want it badly enough.
That might be true in her case, but in mine it’s just not so. No matter how much I want to win the 100 metre sprint, it’s never going to happen.
But that’s OK. To me, the single most important contributor to avoiding frustration and enjoying emotional balance despite living with FA is having the right perspective. Consider the following lesson from the world’s greatest private detective: Now, a few words on looking for things: When you go looking for something specific, your chances of finding it are very bad. Because of all the things in the world, you’re only looking for one of them. When you go looking for anything at all, your chances of finding it are very good. Because of all the things in the world, you’re sure to find some of them. Daryl Zero, The Zero Effect (If you’ve never seen the movie, do. It’s wonderful!)
I face the world with a perspective that’s similar. If I have only one specific goal, my chances of achieving it are slim because of all the things I could achieve, I only aspire to one of them. On the other hand, if I aim to enjoy myself, try hard, bring positive energy and feel satisfaction at anything I do, my chances of achieving those objectives are very good indeed because I do lots of things.
I know FA imposes limitations on me so I only take on projects that I can realistically manage. I don’t just give up and do nothing. I do challenge myself but I’m constantly reassessing so my expectations are realistic. I might be the only one who knows what those expectations are at any time, particularly if I’ve needed to readjust them for any reason, but I’ll enjoy real satisfaction if I meet them.
I’m more an Omnilympics kind of person. Something’s possible so I’ll do that. And then I’ll say, in the immortal words of President Bartlet: “”What’s next?”
If you need something done, ask a busy person they say. And they’re right. You see, what keeps busy people busy is that they’re getting things done. Add the thing you need done and it joins their list. They’ll get it done too.
Or you could set out to start getting things done yourself. Start with small things. Once you set out to accomplish one thing, as soon as it’s accomplished you want to tackle another. It’s contagious. Add the thing you needed done, and you’ll get that done too.
There are two schools of thought on approaching a to-do list. One says to prioritise the most important projects and focus single-mindedly on accomplishing them. I disagree. My recommendation is to intersperse that work with a number of smaller easier tasks so you’re notching up a continuous stream of accomplishments along the way. (As Adm. McRaven said in the inspiring commencement speech at UT in 2014 “If you want to change the world, start off by making your bed.”)
I feel the same applies to exercising, especially for FAers. Next month the first RideAtaxia Australia event will be held in Melbourne and it’ll be headlined by Kyle Bryant and Sean Baumstark, the two FAer stars from The Ataxian, a movie which chronicles their participation in the Ride Across America event in 2011 (now that’s a virtuous cycle!). But no-one just takes part in such a huge endeavour straight off. The secret is to start small.
Accomplishing things is habit-forming so set small targets at first, even very small targets. The challenge isn’t to do the big thing so much as it is to do something. Then do a little more and then a little more still. That’s our virtuous cycle – set yourself targets that are realistic and you’ll enjoy achieving them. Then make those targets a little more challenging and enjoy achieving them a little more. And so it’ll go on.
Every FAer should exercise. Focus on what you can do, no matter how modest. Then next time do just a little more. If you want to read a little more about this, there’s an excellent article here.
(Support FAN’s virtuous cycle in RideAtaxia Australia 2018 by clicking here.)
I would just like to write a short story about my life with Frederick Ataxia.
I feel it may be of some value to other sufferers.
I was born on the Southern tip Pennisula of Tasmania, not quite the South Pole!! Cold,very cold. We had 300 acres of fruit orchids & a huge veggie patch.
I was diagnosed when I was 10 & my sister now passed two decades ago at the end of 57.
Walking was my first problem. Living in these Countries walking was something you had to do. My older sister was very adventurous & when my grandparents moved to the Gold Coast in the late 60s we all ended up moving there. Without going into detail i married at 19, during this time my disease deteriorated & by the time I was 22 I was in a wheelchair. I moved to Brisbane where I founded the first Australian New Zealand Association for sufferers of FA. Now there are many groups all over Australia. I moved back to the Gold Coast but there was no response for another group and after seventeen years the Brisbane group folded.
I am now a grandmother and my eldest will be 20 next month intending to be a Heart Surgeon.
I am about to turn 65 but I cannot do much for myself. My eyesight & my hearing are very poor & my speech is very awkward, I am flat out trying to understand myself.Lol!
