Hi all. I thought I’d post a bit of an introduction before I post any specific queries or discussion topics. I’m a 32 year old male from the UK. I appreciate that I’m not posting in the Britain sub forum but then nothing about this post specifically relates to the UK I guess. I tested positive for the KD mutation about 4 years ago after my mother discovered it in the extended family and subsequently tested positive as a carrier.

I ‘think’ I’m more or less in the presymptomatic stage at the moment, by which I mean I don’t think any of the major symptoms have begun to take hold. That being said I occasionally get cramps in my lower legs (usually in the middle of the night) and am prone to annoying muscle twitches, also in my lower leg. Fertility tests came back reassuring about 3 years back despite some initial difficulties, and I now have two young boys (so the KD is suitably wiped out from my line of the family). The KD genetics results at the time showed quite a high number of repeats, which in other repeat conditions seems to tally with a greater degree of illness, so I’m expecting the worst.

I’ve recently made an effort to up my exercise game with a view to putting my body in the best possible condition for when the KD really begins. I’ve been vegetarian for about 10 years and have been teetotal for around 7 years. I enjoy coffee and very spicy food however. Currently running about 2x8 km a week and am hoping to restart some weights for the upper body strength - which I suppose leads to my first main area of concern; fitness. Does anybody have experience with leading a relatively healthy and exercise orientated lifestyle prior to the onset of the symptoms? Do we think that there is logical merit to not only cardio excercise at this stage but also to building muscle mass (weight training etc)? I’m not proposing becoming mr universe of course, but am seriously considering whether piling on muscle now will help me fair better for the future. I’ve been reading some of the other articles here keenly for some time, especially people’s take on yoga etc, but I guess what I’m after is info from the perspective of people’s time prior to entering full KD mode.

Thanks in advance, any pointers or tips are hugely appreciated as I do feel anxious with regards to what’s lying in wait down the line etc.

Welcome Lytton!

I wish I could do my younger years over again. In hindsight I think I made big mistakes that caused a lot of damage. What is working for me now is very different from what I did then. I'll follow up soon when I have time.

Hello Lytton
I was diagnosed with KD in my mid-50s, at that time I as searching for an answer to why I was experiencing frequent nighttime episodes of laryngospasms and why I felt so weak and unstable.
However after learning about KD I was able to determine that I had symptoms much earlier in life. I had hand tremors and other facilitation that effected my use of hand tools in my early 30s etc.
After reading the exercise guides on the KD website I started working with a physical therapist with the goal of stimulating my leg and arm muscles without doing damage. The caution in the exercise guides was to do only 75% of your current physical capabilities.
I am still working with my therapist and instead of decline I have actually gained some strength and stability to the point that I can walk using just a cane for about 30 minutes without being fatigued (approximately 1 mile). I concentrate on standing very erect and tighten my core muscles; my therapist told me that doing this was important and I found it to be sound advice.
I will be 65 years old next month.
I wish you all the best as you learn how to live with KD.
David

Lytton,

Exercise is by far the most potent tool for muscle health. But it works its magic by causing damage which stimulates repair and growth mechanisms that ideally over compensate and make us stronger and better prepared to handle the next challenge. The KD gene, aging and many other factors (diet, sleep, stress, toxins, etc.) affect this, both the amount of damage done by exercise and our ability to respond positively. Without exercise most everyone loses muscle rapidly. We know this from people immobilized through illness and injury such as with casts for broken bones and by astronauts spending time weightless in space. But too much exercise exceeding ones recovery capacity can also be harmful such as the extreme case of rhabdomyolysis as sometimes seen in athletes who over train or often in new military recruits in basic training.

The androgen receptor protein after binding with testosterone or other related ligands moves into the nucleus of the cell where it can affect the expression of other genes. The mutant AR of KD is more resistant to post signaling recycling which appears to cause very broad transcriptional dysregulation. The nature of this process and the range of effects are incompletely understood but the expression of a very large number of genes have been found to be affected, the expression of a few genes is increased and the expression of many others is decreased. Aging, exercise and all the other factors I mentioned before also affect gene expression and our goal with exercise (and other interventions) is to counter the negative aspects of aging and KD on gene expression while hopefully avoiding excessive damage.

