We had a little black cat named Nemo whom we rescued from a sunken window well. He had an umbilical hernia and could not jump out of the window well. His mother may have left him there or he fell in, but he was not going to survive. We rescued him and brought him to the vet. He was too young (6 weeks) and weak to have the hernia fixed, so we took him home and nursed him for a while. An older male cat named T-bone fell in love with Nemo almost immediately. T-bone would clean Nemo and sleep with him as well as share food. T-bone was not jealous or mean with Nemo at all and as Nemo got stronger they would play and sleep together. They became best buds.

We loved telling people about “finding Nemo” in the window well and T-bone finding Nemo as a new best friend.

At about 3 months of age we took Nemo to the vet to be spayed and have the hernia fixed. We called the procedure a “nip and tuck.” The surgery went well, but Nemo did not do well with the anesthesia and he came home very lethargic. Again T-bone became a nursemaid to Nemo; grooming and almost guarding Nemo. Eventually Nemo got better and because we feel T-bone insisted, we adopted Nemo. https://www.facebook.com/media/set/?set=a.1035843128646.2006528.1002500072&saved#!/photo.php?fbid=1056939416040&set=a.1035843128646.2006528.1002500072&type=1&theater

T-bone and Nemo were a wonderful pair of cats. Nemo grew to be much bigger than T-bone, but T-bone was still the big brother – and a wonderful big brother to Nemo. They would run and play all the time. T-bone being very gentle and Nemo being the rambunctious little boy. Sometimes while roughhousing the bigger Nemo might cause T-bone to cry but T-bone never made Nemo cry. They were so sweet.

About 2 years ago, T-bone got sick and was put on chemo therapy. This made T-bone very listless and his little buddy Nemo seemed to know and it was now his turn to be the nursemaid. Nemo was grooming and guarding T-bone. Nemo also seemed to know to not play or roughhouse. They could read each other so well. As T-bone got better Nemo reverted back to the little brother and that was great therapy for T-bone as well. After recovering, all was good for Nemo and T-bone.

About 4 months ago, Nemo had an unexplained fever and weight loss. T-bone was back to the role of nursemaid for Nemo. We took Nemo to multiple vets. He was very sick with an unknown autoimmune disorder causing fever, weight loss and severe anemia. It seemed his body was attacking his own blood cells. The vets put him on numerous antibiotics, chemotherapy agents, and immune agents (cyclosporine). Nemo continued to lose weight. He had transfusions, IVs, and lots of trips to the vet. Through all this T-bone was wonderful. With the overnight stay at the vet, we thought it might even help to have T-bone stay with Nemo, but the vet would not allow that.

We gave Nemo IVs at home and various injections and medications. When Nemo had the strength to eat T-bone, a chow hound, would never try to steal Nemo’s food. When Nemo would not eat, we had to coax food in him.

Every visit to the vet brought bad news with worse anemia (10%) and weight loss (losing half his body weight). After returning from every vet appointment T-bone would greet and groom Nemo. The vets often commented how good Nemo’s appearance and coat was for such a sick kitty. We told them about T-bone being Nemo’s nurse and groomsman and they would just smile and nod.

After nearly 4 months of bad news we got our first bit of good news. Nemo had gained one ounce. It was not much but is was the first time he had shown any improvement. It was a great moment. That was on a Monday morning. We told all our friends the happy news of a one ounce weight gain. After coming home that Monday evening we found Nemo hiding under the couch unable to move his right side. Nemo had had a stroke. We called the vet and did what we could do for him. But Nemo was not going to recover. We made the decision to take Nemo to the vet and have him put to sleep. We literally told T-bone how sick Nemo was and that he was not coming back from this vet trip. I firmly believe T-bone understood.

In a very gentle and touching display of affection, T-bone started grooming and cuddling with Nemo. It was like he was saying goodbye to his little brother and best friend. https://www.facebook.com/media/set/?set=a.1035843128646.2006528.1002500072&saved#!/photo.php?fbid=2170723019934&set=a.1035843128646.2006528.1002500072&type=1&theater

A short time later Nemo left this world with his human mom and dad holding him. His eyes were bright and his fur shiny from the attention T-bone gave him. He is missed very much by all and especially T-bone.