My body is very much incappacitated. M y brain is very active but my frustration is killing me. I use to play the piano but now my hands are so twisted I can’t even stretch myself. I would like to know the thoughts of other sufferers & how they look forward to making a future with FA.
I have written my autobiography, who knows when I will finish it. Maybe others would like to share some of there life.
In the many years since diagnosis, how I describe FA has become pretty standard: with resignation. People would enthuse to me back then about how fast progress was being made in medical research and assure me how convinced they were that there would be a breakthrough in FA that I’d benefit from very soon. As time went on though and my FA progressed, it’s felt appropriate to become stoic. I’m a big supporter of FA research, but I became increasingly convinced that it would benefit FAers much younger than I when a breakthrough was eventually made.
FA is a neurological condition, it’s progressive and degenerative. I do everything I can to slow that progression but even if I’m successful all I do is slow it down, the progression is still happening. However my condition is today, tomorrow it will be a little bit worse. There’s neither treatment nor cure. It’s inexorable and irreversible…
They’re still quite a way from achieving that but I don’t care. I want them to do their work diligently and get it right. Treatments will benefit me whenever they’re proven, especially the holy grail of DNA editing so cells will produce frataxin efficiently. Supporting fundraisers is all very well but when it’s personal I’m more engaged. I’m impatient again and it’s a good feeling!
According to Deloitte, smartphone penetration in Australia is at almost the highest level in the world, at 88% in 2017. They’re so useful I reckon penetration among FAers should be 100%.
Here are just three apps I have on my phone that are particularly useful considering that I have FA (there are lots of different versions of each of these you should be able to find one that’s free):
Flashlight: Humans primarily use three functions to balance. 1. The vestibular system, the three interlocked, liquid-filled little rings inside our ears. 2. Feedback from whatever part of our body is in contact with the ground (usually our feet). And 3. Eyesight. With FA the first two deteriorate quite dramatically so we tend to rely disproportionally on sight. If your mobile phone has a flash, you can install an app that controls it as a flashlight. So long as you have your phone with you, you’ll always have access to light. This is invaluable. (Personally, I have my phone on a lanyard around my neck, so I can have a light on and two hands free if needed).
Heart rate monitor: Dr Lynch says that when death is caused by FA, in more than 65% of cases it’s directly attributable to heart complications. The two complications most common in FAers are 1. Hypertrophic Cardiomyopathy (thickening of the walls of the heart) and 2. Tachycardia and/or Atrial Fibrillation (irregular heartbeat/heart rate that goes bananas from time to time). The good news is that because heart complications are an issue for so many non-FAers too, there’s lots of care available. FAers who attend the Brisbane Clinic will be having an annual echocardiogram (where they monitor for cardiomyopathy) and perhaps also 24-hr holter monitoring (where they monitor for tachycardia and/or atrial fibrillation). It’s worth installing a heart rate monitor app on your phone so if ever your heart feels like it’s racing you can check if it’s really so, and be able to tell your cardiologist at your next appointment.
Sound level app: The hearing issue most often experienced by FAers is difficulty isolating a sound (like the voice of someone you’re having a conversation with) when in a noisy environment. Again, we’re fortunate that high levels of ambient noise are increasingly being recognised as hazardous to all and there are apps available to monitor the situation. My favourite is Soundprint which not only lets you monitor where you are but also post a note for other users. Consequently there are results already posted by users all over the world, including Australia, that you can check before you go out.
What other apps do you find useful in living with FA?
Neils Bohr, a Danish physicist, is reputed to have said “It’s difficult to make predictions, especially about the future”. He was one of the smartest men to ever have lived. I guess he had an enormous respect for weathermen!
Well for us FAers, predictions are what we seek most in the world. It’s not hard to find out the list of things that’ll go wrong with us. What is hard though is getting an idea of when.
Unfortunately, the answers just aren’t available. There aren’t enough of us to have built a giant database yet with all our data so statistical analysis can be done. The only thing they’ll tell you is that speed of progression seems to be linked to the lower of your two repeat numbers.
The reason is variables. There are just too many. Going back to my earlier analogy, weather forecasts tend to be accurate a few days in advance. They’ll give guidance up to about a week but after that so many variables could have an impact that confidence in their predictions falls pretty rapidly. It’s the same with predicting when progression will effect specific change for an FAer.