Many of the genes affected in KD are involved in metabolism and it is increasingly recognized that KD, like many other diseases of muscle and nerves as well as most of the chronic diseases of aging are metabolic diseases. Common to those diseases is mitochondrial impairment. Mitochondria, key metabolic organelles in our cells, function as power plants, burning the fuels we eat - carbohydrates, fats and protein to generate ATP, the molecule which provides chemical energy to power almost everything we do. Cells with large energy demands such as muscle can contain thousands of mitochondria. Mitochondria are symbiotic organisms with their own separate DNA and a purely maternal inheritance pattern in humans and most other sexually reproducing life too. Mitochondria appear to be descendants of bacteria which have major differences in the structure and coding of their DNA from our DNA. But mitochondria have a tiny genome compared to other bacteria with just a few genes that control the assembly and operation of the power plant. The vast majority of proteins needed to enable mitochondria to reproduce, function, be repaired, etc. are supplied by the host cell. This arrangement likely evolved over time as it greatly reduces the material and energy cost of producing mitochondria allowing host cells to harbor greater numbers of mitochondria and have greater amounts of energy. This arrangement while super potent is also somewhat fragile. If something diminishes the host cell's ability to sense and provide for the needs of its mitochondria things can spiral badly out of control. And the mutant protein of the KD gene along with many other factors impacts the quality of our cells' hosting of mitochondria.

Exercise produces several forms of damage. Very heavy loading of a muscle such as slow resistance/weight training and explosive high speed sprint training can produce micro tears in muscle fibers that stimulate growth making fibers bigger and stronger and high output anaerobic efforts stimulate increased anaerobic capacity. Likewise extended aerobic efforts appear to be better for increasing aerobic capacity. Other goals of exercise include flexibility, balance, coordination and stimulation of heart and circulation, lungs, liver, nerves, mind, lymph, etc. So you want to incorporate a great variety of activities and exercise and do your best to sort out the amount and intensity of each that gives you the best results over time.

Although we know a great many details about how mitochondria function, things which sabotage them and things they need to function well, medical testing is currently pretty limited in its ability to diagnose what is going wrong metabolically to guide our choices/dosing of diet, supplements, pharmaceuticals and exercise, etc. Perhaps our best tool to evaluate how we are doing is our exercise performance. If you regularly exercise in a way that you can track aspects of performance, such as peak strength and sustained output - such as speed for a distance of walking, running, biking, etc. you can judge how well you are doing over time. With so many factors affecting performance it is hard to sort out cause and effect. Am I exercising hard enough or long enough or too much? Am I getting enough of the right anti-oxidants or too much, the right amount of protein, etc. Your results can be impacted by things of which you are scarcely aware, a slight cold, a touch of food poisoning, the quality of ones sleep, etc. But it is a learnable skill that we can get better at with effort. Emphasize activities/exercise you can do often with regularity, the more habitual the better, that are measureable/trackable which can provide better feedback to evaluate how well you are doing. The more aware you become of other relevant factors and tracking their changes the better you'll be able to guide your choices in everything you do to manage your condition with KD.

I've been using this approach for a little over two years and yesterday morning set a new personal best walking a mile in 35 minutes. Kind of pathetic compared to most men my age without KD, but previously I could hardly walk 25 feet without falling down. I'm increasingly confident I'll be able to continue making improvements for a long time to come.

BTW, there are potential pitfalls to a vegetarian diet, especially in the context of a muscle wasting disease. It can be done well, but I made the mistake of assuming vegetarianism was inherently more healthy and didn't give the details as much consideration as I should have. It worked well for me for a while and when it stopped working well I doubled down and went vegan but again without sufficient consideration and made my condition worse. Nutrition is a huge, complex and controversial topic which I'm hesitant to dive into deeply, but if you have specific questions I'd be happy to share my opinions or references to things I've found helpful.

This message has been edited. Last edited by: ToddAllen,

Thanks for the responses so far guys, I hope you don’t think I’ve just ignored everyone and not returned - I’ve been checking back regularly but am so busy it’s hard to get a minute to do some typing.

