“Discussions from the Society for Inherited Metabolic Disorders (SIMD) Meeting” -Tony

The Society for Inherited Metabolic Disorders (SIMD) holds a 3-day meeting every year to discuss and share ideas about metabolic disorders. This year, the meeting included a satellite session on Cerebral Creatine Deficiency Syndromes, hosted by the Association for Creatine Deficiencies. Our ACD team was represented by the irrepressible dynamic duo Heidi Wallis and Laura Trutoiu.

I have been fortunate enough to watch (and re-watch several times!) a recording of the meeting. It was a wonderfully riveting 4 hours, complete with fuzzy and distorted audio; a true delight for any insomniac. And yes, we Australians love sarcasm.

There were some interesting conclusions and some good reminders about therapies. A large part of the meeting was about GAMT. Having survived the experience, I have tried to distill a hopefully succinct summary and then provide a discussion of the current thinking presented at that meeting. The meeting also highlighted for me the gaps in medical knowledge and where there is room for exploration.

Once I started writing, I realized this was going to be too long for just one blog, so I’ve divided it up into two parts. This is the first part: a main summary with a review of some of the details as discussed at the meeting. The second part presents my thoughts on what wasn’t discussed and offers some more challenging thoughts and ideas for the future.

My involvement here is as a dad with a 5-year-old daughter with GAMT deficiency. I live in Sydney, Australia and work as a doctor in general practice and orthopedic surgery. I have also lived in Dublin, Ireland, for 3 years working in medical research (laboratory and clinical work). However, when it comes to metabolic disorders, my expertise is very limited – I know more about creatine deficiency syndromes by being a father rather than by being a doctor.  So I watched the conference talks with two hats on: as a dad and as a doctor.

So please, grab yourself some snacks and tighten your seatbelt.

The main summary of the meeting – the stuff you probably already know

A large part of the meeting presented information about the history, underlying biochemistry, diagnosis, clinical presentation, and the standard treatment. That’s a lot of information for one blog and I think much of that information is already out there. Understanding the underlying biochemistry is crucial to all of this but it’s a big topic and best left for another time; I will save that for another blog if people are interested.

Here’s a quick summary of the 4 hours of talking:

  1. AGAT Deficiency

Diagnosis is by finding a low Guanidinoacetate (GAA) and a low Creatine, preferably using blood (ie “plasma” levels). Treat with creatine. Monitor creatine levels and use MRS to show an increase in brain creatine levels after about 1 year. Check urine for creatine crystals, which indicate the dose of creatine might be too high.

  1. GAMT Deficiency

Diagnosis is by finding a high GAA and a low Creatine, again preferably using blood plasma levels. Treat with creatine, ornithine, possibly sodium benzoate, and possibly diet. This therapy is increased stepwise over time to achieve the desired results. The value of diet restriction remains an issue, although there was consensus to at least limit total protein intake. Creatine alone can reduce GAA levels by about 50%, but you really need to give ornithine to get the GAA levels down to safe levels. Aim to get the plasma GAA level below 5.0 micromol/L. The earlier you start treatment, the better the outcomes, especially if started from birth. This is a good treatment, but still not perfect, especially when children can refuse their treatment. It could be better, such as if there were a drug to inhibit AGAT (and hence reduce GAA synthesis).

  1. Creatine Transporter Deficiency

Diagnosis is suggested by a high urine creatine/creatinine ratio. MRS and testing creatine uptake in fibroblasts confirms the diagnosis. There is wide variation in the severity of disease and most affected patients are male. In some patients, possibly those with a milder variant, supplementing with arginine and creatine might give improvement. MRS might help evaluate a response to therapy but this depends on the equipment being available and having good analytic systems in place to quantify the creatine levels on the scan. There is a lot of uncertainty regarding treatment and some will also add glycine. There are inconsistencies in the study results – it is not clear if any treatments are helpful or not. If we had a more reliable and precise way of detecting creatine increase in the brain, this would be a helpful addition to guide therapy.

So there you go. Not much new in the scheme of things really. It confirmed that the current approaches seem to be the best.

Treatment Variables and Controversies – the stuff we aren’t sure about

The SIMD meeting explored some topics in more detail. In particular, the Q&A segments at the end of each talk seemed to provide more of the nitty-gritty stuff. 

  1. AGAT deficiency:

What dose of creatine should you use? Creatine supplementation is the only treatment on offer and is effective, but the best dose to use remains unclear. Should it be 100, 200, 400 or even 800mg/kg/day? Treatment using creatine as high as 800mg/kg/day has been used, but patients have developed crystals in their urine, so the maximum dose is probably closer to 600mg/kg/day.