This is a problem for two big reasons. The first of course is that when we ask what’ll go wrong with me as my FA progresses and when are those things likely to happen?, the answers we get are “We can’t be sure.” and “We can’t be sure”. The second reason is that unless they can describe how your progression is expected to go, a drug company can’t show that their drug changes that trajectory or by how much.
And that’s why almost every research project we FAers take part in which notes change over time has an element in its conclusions noting that what they measured might be useful as a biomarker. What they’re suggesting is the confidence level they have that what they measure will change according to a predictable path as FA progresses. So far it’s a bit like the weather prediction – seems to work fine short term but other variables have an impact in time so things become inaccurate.
Identifying biomarkers that support prediction as FA progresses is important for many reasons; for example, robust biomarkers are of immense value as outcome measures for clinical trials, preferably double-blind placebo-controlled trials: two cohorts, one given the drug and the other a placebo and no one, not even the scientists overseeing the study, knows who is in which group. So long as the groups are big enough, the averages can reduce the impact of an outlier individual result.
Life Of Brian (1979) - clip: "You're all individuals" - YouTube
I’m not a scientist, nor a medical researcher. I’m just a normal FAer. I was invited to the Symposium as part of a Patients Panel, a Q&A session for researchers who might work in a lab and might interact only with FA cells, to meet and understand real FAers, the people who’ll benefit most directly from their work. (Subsequently all the FAers on the panel, including me and Samantha Dwyer from FAN, were invited to become FA Ambassadors for FARA – more on that later).
To be there was humbling but rewarding. It’s amazing to appreciate the range of brilliant minds, all approaching the challenges of FA from different perspectives. There was much detail I couldn’t hope to understand, but I understood the wide range of areas they were working in or on.
So, forgive me for what I just didn’t understand. Here’s a summary of what I think I did:
The thing we probably all know about FA is that it’s genetic. What I’m always impressed by is how the explanations seem so straightforward. Here’s a distillation of what I understand from all I’ve been told or have read: “Your gene is like an instruction book within each cell and the result is production of protein appropriate to that cell’s function. The problem in FA is that there’s an expansion of a repeated sequence (GAAGAAGAA) at one point on the FA gene (FXN) and that causes confusion like if a single page in an instruction manual was there 1,000 times over and you had to read every page before doing a job”. If the problem’s so well understood, might the solution be easy to find?
Unfortunately, it’s not that simple. Our genes are in the nucleus of every cell in our bodies and each of us has as many cells in us as there are stars in the universe. And some genes are turned on and others are turned off in different kinds of cells, which is what makes them bone cells, heart cells etc. If we change (correct) a gene in one cell, we want to be sure that the change occurs in all the cells of that type.
There is one branch of work being done to reverse-engineer adult cells back to stem cells. Then, if a way can be found to correct the gene problem in these cells, they can be directed again to specific types like heart, cerebellum, dorsal root ganglia etc., basically the parts where FA impacts most severely.
Do you remember the original Ghostbusters movie? Early on Dr Spengler says they should “never cross the streams” of whatever comes out of their guns. At the climax of the movie he shouts that that’s exactly what they should do. Well there was a presentation about fixing FA genes which included something about reversing polarity that reminded me strongly of that. It was mostly about viruses though. The polarity bit seemed to be about the new instruction page that will replace the repeated pages that are the FA problem.
The presentation was about identifying the right virus to carry this repair kit into the cells. Viruses are pretty good at doing this (after removal of their dodgy bits) but in many cases the body spots them and the immune system gears up to do its antiviral stuff. In a few experimental cases things pushed too fast with fatal consequences so progress now is slow and very careful. The most recent and promising route involves AAVs which are so small they don’t provoke immune responses from the body. They’re very simple viruses though, tending to deliver their payload then die off so whatever they’re given to carry and deliver must be perfect and work first time.
When they’re doing test drives of stuff like this they include also a gene alteration that’ll make the impacted cell glow phosphorescent green and I’m left with an image in my mind of a whole human organ glowing solid green. Key take-out: it looks like they’ve identified the right tiny virus and the right instruction book alterations. They’re getting close to identifying a cure for FA (although there’s still lots of work to be done to make sure there aren’t unintended consequences).