This one stop shop concept for the diagnosis of the creatine deficiency syndromes will save time and angst for the doctor, patient and caregiver and is especially important as these diseases, when treatable, require early treatment to achieve optimal benefits. There are many anecdotal stories of families who have identified a deficit with their child at an early age but take years for a diagnosis. The late diagnosis often leads delay in treatment and can result in prolonged deficits in the patients. Time is brain for many of these patients and our new system will save time.

We are happy about the launch of our new diagnostic technology. Please spread the word to patients, doctors and advocates so that we can diagnose these patients early and effectively. Check out our facebook group https://www.facebook.com/#!/groups/127389967322193?ap=1 for future updates and more discussions on the creatine deficiency syndromes. Watch this space as well to see what we will be rolling out as we continue to work to help caregivers and patients with creatine deficiency syndromes.   

Questions about the test can be sent here: moleculargenetics@cchmc.org, Questions about creatine deficiency syndrome research in Cincinnati can be sent to Dr. Clark, joseph.clark@uc.edu.

*Please note, I am not a representative of the University of Cincinnati and/or Cincinnati Children’s Hospital Medical Center, but want to make everyone aware of what these outstanding institutions are doing.

There is a local research project being worked on to pre-treat US service members in hopes of decreasing post traumatic stress disorder (PTSD). I’m aware of it but not involved. Anyway, there are people who are against the research because, in their words; “the soldiers should feel bad for what they are doing.” WHAT? The lesson I learned here is that the depths of human ignorance knows no bounds.

Let me continue to explain because it boggles my mind that people are so misinformed. PTSD is post traumatic stress disorder. People who suffer from it are seriously adversely affected by traumatic events. An important difference between being stressed by something and having PTSD is with PTSD a person re-lives those traumatic events. They can have nightmares, day terrors, flash backs etc. So the trauma continues to occur. IT IS NOT GUILT. In world war I soldiers who came back from the front were diagnosed with “shell shock” often caused by the constant shelling. They had what we now call PTSD, but might never have seen action, so there is nothing for them to feel guilty about. Nonetheless they were incapacitated by the events in WWI. The last surviving WWI shell shock victim died in the late 1990s, never recovering. I believe that the people who are working on ways to prevent PTSD are doing a great job and if we can prepare our service members so that they can come back and enter society as opposed to entering institutions that will be a big win for society. My continued concern is that there are people out there who think our soldiers have something to feel guilty for.

A colleague of mine, who was a highly experienced and successful scientist, made a comment to me that on average it takes ten years for a new discovery to be generally adopted by the scientific community. At the time, it seemed inconceivable to me that scientists who are often striving to do groundbreaking work that forms the foundation of the next generation of discoveries will be “accused” of taking ten years to adopt a new technology, but that is what he said and he was not wrong. He went on to say that discoveries need to be tested by others and validated and that process takes time.

Everyone knows that Aspirin would never be approved as a drug today because of all the complications, side effects and “unclear” actions that it has. Consider Fleming who discovered Penicillin in 1928 and it was not until world war II when it was widely used. The first patient who received it was a former police officer (bobby) who was described as waking from the dead after receiving penicillin. The officer eventually died because we needed to learn that antibiotics need a course of the drug to ensure that bacteria are gone. Today it would take 17 years before it would be adopted by the FDA as a drug, if it could ever be approved, because of all the side effects and allergic reactions to it. Think about that for a minute, a drug that spawned an industry of antibiotics would likely be rejected as a therapy today. It should make one ask if there are other equally ground breaking discoveries that go unnoticed.

I used to think that getting noticed by other scientists was a matter of getting the big discovery and waiting for the accolades to come. It appears that as long as you are willing to wait ten years, that plan works. I’ve got two personal stories to relate on that subject.

Story 1. In 2000 I published an article that summarized the discovery of bilirubin oxidation products (http://www.ncbi.nlm.nih.gov/pubmed/11106420). We called these molecules BOXes because of what they were: Bilirubin OXidation products. There is a double entendre there in that the BOXes were also discovered when I worked in the department of Biochemistry OXford University. So BOXes means bilirubin oxidation products and Biochemistry Oxford.