Does SAMe build up in these patients and then cause new problems? There have been concerns raised that there might be a build-up of S-Adenosyl-L-Methionine (SAMe) in AGAT patients. This is because about 40% of the body’s SAMe is used to make creatine (the GAMT enzyme combines SAMe with GAA to make creatine). Since AGAT patients don’t make GAA, does that then cause SAMe levels to build up and cause problems? The answer appears to be “no”.

  1. GAMT deficiency:

How much creatine should you use? Dr. Schulze suggests using creatine 400-800mg/kg/day. Not really explored beyond that. See the section above on AGAT deficiency for a discussion on creatine dosages.

Which form of creatine should you use? Not really explored. During the Q&A section, Dr. Schulze said that most creatine products you can buy over the counter are good, having 98-99% purity. He suggests using creatine monohydrate. He said there are some “more expensive products that have less creatine, although they pretend to be more efficient” with “not a single line of evidence for that”. 

How long do you need to be on treatment before brain creatine levels reach normal levels? In AGAT patients, it takes about 1 year and they commonly get to about 60-80% normal creatine levels. In GAMT, it is slower because GAA competes with the creatine at the blood-brain barrier. Lowering GAA levels speeds up and improves the brain’s uptake of creatine.

What is the best total daily ornithine dose? It depends because there are two theories on how to reduce GAA:

(1)  If you are not doing diet restriction, then you are using ornithine to inhibit the AGAT enzyme from making GAA. The blood ornithine level needs to be over 250micromol/L to inhibit AGAT.  In this case, you must use “High Dose” ornithine, which is 800mg/kg/day for children (because their brain is still developing and is more vulnerable to GAA) and 400mg/kg/day for adults. Ornithine levels in the brain are about 10% of the blood levels. We don’t know if the level of ornithine in the brain gets high enough to inhibit the formation of GAA in the brain.

(2)  If you restrict arginine in the diet, then you are reducing GAA by limiting the arginine available to AGAT. Hence, a “Low Dose” ornithine (as low as 100mg/kg/day) might be used. This low dose of ornithine is given not so much to inhibit AGAT but rather because you need to supplement the urea cycle (because arginine is being restricted).

These are both just hypotheses. A recent study suggests that diet and high-dose ornithine both work and that doing both together might be slightly more effective at lowering GAA levels.

 

What form of ornithine should you use? Start with L-ornithine HCl and escalate the dose until you achieve the desired GAA level. If you use very high doses (800mg/kg/day), then there is a risk of metabolic acidosis and so consider changing to L-ornithine L-aspartate (LOLA). The actual amount of powder you measure out for each dose will vary according to the type of ornithine used. You need to take the molecular weight into account. A simple guide: to give a dose of 4g of ornithine, you need to give 5g of L-Ornithine Hydrochloride (Ornithine HCl) or 8g of L-Ornithine L-Aspartate (LOLA).

How often should you give ornithine? Frequently. It is rapidly cleared by the body to give it 3-6 times a day. Dr. Schulze said that the half-life of ornithine is about 1 hour and that a dose of ornithine lasts about 3 hours in the body.

The “half-life” refers to the time it takes for the blood level to reduce to half. For example, if a drug has a half-life of 1 hour, and if the blood level of that drug is 400 at 3 pm, then it will be half that an hour later (ie 200 at 4pm) and then half that again during the hour after that (ie 100 at 5pm) and so on. In other words, the blood level halves during each half-life time period. I searched for data on this for ornithine and I would love to see more data if anyone has some. This is important because the shorter the half-life, the more frequent the dosing needs to be.

The published data I found suggest ornithine lasts longer than 3 hours. One study (Pharmacokinetics and bioavailability study of L-ornithine-L-aspartate in healthy volunteers – a comparative study of two oral formulations. Kowalski et al., J Pharm Biomed Anal. 2006 Jun 7;41(3):1061-4) found the half-life to be about 4 hours in healthy volunteers. Another paper (Pharmacokinetic and Pharmacodynamic Properties of l-Ornithine l-Aspartate (LOLA) in Hepatic Encephalopathy, Kircheis et al., Drugs. 2019; 79(Suppl 1): 23–29) found the half-life to be 2 to 2.5 hours in healthy volunteers. They found a dose of ornithine takes about 30 minutes to be absorbed and reach its peak level, it then gradually drops away and returns back to baseline (untreated) levels after about 7 hours. So overnight, ornithine levels will drop and return to untreated levels. (P.S. This study also looked for toxicity in animals and showed that even very high doses appear very safe.)