ToddAllen - thanks for the insight. Interestingly I’ve spent most of my working life in histology and, more recently, genetics laboratories. I find that the genetics of KD is itself very interesting, whereas others might see it as a frustrating or even frightening minefield. A minefield it is nonetheless. I’m glad to hear you’re making progress and seeing improvements. I’m curious to know whether you were particularly fitness conscious prior to the onset of your symptoms or whether it was something you chose to focus on more recently? Only if you’re happy divulging this sort of information of course. I’m tracking my running distances and times at the moment but I really want to reintroduce some manageable weight training for the upper body again. As for diet it’s something I monitor to a degree. I know my portion sizes are excessive, primarily because I enjoy cooking and eating food too much. I’ve always ensured that I’m getting a balance of food types, including making sure that I’m getting the suspect protein and B12 from sensible sources. I always assumed that if I missed the occasional amino acid here and there that it wouldn’t make a huge difference, but worked on the assumption that it was only vegans who really needed to stay sharp. My protein sources primarily come from cheese, eggs and nuts. Supplement wise I entirely abandoned multivitamins mainly because I was convinced by the scientific literature that most of them appear to not absorb at all. The exception is omega 3 supplements (vegegetarian) which I take daily. You presumably felt worse off for sticking with vegetarian/vegan diets then?

>> Thanks for the responses so far guys, I hope you don’t think I’ve just ignored everyone and not returned - I’ve been checking back regularly but am so busy it’s hard to get a minute to do some typing.

I'm glad you are still here and my delayed response didn't exceed your patience.

>> ToddAllen - thanks for the insight. Interestingly I’ve spent most of my working life in histology and, more recently, genetics laboratories.

My background is computer science and math and I was a video game programmer professionally. My formal education in biology ended in high school, but the internet is a bottomless pit of information for KD and all things related, some of which makes sense to me and some of that might be correct. I look forward to discussions with you that may help each of us sort it out.

>> I find that the genetics of KD is itself very interesting, whereas others might see it as a frustrating or even frightening minefield. A minefield it is nonetheless.

On the bright side, diseases with simpler pathologies often develop much faster and can be devastating.

The root cause of KD is simple and I expect gene therapy approaches will eventually address it and could be of great value when applied before disease has progressed far. The cascade of things going wrong over time from that simple beginning appears complex and resistant to pharmaceutical monotherapy approaches. Although the scientific method works best looking at a single factor at a time in isolation I hope research will shift to looking at multi-factorial approaches to KD management as many factors influencing disease progression have been identified. I ran out of time waiting for that research and dove in trying a great many things all at once. Despite inadequate tools to evaluate the individual effects of the things I'm trying my results are encouraging and I'm hopeful that ongoing refinements and progress in medical research can hold off my physical decline for much of my remaining years.

>> I’m glad to hear you’re making progress and seeing improvements. I’m curious to know whether you were particularly fitness conscious prior to the onset of your symptoms or whether it was something you chose to focus on more recently? Only if you’re happy divulging this sort of information of course.

I began to suspect I had my grandfather's disease in my early teens. In 8th grade I started running and bought my first set of weights and began lifting. I was guided mostly by fitness magazine articles and progress was slow through high school. When I went to college I got more focused and found friends into weight lifting, running and tennis and made better progress becoming more fit and athletic than most students, but was always weaker and slower than my exercise partners. My first big purchase out of school was gym memberships for my wife and myself at Bally's but only sporadically made good use of it as I often was too focused on work and home. By my early 40s I had mostly given up on exercise other than some bicycling having come to believe I couldn't outrun an "untreatable" neurological condition. But now I think my neuropathies were largely due to my increasing metabolic derangement and research suggests KD is primarily a disease of muscle.

I tried to be health conscious but unfortunately gave it less thought than fitness. I avoided common pitfalls like drinking, smoking and excess caffeine. The most serious substance abuse issue I developed was orange juice although in hindsight it was a bad mistake. And I often did a poor job managing stress and sleep.

> I’m tracking my running distances and times at the moment but I really want to reintroduce some manageable weight training for the upper body again.

If you don't have easy access to weights you might try getting started with a resistance band set with a door anchor. ~$25 and easy to store. I also have free weights but think I could get by with just the resistance bands if I didn't have room for the weights. I also like body weight moves like chin ups, dips, push ups, burpees, etc. I do cheater versions but am making progress towards doing them in normal fashion.

I'm trying to regain the ability to run. Last year I tried too soon and only made it a couple paces before tearing the meniscus in my left knee. Since then I've been jogging in a swimming pool and I've done short slow jogs with my walker. I want to try "sprints" up a short grassy hill in a nearby park which should keep my speed slow and make falls gentle but I'm not yet ready. During my decline I think I focused too much on endurance activity. When I was younger and my gains were best, I focused mostly on strength and speed. I think strength and speed work is vital for me now but it requires more care to avoid injury.