I worked on and studied BOXes for several years before the first publication and continued studying them since then. To date, I was pretty much the only person who published on them. I’m sure you can do the math and it has been 11 years since they were “discovered” and made public. So has the scientific community “Noticed” BOXes? The answer is yes. There was recently a conference on Heme, heme degradation products that focused on BOXes. This is because bilirubin comes from heme.

I was an invited speaker at the conference and the session chair and conference organizer introduced me as a keynote lecturer and as “the father and founder” of this field. I have to admit I was a little shocked and very humbled by his introduction. But, I’m also proud and yes I’m showing off, but there you are. My discovery of 11 years ago has been adopted, validated and accepted by the broader scientific community. I did like I had said above in that I reported my discovery, continued building on the technology in subsequent years and waited for someone to notice. So that is a nice story. It is all well and good, but what if there is a discovery that needs to be adopted faster because it is really very important? That is the subject for story 2.

Story 2. In this story everything is brand new so the discovery has not been published yet. Remember with BOXes I worked years before the first publication. Now, I have a discovery that is extremely important. Indeed, it is so important that I cannot and should not wait ten years for it to get noticed. The discovery is that I can treat people with a disease. I firmly believe, however, that I will need to play a much more active role in getting the broader scientific community to adopt this technology and this treatment so the patients with the disease can be treated. But how?

I have not been trained in being a self-promoter nor do I have a publicist to get the word out there. I’m not trained in the methods for getting drugs approved by the FDA. With 9 years of college and 20 years of science experience, I need a whole new education. Obviously, I need help doing this, but I have a lot to learn and a lot to do. It is a great opportunity, and as a scientist who went into this field to “help people” (http://www.amazon.com/My-Ambulance-Education-Death-Streets/dp/1554074479/ref=sr_1_1?ie=UTF8&s=books&qid=1308100497&sr=8-1) this could be the most significant contribution to humanity I might ever make. So, I don’t want to screw it up. It is worth repeating: “I really do not want to mess up this opportunity.”

My unanswered question is: How does one accelerate the mind opening experiences of the broader scientific community? Every day delayed is another patient treatment opportunity lost. I can’t waste time. I know I need to publish it and I know I need to advocate for this new treatment, but the plan for the subsequent steps needs to make this go faster than the normal ten year cycle.

Holy cow it is amazing how medicine and research is a popularity contest. I went to the National Athletic Trainers Association Meeting recently and did what I love to do. I trolled through the exhibit hall looking for interesting and ridiculous technologies. This year did not disappoint.

I counted something like 25 exhibits with concussion in their banners and advertisements somewhere. I was looking for concussion and mild traumatic brain injury technologies because I work as a technology scout for the Point of care Center for Emerging Neuro Technologies in Cincinnati. Some exhibitor claims were marginally legitimate and some were scare mongering. I tried to go up to every booth that was talking concussion and speak with the vendors to see what they were trying to sell to the athletic trainers and it was often pretty dismal. I’ve written about this conference before (http://www.josephfclark.com/blog/?p=129) so I’m not opposed to telling about how companies tout snake oils to the nation’s athletes. Remember these athletes are often kids on school teams and club sports so I’m talking about children here.

I’ve been doing research into injury of the brain and bleeding in the brain for nearly 20 years and I know there is a lot we do not know. But with a tiny amount of misinformation the people flogging all sorts of things claiming to be the best product for treating concussion. So here I’m going to present my impressions on what I think of a few vendors. I can’t review them all due to space constraints, so I’ll chose a couple of good ones and a couple of bad ones.