What is the role of diet? First and foremost: diet alone does not work. You have to give ornithine.  The debate is really about how useful is it to restrict diet when treating GAMT deficiency. Dr. Schulze said that metabolic specialists always think about diet when treating metabolic disorders. A strict diet would be to limit arginine to 15-25mg/kg/day, which is about the same as a protein restriction of 400-700mg/kg/day of protein.

Schulze: diet has value for some patients but not all. It is easier to introduce a bit of the restricted diet from the beginning and maintain that, rather than introduce it later on if the patient is not improving. If all goes well, then discontinue, rather than the other way around.

Longo: not a big fan of restrictive diets; impractical, unattractive. 

Both agree patients should avoid excessive protein intake, but that was about it.

What other medications reduce GAA? Only briefly explored. It is suggested one can try sodium benzoate 100 – 250mg/kg/day. Some research has shown it does not change the GAA level, but there is evidence it may help clinically. Research by Dr. Longo shows a relationship between glycine levels and GAA, so he seems more positive about its benefits. There are no data for supplementing with SAMe.

How low should the GAA level be? Treatment success is a blood GAA level below 5micromol/L. Levels as low as 2 or 3 have been achieved, but how much better this is compared to a level of 5 is unclear. Clinical signs are a better guide than blood levels. Dr. Schulze noted that when he is consulted about patients who are not doing so well, he always finds the GAA level is above 5, never 2 or 3. If there are clinical symptoms and the GAA is higher than 5, then be more aggressive such as add additional treatments or increase dosages if possible or try a stricter diet.

Is the injured brain more sensitive to GAA? Probably not, but we don’t really know. The differentiating brain is extremely vulnerable to creatine depletion and high GAA toxicity. After that, the main problem of a high GAA relates to seizure disorder/epilepsy. As a comparison, Dr. Schulze mentioned another metabolic disorder, Arginase deficiency, where patients all have higher GAA levels (4 or 5 or so) but usually don’t have seizures (a few do, but not most).

Do blood levels of GAA accurately reflect the brain levels of GAA? This was a good point made by Dr. Schulze (I discuss this more in Part 3 of the blog). The two appear to correlate well, so monitoring blood GAA can act as a guide to what is happening in the brain. But there is no standard formula for this. Doctors need to also let the clinical picture guide them.

What is the safe level of GAA in the brain? We don’t know. With maximum treatment, brain (CSF) levels of GAA get at low as 1.0- 1.5 micromol/L, but this is still about 10 times higher than normal.

Can brain GAA levels be measured using MR Spectroscopy? No, the peak is too small. (The audio was very distorted and fuzzy at this point so I might be wrong here.)

What is the best timing for blood tests? Not discussed. When a dose of ornithine is given, it takes 30-60 minutes to be absorbed. Then it will take further time to affect AGAT and reduce GAA. So the timing of blood tests will affect the level of GAA measured. This makes research and decisions on treatment more complicated.

Is there an age or time when therapy can be discontinued, or when there is nothing to gain from treatment? No. Even if one has significant impairments, one should always start treating in GAMT.

How good is using urine to screen for GAMT compared to blood? A newborn baby screened by urine was missed after the newborn bloodspot had screened high for GAA. After the neonatal period, urine is still an excellent and cheap screening test (ie about 1-month-old), when it appears to be close to 100% accurate at picking up GAMT. 

  1. Creatine Transporter Deficiency (CTD)

How do we diagnose CTD? The diagnostic workup is:

Urine creatine/creatinine ratio: increased (quite a few false positives)

MRS: absent creatine peak (best tested using a short echo time)

Fibroblast creatine uptake test: decreased or no uptake of creatine

Where is the creatine transporter normally located? Where is it important? The creatine transporter (called “SLC6A8” – such an easy name to remember) is present throughout the body. It is present in muscle, brain, skin cells, heart cells, intestines, kidneys, and the eye (retina). Interestingly, muscles, heart, and retina appear unaffected. Oral creatine supplementation does elevate blood creatine levels, which suggests gut transport also seems unaffected.

The transporter is important in the kidneys to reabsorb any creatine that has been filtered out of the bloodstream. This, unfortunately, is affected in CTD and is why people with CTD have unusually high levels of creatine in their urine (which forms a basis for the initial urine diagnosis). 