> As for diet it’s something I monitor to a degree. I know my portion sizes are excessive, primarily because I enjoy cooking and eating food too much.

Being chronically overfed like I had become I think is very harmful, even if it is modest and fat gain is slow, as it can block autophagy and I think the anabolic signalling of the overfed condition degrades when constantly activated. I've been cycling modest over feeding and under feeding seeking a balance to the challenges of gaining muscle and losing fat. I hope to achieve a desirable body fat percentage and focus more on muscle but my days of easy fat loss are past and progress is slow. When I've aggressively pushed fat loss with lots of fasting I also lose muscle.

I used to eat a lot more calories than other people of my size and activity level and for a long time without gaining weight. Not sure to what degree that may be related to KD, but I was losing muscle though slowly at first. I've been trying to track body composition for the past couple of years and wish I started sooner. I've found dexa scans helpful as they give a sense of where the fat is. Skinfold calipers can measure subcutaneous fat and a tape measure can guesstimate visceral fat but I've come to think tracking intramuscular fat may be the most important of all. I'd love to do that with MRIs if they weren't ridiculously expensive.

> I’ve always ensured that I’m getting a balance of food types, including making sure that I’m getting the suspect protein and B12 from sensible sources. I always assumed that if I missed the occasional amino acid here and there that it wouldn’t make a huge difference, but worked on the assumption that it was only vegans who really needed to stay sharp. My protein sources primarily come from cheese, eggs and nuts. Supplement wise I entirely abandoned multivitamins mainly because I was convinced by the scientific literature that most of them appear to not absorb at all. The exception is omega 3 supplements (vegegetarian) which I take daily. You presumably felt worse off for sticking with vegetarian/vegan diets then?

At roughly 30 I had high LDL and my doctor prescribed a statin. After reading about them it seemed risky with a muscle wasting disease and instead I went vegetarian which brought my LDL down some for a while. When it went back up going vegan nudged it back down. I also thought it was a good thing to do ecologically and I'm disturbed by industrial ag's animal husbandry practices. Healthwise though I think it was a disaster for me. In large part because I was oblivious to various deficiencies made more likely, especially B12. At the time I held the common misguided belief that LDL was bad cholesterol and didn't know that blindly lowering it might be a bad idea, especially when HDL is dropping and triglycerides are rising which correlates with declining quality of LDL.

After looking into nutritional research of animal based foods I'm fairly convinced that plant based protein is inferior for supporting muscle mass and function, not just in the mix of amino acids but because of valuable things like carnitine, carnosine and creatine in meats. I also supplement those but nutritional supplementation may be inferior to nutritional foods. The vitamins in plants are more often in precursor forms which can have limited availability depending on ones genetics and metabolic health. Phytoestrogens are likely unhelpful for androgen insensitivity/gynecomastia. And high levels of phytates may inhibit digestion of protein and absorbtion of minerals like zinc, calcium and manganese. The evidence of health risks for animal products is weaker than I thought and I suspect most of the risk is due to products from unhealthy animals processed and prepared in unhealthy ways. And I've come to believe that the fats I chose in my fat fearing days, refined vegetable/seed oils, were a big mistake.

I agree with you on the multi-vitamins. It looks to me that for many vitamins and minerals having them in appropriate balances is often more important than absolute amounts. The forms of vitamins and minerals in most multi-vitamins appears to be based on things like cost and shelf stability and if one has impaired processing of any of their forms instead of correcting deficiency one may be aggravating imbalances. Also it looks like chronic high dosing of anti-oxidants such as vitamin C and E can be problematic for muscle and mitochondria. Although it is more work I think it is better to periodically analyze one's diet for micronutrients and when possible choose foods to address deficiencies and use individual supplements on a limited as needed basis.

"The root cause of KD is simple and I expect gene therapy approaches will eventually address it and could be of great value when applied before disease has progressed far."