Lets start with the bad and ugly. Gladiator Mouth Guards make custom mouth guards. They are good mouth guards for protecting teeth, but the person I spoke with was one the slimiest sales persons I met at the conference. In bold headlines their banner said 1.6 million concussions in the USA. There are 1.5 to 1.7 million traumatic brain injuries in the USA (http://www.cdc.gov/TraumaticBrainInjury). Where does their 1.6 million number come from? After stopping by that booth, I wanted to go back to my room to shower off the slime due to listening to inflated claims of the mouth guards protecting against concussion. First and foremost there are numerous peer reviewed papers that say that mouth guards do NOT prevent concussion (http://www.ncbi.nlm.nih.gov/pubmed/19433427, http://www.chicagotribune.com/health/ct-met-concussion-sidebar-20110625,0,3241267.story.). There are a couple that suggested that mouth guards might lessen concussion, but those have not been substantiated (http://www.ncbi.nlm.nih.gov/pubmed/21228647). Gladiator claims their mouth guards prevent concussion. The sales person tried to snow me with information concerning thickness of the guard, the thickness decreases temporal mandibular joint injury (TMJ) and he kept saying TMJ is concussion. By the way, TMJ is not concussion. Later he redefined concussion as a bruise in the brain – we do not know what a concussion is, so I was amused that a high school graduate trained in molding mouth guards was defining it for me. Next he showed me data that mouth guard thickness dissipates energy. That is true, it dissipates energy to the teeth, not the brain. He rattled off three “published” references to support his claims, which I have since looked up and they do not exist. Gladiator has no data to substantiate their claims and it made me sick. Their mouth guards do not prevent concussion. However, do feel free to use their product to prevent lost teeth, but do not believe them concerning concussion. Before using their product do wash it thoroughly because the whole company seems slimy.

Did you see the balance testing technologies in the exhibits? Those are interesting and may be important, but do you need to be a balance expert to use them? What if you want to do more than balance to assess a concussion? Is it good for pull from play as well as return to play decisions, meaning can you get their little board on the field? They recommend a couple of tests that are scientifically sound that do assess balance and the vestibular system. So you get some solid information from that technology.  If you choose to use their product have someone who knows what the data means and have some standard tests you’re comfortable with. Also, please use more than one test to assess concussion.

All I want to say about ImPACT is if you use it, use something else to compliment it. Players are getting good at gaming the test at baseline and practicing it for their return to play evaluations.

Dynavision. I saw this at the NATA in 2010 and fell in love with it. This year they had a booth and the Gatorade booth had two of their products as a competition. We, in Cincinnati adopted it for our concussion management program and I programmed it to do some tests that I liked. Their off the shelf programs are solid and the platform is flexible enough to be able to assess multiple brain functions. So if you think it just does visual motor, you are wrong. It can assess memory, cognitive function, executive function and even computational competency. I’m not sure if they have a concussion panel of software tests with their devices, but we made a panel to be used with our players in Cincinnati such that they got baseline on the Dynavision and additional testing protocols when a concussion was suspected, so they could not throw the test. Concussion testing for us in the University of Cincinnati takes 5 minutes on the Dynavision. By the way, the University of Cincinnati legal office wants me to remind you that I do not represent the University, and cannot speak for the University, I just work here and have to say that so I can keep my job.

There was an unassuming guy sitting alone at a booth with an iphone app for parents and coaches to do concussion assessment on kids. It was a simple question and answer session on the $4.00 app that can be administered by a lay person with a scoring system that gives recommendations as to what the concussion risk for an athlete is. It was simple by nature but better than having a panicked parent calling me to ask what I think. I’m going to get the app and have a closer look, but they did not over sell it and were not trying to scare people into buying it. While nothing is decided, the Point of Care Center for Emerging Neuro Technologies, a Center funded by the NIH (http://www.ece.uc.edu/POC-CENT/) may evaluate the app and endorse it or help improve it. Every ATC and student trainer should be well beyond needing and using this, but you may want to look at it and recommend to parents or coaches so that if a parent calls you and says; “I have an I phone app concussion score of 27 what should I do?” You’ll know what they are talking about.

There was a booth that advertised, “become a concussion center” on the front of it. As I have mentioned before I’m part of an NIH funded neuro center, so I was interested to see how they were proposing to have organizations become a concussion center. This was a for-profit organization called Concussion Health that would train people on concussion management. Training is well and good, but how does that make a center? I’m not sure where I stand with this organization yet. I scheduled a meeting with one of their people but missed the appointment on Wednesday morning, I was late. When I went to their booth Wednesday morning it was taken down and no one was there. So they were only at the show Monday and Tuesday. But if a-for profit company claims their training will make your organization a recognized concussion center, ask the question, “recognized by whom?” and run a way. If you want to learn concussion management they may have some information to help you but be careful of over inflated claims.