The main deficiency of creatine transportation appears to be in the brain. Most of the transporter is expressed at the BBB (Blood Brain Barrier), the BCSFB (Brain Cerebro-Spinal Fluid Barrier) and on neurons. Some neurons express the transporter much more than others, but the reason for this is unclear. This is why CTD presents an extraordinarily difficult problem – there are several layers for the creatine molecule to pass through to get inside brain cells and it needs a transporter to get through each of those layers, while at the same time the kidneys are leaking it out at a higher-than-normal rate.

What is the current standard for treating CTD? The following treatment appears safe:

  1. Increase blood creatine levels and hence try and push creatine into the brain

Creatine 200 – 400mg/kg/day

  1. Increase creatine production within each cell by supplying the ingredients

Arginine 200 – 450mg/kg/day

Glycine 150 – 200mg/kg/day

 

How do we assess if the treatment is working? This is very hard to do, especially when any improvements are small. Placebo effects are very potent and affect our interpretation of what is happening. “Placebo effects” are where improvements are seen simply because people are given treatment rather than because the treatment is effective. For example, studies of epilepsy drugs show that patients treated with empty pills (the control group) can still improve during trials simply because they believe they are being given treatment. One could do cognitive and behavioral testing, but these are not easy to do reliably, precisely, and reproducibly.

The main discussion at the conference centered on using magnetic resonance spectroscopy (MRS) to quantify the amount of creatine in the brain; this can then give an objective measure of any improvement in brain creatine levels. But the precision of MRS was questioned. MRS was developed to detect the presence of chemicals like creatine in the brain, not to measure the amount. It is not precise enough to differentiate a small rise in brain creatine, such as from say 15% to 20%.

If you choose to treat CTD, you need to have a standard quantitative MRS protocol to compare creatine levels before and after therapy. Clinical progress is slow and you need to wait at least 1 year to notice clinical improvements to see if the treatment is working. The functional deficit, eg a lack of synapses between different neurons, even if repaired, takes a long time to translate into clinical improvement. Quantitative MRS appears to be the best option early on for detecting if therapy is producing a benefit, but it’s too imprecise to show small improvements.

 

Does the treatment work? Hard to know because we don’t have an easy, reliable, reproducible way to measure any improvements. The speaker here was very pessimistic and said the evidence that treatment works is unconvincing and stopping all supplements is an acceptable option too. Arginine has many, many functions and interactions in the body and he felt it may be naïve to expect that increasing arginine will have an effect on creatine levels. But giving creatine and arginine appears reasonable.

Clinically, milder cases seem to respond better to treatment. One patient was discussed (“patient 8”) who did show some residual creatine transporter activity when his/her fibroblasts were tested. This patient seemed to improve developmentally and had fewer seizures after treatment was started, but brain MRS was unable to show a rise in brain creatine levels. This may just be a failing of MRS due to its low precision. If treatment does work, the increase in brain creatine may be too small to show up on the MRS, yet it might still be enough to have a clinical benefit. It may be best to go by the clinical appearance for each child individually.

 

What about the role of mTORC1? This was mentioned briefly and is an area I am unfamiliar with, so I’m not sure if what I’m saying is completely correct. All cells must check that they have adequate energy, nutrients, etc. before starting protein and enzyme production. mTORC1 is a special protein complex found in cells which monitors a cell’s level of nutrients and energy. If the conditions are right, mTORC1 activates the cell to produce whatever proteins and enzymes it needs to function properly. If a cell has insufficient energy levels, mTORC1 can be suppressed. Studies show that mTORC1 activity is suppressed in CTD (and AGAT) models. Arginine is known to stimulate mTORC1 activity and so arginine may indeed be beneficial as a treatment.

 

What about other forms of creatine to by-pass the missing transporter? There is nothing ready for clinical use but it is being researched and some forms look promising. Creatine gluconate doesn’t look promising.

Anything else? Are there other transporters? Why are some organs less affected (e.g. heart muscle) and can we learn from this to improve brain transport? Is there a different transporter that moves creatine out of cells and if so, can we block it so creatine levels in the cell can rise higher? There is a lot of the basic science still missing.

 

Thank you to Anthony Tedesco for your time and efforts in summarizing this meeting so well. As always, the ACD advises that patients and caregivers never make changes to their supplements, diet, or treatment in any way without consulting with their treating physician first. This blog post is intended to share the author’s views on a discussion. It is not meant to be used as medical advice. If this post raises questions about your currently prescribed treatment, we recommend that you discuss these questions with your doctor and do not make any changes on your own.

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