This is interesting actually as I was chatting to my genetics councilor about this a couple of years ago. There's been this huge initiative in the UK over the last few years called the 100k genome project. It's basically a government backed project working with public and private partners to do a shed ton of sequencing and identify new genetic diseases, among other goals. The results have been positive to an extent in that several very rare diseases have been identified (and probably named) which were previously unknown. My councilor raised a good point however in that he's torn during his consultations sometimes between inspiring hope in his patients by reminding them about "ongoing research" but also being realistic about the priorities of pharma companies and their monetary goals. Indeed, there is sometimes less incentive for public and private bodies to work on stratified solutions to very rare diseases (perhaps ours included) because the instance rate is so low in a population that there may not be much to gain financially from the years of R&D that goes into drugs and general medical intervention. I want to remain optimistic that advances in translational/stratified medicine may yet yield results for us, but I've also got to accept that the overwhelming majority of people have never even heard of KD by name.

"If you don't have easy access to weights you might try getting started with a resistance band set with a door anchor. ~$25 and easy to store. I also have free weights but think I could get by with just the resistance bands if I didn't have room for the weights. I also like body weight moves like chin ups, dips, push ups, burpees, etc."

I have a basic set of dumbell and barbell weights in the garage which can be loaded reasonably heavy. I stick to bread and butter techniques generally (curls, raises etc) but don't have the time for gym membership at the moment sadly.

"After looking into nutritional research of animal based foods I'm fairly convinced that plant based protein is inferior for supporting muscle mass and function, not just in the mix of amino acids but because of valuable things like carnitine, carnosine and creatine in meats. I also supplement those but nutritional supplementation may be inferior to nutritional foods. The vitamins in plants are more often in precursor forms which can have limited availability depending on ones genetics and metabolic health. Phytoestrogens are likely unhelpful for androgen insensitivity/gynecomastia. And high levels of phytates may inhibit digestion of protein and absorbtion of minerals like zinc, calcium and manganese. The evidence of health risks for animal products is weaker than I thought and I suspect most of the risk is due to products from unhealthy animals processed and prepared in unhealthy ways. And I've come to believe that the fats I chose in my fat fearing days, refined vegetable/seed oils, were a big mistake.

I agree with you on the multi-vitamins. It looks to me that for many vitamins and minerals having them in appropriate balances is often more important than absolute amounts. The forms of vitamins and minerals in most multi-vitamins appears to be based on things like cost and shelf stability and if one has impaired processing of any of their forms instead of correcting deficiency one may be aggravating imbalances. Also it looks like chronic high dosing of anti-oxidants such as vitamin C and E can be problematic for muscle and mitochondria. Although it is more work I think it is better to periodically analyze one's diet for micronutrients and when possible choose foods to address deficiencies and use individual supplements on a limited as needed basis."

The problems I mainly associated with meat based diets derive mainly from the growing body of research which focuses on cured meats, particularly of the pig variety. A lot of these seem to stem from the curing process itself rather than anything innately wrong with pig meat. It's hardly unsurprising that ingesting particular quantities of carcinogens can be detrimental to one's health. The last sizable review of evidence I read concurred that absorption from plant based diets, whilst probably sufficient in earlier life may become more problematic later on as a general decrease in absorption capability kicks in with age. I was always reassured and inspired to an extent with the growing popularity of vegetarian and vegan diets among athletes/sportsmen, especially some of the big UFC fighters (and their intense training schedules that I couldn't possibly match ha). The last big meta-analysis I read through seemed to show basically zero effect from general multivitamin supplementation, and worse (and quite bizarrely) a slightly increased risk of skin cancer from prolonged multivitamin intake. I'll have to see if I can find the link for that paper. Of course a lot of people might just say well knock a load of whey protein shake back if I'm worried about not absorbing quite enough protein, however I have my concerns about that - I worked in a large renal center in London for a few years with some top renal consultants in pathology. They were concerned about a slowly developing consensus in the renal world about the pitfalls of prolonged whey protein intake. I think the worry comes from a lot of people using them post-gym workout despite only carrying out minor to moderate exercise. There's real worry in the renal profession that long-term use could be putting huge pressure on some people's renal system as the body struggles with unnecessarily high levels of whey protein. There's also research linking excessive protein to cancer and diabetes, so I've tried not to worry too much about overcompensating. That being said I remain open minded to a degree and I appreciate certain diets will never be popular with everyone. I'll have to be pragmatic going forward but I'm reluctant to make any drastic changes at the moment as I feel genuinely quite well with my food preparation at present. Which supplements do you specifically take out of interest, and in what form?