Did you see the booth where a guy was wearing a football helmet and was saying DHA was good for treating concussion? They were touting one study with brain injured rats that DHA was good for the rat brain (http://www.ncbi.nlm.nih.gov/pubmed?term=tbi%20dha%20bailes). The study was done by the same guy who said that creatine supplementation caused heat stroke (http://www.ncbi.nlm.nih.gov/pubmed?term=creatine%20bailes%20heat%20stroke), which was heavily refuted (http://www.ncbi.nlm.nih.gov/pubmed/12532918). I think I’ll leave it at that.

So if like me you left the NATA conference more confused about concussion then when you arrived, I understand. If you left thinking you learned a lot, good for you, but was the information correct? Did you see scientific evidence or did you hear inflated scare mongering claims of science from slimy vendors? Was their science reviewed by peers to validate it and published in reputable journals? There was a lot of junk science packed in colorful marketing schemes with the goal of separating your training room from its money.

CONCUSSION, CONCUSSION, CONCUSSION;

but that is not the only thing that impacts the brain in athletes.

Today’s article is co-authored by Dr. J.F. Clark, Professor of Neurology and Dr. O. Choutka, Chief Neurosurgery Resident, University of Cincinnati.

Mild traumatic brain injury, and concussion, is high in the public consciousness right now because of several articles concerning high profile athletes being found to have chronic traumatic encephalopathy or CTE. The CTE is generally diagnosed after these people have died and has largely and exclusively been attributed to their playing of sports and having diagnosed or undiagnosed concussions. Here is a discussion of CTE, first “discovered” in football players in 2002 http://www.youtube.com/watch?v=QpT3abxkDao. The first 1 min 40 seconds is a tribute to the Late Senator Byrd.

 They speculate that 20% of boxers might get CTE based on pugilistic dementia numbers, but 9 out of 9 football players studied had CTE. It appears that modern athletes who are prone to taking anabolic steroids and getting shots to the head are more prone to CTE.

 Lets discuss the general aspects of CTE. The observation of CTE tends to be made when an athlete has personality changes, aggressive behavior, attention issues, and inability to focus on a job or task. After a person suspected to have CTE dies the final diagnosis is made by examining the brain for plaques and protein changes in the brain. Therefore, CTE can only be diagnosed after death. These personality changes are also seen with anabolic steroid abuse.

 Note at 20 min 20 seconds they dismiss anabolic steroids. Anabolic steroids alone are not known to cause that type of pathology. That is clearly stated and not refuted. However, there is information concerning brain protein pathology with steroid use: http://www.ncbi.nlm.nih.gov/pubmed/11876781.

 Lets first be clear that the evidence that anabolic steroids ALONE cause CTE is not at issue here. Anabolic steroids are a nuclear receptor mediated signaling agent that amplifies nuclear signals. Athletes who take anabolic steroids see no muscle growth benefits if they are not working out. But if they combine steroid abuse and vigorous exercise many metabolic signals involving muscle growth are amplified. More protein is synthesized and the muscles get larger and stronger.

 There is a component of “damage” that occurs to muscle with many types of exercise. Eccentric exercise causes muscles to leak enzymes such as lactate dehydrogenase and creatine kinase and these are known to be elevated post exercise. These muscles respond with extra protein being set down inside and outside the muscle cells. Anabolic steroids for muscle are purported to accelerate healing – but as many say – at what cost. Notwithstanding there is a preponderance of literature that supports the thesis that anabolic steroids are more active with injury.

 The brain is not muscle. But the brain’s nucleus has steroid receptors and the brain can be injured. Some of the things that occur with CTE is that the cell’s have extra protein, tau protein, around them. There is a build up of extracellular protein and that there are plaques in and around brain tissues. This is distinctly different than what happens in muscle, but can be associated with signals coming from the nucleus. Remember muscle is not the brain, so different responses to steroids are expected.

 Synthesis of circumstantial evidence.

CTE may have been seen in 1 in 5 boxers many years ago – before the disease had it’s new name.

A majority of modern athletes tested in the anabolic steroid era have CTE.