To impress upon us the breadth of exploratory routes there was a presentation even from a plant guy. A plant guy? you ask. Yes I say. As you probably know, FA is caused by a GAA repeat expansion on the FXN gene. Now they’ve identified a plant which has developmental issues due to a genetic problem and looking more closely they’ve identified that it’s a triplet repeat. It’s less dangerous and more easily monitored to explore ways to fix this problem in the plant. If and when a solution is found it won’t be immediately applicable to FA as it’s a different gene but it’s bound to raise important suggestions to explore.
It’s always been said to me that FA involves neuromuscular degeneration but there’s no impact on cognitive ability. Results were presented from a study that says it’s not so simple. Potentially most exciting to the scientists with machines that can measure this stuff is that over time, with FA progression, there are measurable changes in brain volume, most notably in “white matter”. What I found equally if not more important were results from a separate study that suggests FAers might be using their brains differently than non-FAers. Hence, while there might be measurable physical changes in the brain over time, it seems likely that brain plasticity is causing FAers to change how the remaining brain is used, to compensate.
Another presentation relevant mostly to specialists with access to big machines was about a way to more effectively monitor the heart as FA progresses. More than 50% of FA deaths are due to heart problems and most FAers have cardiomyopathy (thickening of the heart wall) so while I didn’t understand the specifics I want my cardiologist to be aware of this presentation before I have my annual echocardiogram.
Two studies were presented about rehabilitation, one about speech, the other about physiotherapy and they both had similar findings – intensive therapy over a short period leads to significant improvement. Next step is to design a way for an intensive programme to be delivered/monitored and then how a less intensive maintenance programme can be designed for ongoing use (the other 11 months of the year).
Another study looked at the personality, social skills and psychological health of FAers compared with non-FAers. It comes as no surprise to me that FAers were found to show more symptoms of depression, stress and negative social behaviours. My personal view though is that in matters like this it might be more accurate to evaluate someone’s life with FA rather than draw conclusions about FAer vs. non-FAer. I’m reminded of a report from some time ago that revealed that people with disabilities rated their quality of life higher than people without, and explored the assumption the opposite would be true (contact me for more info on this).
In summary then, there’s an enormous amount of research going on in FA right now, and exciting progress is being made toward finding a cure. Research is also going on into how we can monitor, maintain and even improve our health in the meantime. My favourite Ron Bartek (head of FARA in the US) quote is “there’s never been a better time to be a sick mouse” but in reality, there’s never been a more exciting time to be an FAer!
There’s a character in The Hitch Hiker’s Guide to the Galaxy by Douglas Adams called Rob McKenna. Rob is surly, grumpy and intolerant because it’s raining. In fact, wherever Rob is, it’s always raining. As Douglas Adams explains: “… for, though he did not know it, Rob McKenna was a Rain God. All he knew was that his working days were miserable and he had a succession of lousy holidays. All the clouds knew was that they loved him and wanted to be near him, to cherish him, and to water him.”
FA is a bit like a storm. If you’ve been diagnosed with FA, consider yourself a Storm God. FA is genetic. It’s in every cell in your body. All it knows is that it loves you and wants to be near you, to cherish you, and to stop those cells from producing Frataxin!
If your FA is a storm, your diagnosis is a lighthouse. The storm can be just as hazardous but at least you know where you are.
FAers have differing reactions to a confirmed diagnosis. For many it can take a considerable time and they go through stages, like stages of grief, before accepting their FA as something that’ll henceforth be part of their life.
Two things are worth bearing in mind about your diagnosis:
You’re lucky: Going by the generally accepted figures that there’s a 1-in-45,000 incidence rate of FA globally among Caucasians, there are probably more than 500 FAers in Australia. FARA has details of less than 200 which suggests there could be more than 300 out there either not diagnosed or misdiagnosed.
Once you accept it, you begin to take back control of your life. You can use your diagnosis like an anchor or navigation point that all other aspects of your life need to take account of. The way Kyle and Sean describe it in their excellent podcast series (link), once they began educating others about FA and joined fundraising for research each felt “I was controlling my FA rather than it having control of me.”
You know you’re a Storm God so use that knowledge! Be purposeful. Use your diagnosis as a starting point and set up your working conditions so you won’t be miserable. Plan holidays that won’t be lousy. Be Godly and enjoy it.