Anabolic steroids alone with no injury or stimuli have fewer effects on bodies muscle etc.

It is not known if anabolic steroids in conjunction with concussion or mTBI may lead to increased incidence of CTE.

 We believe that the increased awareness on concussion and mTBI is laudable and important public health issue. But we also want to call attention to concomitant illicit and legitimate compounds that may be contributing to some of the data that is making national news. Avoiding steroid abuse may abrogate some of the  incidence of CTE.

I was curious to find an informational aspect to the website on the Mayo Clinic site. So I poked around it for a while and was disappointed. It was not so much that it lacked depth enough, because it was very incomplete. Or that it catered to non technical people, which is fine, but importantly it was down right wrong. So wrong on some points that I emailed them to point out their errors.

Their site incorrectly stated that creatine was synonymous with beta guanidinopropionic acid (GPA). I have previously blogged that nutritional supplements that contain GPA should not be taken (http://www.josephfclark.com/blog/?p=129) and tried to advise the Mayo Clinic of this. My email conversation with the information people at May is reproduced below without their permission. 

=-=-=-=-=-=-=-=-=-=-=-=-=

From: JOSEPH.CLARK@UC.EDU

Sent: Friday, April 15, 2011 9:30 PM

To: info@mayo.edu

Subject: http://www.mayoclinic.com/health/creatine/NS_patient-creatine/DSECTION=synonyms

Question or Comment: Beta-GPA is not creatine. You list several molecules here that are not creatine. Plus the info page says that creatine is stored in the muscle. That is not true it is used in muscle, not stored. There are multiple factual problems with the write up on creatine.

=-=-=-=-=-=-=-=-=-=-=-=-=

My message is short and does not offer a fix. But I did call attention to their mistakes. I was hoping that a fairly reputable institution like the Mayo Clinic might want to check their facts before putting things out there. Quite frankly if someone took GPA thinking it was creatine it could be a problem for them as discussed in my blog referenced above. To give Mayo credit, they responded very quickly with the following.

=-=-=-=-=-=-=-=-=-=-=-=-=

Dear Joseph; Thank you for your e-mail. We value your feedback and appreciate you taking the time to share your comments with us. The information found in our drug guide is from the United States Pharmacopeia, which we license from Micromedex, Inc. The information contained in the Micromedex products is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor or pharmacist before taking any prescription or over-the-counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor or pharmacist can provide you with advice on what is safe and effective for you. The use of the Micromedex products is at your sole risk. These products are provided “AS IS” and “as available” for use, without warranties of any kind, either express or implied. Micromedex makes no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, MICROMEDEX MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE MICROMEDEX PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Micromedex does not assume any responsibility or risk for your use of the Micromedex products.

Sincerely,

Mayo Clinic Online Services

=-=-=-=-=-=-=-=-=-=-=-=-=

So their response tells me two things: First they do not care if the put out incorrect information and only bother with a form letter response, suggesting this may happen a lot. Second, they are so disinterested in putting out correct information that they license some cheap resource and stamp their name on it (Micromedex products). I hope thier disclaimer makes them feel better because it will not help people using their site’s information.

My goal with this blog is not to slam Mayo or Micromedex but to remind people, and my students, that what is out on the web needs to be examined carefully and often can be dangerously inadequate. Regarding the Mayo Clinic apparently not caring how wrong their information is, that is just sad.

We pick up the conversation between Dan G and myself after I have asked him if his son’s diagnosis is of a new mutation or an established mutation of the SLC6A8 gene.

-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+

 Joseph Clark =-=-=-=-=-=-=-=-=-

Dan, I ask about the mutation causing the disease, because we recommend physicians with patients who have new mutations to try treating with creatine because some mutations may have some residual transport activity. While a slim chance it is still worth a try.

 Dan G =-=-=-=-=-=-=-=-=-

Joseph, very interesting point. I’ll ask the physician for further details. Thank you

 Dan G =-=-=-=-=-=-=-=-=-

Joseph, Below are the answers to the things you’ve asked me. Is it a know mutation?

 I’ve asked Nathan’s neurologist, prof. M.-C. Nassogne of Saint-Luc Hospital (Brussels) if she would be interested in having your reference so you could discuss Nathan’s case. Since she was, may I please provide her with your info?

Thank you.

Dan

 Laboratory where the test were conducted:

VU medisch centrum

Metabolic Laboratory

DE Boelelaan 1117

1081 HV Amsterdam

The Netherlands

 Results:

Material person Fraction

DNA Nathan 10A0400

DNA Sylvie 10A0401

 SLC6A8 (NM_005629.3)

Allele ID Mutation Deduced effect

Maternal c.1428C>G p.(Tyr476X)

Paternal(Y) –

 Conclusion

In DNA of Nathan a hemizygous nonsense mutation was identified in the X-linked SlC6A8 gene. This confirms the diagnosis at the DNA level. In DNA of the mother the described heterozygous mutation was defected.

 Creatine transporter (SlC6A8) deficiency (OMIM 300352) is an X-linked disorder Caused by a hemizygous SlC6A8 mutation in males. Females, whom are heterozygous for a pathogenic mutation in the SLC6A8 gene may be asymptomatic, but also may have clinical symptoms of varying degrees due to skewed X-inactivation. The SlC6A8 gene (NM_005629.3) is mapped at Xq28. The exons, Including the splice sites, were amplified by polymerase chain reaction. The open reading frame (ORF) of the SLC6A8 gene and the splice sites have been analyzed by DNA sequence analysis. We identified a novel mutation in the SLC8A8 gene. The nonsense mutation predids a truncated protein of 475 amino acids that lacks the 3′end of the C•terminus of the protein. The mutation should be considered pathogenic due to its nature (nonsense). Moreover, this mutation halve not been identified in 276 control male chromosomes.

 Joseph Clark =-=-=-=-=-=-=-=-=-

Thanks Dan,

Please pass on my information.

 Joseph F. Clark, Ph.D.

Professor of Neurology

University of Cincinnati

231 Albert Sabin Way

MSB room 7112

Cincinnati OH 46267-0536

Phone 513 558 7085

Fax 513 558 7009

joseph.clark@uc.edu

www.josephfclark.com

It is a new mutation. While treating with creatine is suggested for all mutations (our protocol) this is a severe mutation and success with the truncated protein is of low probability. If you want to chat about this feel free.

 Best wishes

Joe

Joseph F Clark – home page

www.josephfclark.com

The official website for Joseph F. Clark.

 Dan G =-=-=-=-=-=-=-=-=-

Thanks for the info, I’ll transmit it to prof. Nassogne that I hope will contact you shortly. I think she will be interested in your protocol as I believe there isn’t any at their hospital.

I have a question regarding the severe mutation, I understand the notion of a mutation but what makes one severe?

Am I right to understand that Nathan’s mutation is the 277th that was discovered in the Dutch laboratory? How many persons are did you diagnosed to have the SlC6A8) deficiency in Cincinnati? How many different mutations? Prof. Nassogne told us Nathan was the 3d case she diagnosed, the other two boys were 15 and 12 years old which surprised me knowing the deficiency was only discovered in 2001.

Last thing, from reading your blog I understand the research state in your University is still in early stages. Are you aware of any other institution conducting research in this area?

Thank you. Dan

PS. When re-reading my text I was thinking that some of my questions are probably of interest to other parents, maybe you would prefer to share that information on the public forum?

Joseph Clark =-=-=-=-=-=-=-=-=-

Dan, putting this up as a note for the group is fine. The information is your medical information, so I consider it your choice to have public or not.

Re other questions:

Mutations can be severe if the protein is not made or shortened. Other mutations mean the protein is made but not as functional, those can be severe or moderate. So there are grades of mutations.

No, the diagnosis is made comparing to that number of controls. So this is not the 277th patient found by Gajja’s lab.

I politely disagree with you that our research in Cincinnati is at the early stages. We discovered the creatine transporter deficiency disorder here in Cincinnati in 2001. We are the only place in the world with an animal model of the disease. Therefore we are the only place actively screening treatments using those animals.

I am the author of a definitive text on creatine (http://www.amazon.com/Creatine-Phosphate-Scientific-Perspectives-ebook/dp/B00272MBPG/ref=sr_1_2?ie=UTF8&m=AG56TWVU5XWC2&s=digital-text&qid=1302295948&sr=8-2) with many papers on creatine (http://www.ncbi.nlm.nih.gov/pubmed?term=clark-jf+creatine). I am aware of essentially all the institutions doing research on this disorder. They turn to us for answers.

Creatine and Creatine Phosphate: Scientific and Clinical Perspectives

www.amazon.com

Creatine and Creatine Phosphate: Scientific and Clinical Perspectives is an up-to-date summary of both the scientific and medical aspects of creatine and creatine phosphate metabolism and therapy. It covers in detail the basic biochemistry, bioenergetics and biophysics of these agents.

Dan G =-=-=-=-=-=-=-=-=-

Joseph, Thank you for the clarification and extra information provided.

I had certainly no intension in diminishing the work accomplished at Cincinnati and apologies if it may have sound as such. It probably just me being a parent wishing a treatment to be available today rather than tomorrow.

I read your article about the mice model which is indispensable to validate a potential treatment. It would surely be interesting leaning (a not too medical explanation) what a potential drug needs to accomplish for it to be successful in getting creatine into the brain

Thank you. Dan 

Joseph Clark =-=-=-=-=-=-=-=-=-

Dan, it is very hard to explain drug screening without being too technical, but I’ll try. Also please know in advance that it is very complicated, but do not get disheartened by the complexities because I / we are working very hard to address all those complexities.

A drug to treat the creatine transporter deficiency needs to address 3 different proteins whereas most drugs need to only consider 1 protein. So the search for a drug to treat CTD is 3 times more complicated than other drug searches. We need to find a drug that bypasses the defective or absent creatine transporter. Plus that drug needs to act on two different proteins in the brain: mitochondrial creatine kinase and BB creatine kinase.

When we find chemical compounds that might work, we need to make sure they are not toxic by acting on other tissues or proteins. If it appears to be not too toxic we treat the mice who have the disease. This is very complicated because we need to make sure that a reasonable dose and method to administer it can be found.

If all that works we might have enough information to present the data to a government agency empowered to allow us to test it in humans. Before testing it on patients it is required to be tested in healthy human volunteers.

Only after all of the above is done with no errors and no deficits along with good therapy in the mice, can we even think about giving a drug to CTD patients and it would still be considered experimental.

Dan G =-=-=-=-=-=-=-=-=-

Joseph, Thank you for the explanation, it’s concise while remaining non-medical , exactly the right dosage of information to help folks like me understand the big steps to follow. Seems like hard work indeed, I’m sure you and your team are doing the uttermost to discover the required chemical compounds. We all hope your program will start to bear fruit soon. Dan

Joseph Clark =-=-=-=-=-=-=-=-=-

Thanks Dan. Do you want me to post this as a note or blog? As you said, others may have similar questions. Let me know or you can post it too.
Joe

Dan G =-=-=-=-=-=-=-=-=-

Joseph, Yes please do, I’m sure others will benefit from this information. Dan

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That is the conclusion of the conversation between Dan G and myself. Thank you very much Dan for allowing me to share this publically. As many parents know a new diagnosis of a “rare” disease can be heartbreaking and very difficult. In some ways Dan is fortunate in that his son’s doctor has already diagnosed other patients so that experience may help in answering Dan’s questions. I hope I’ve helped too.

If you know anyone; physician, scientist, family member interested in understanding the creatine deficiency syndromes or who needs a place to chat about how to care for people with creatine deficiency syndromes, please refer them to the facebook group, Creatine deficiency support group.

https://www.facebook.com/?ref=home#!/home.php?sk=group_127389967322193&ap=1

So to not be a disappointment, maybe I should say something.

If you can’t tell, I’m passionate about science and medical research. It was evident when I worked on the ambulance and in the emergency room as evidenced in “My Ambulance Education.” It continued as an athletic trainer, graduate student and college professor. It is very important to me that my work have relatively transparent and soon benefits to society, so I do medical research to improve people’s health. I’ve blogged on many of these subjects.

I blogged on how EMS people may have to deal with patients with a neurologic deficit that caused them to try to refuse transport to a hospital or deny aid. My goal here was to put in writing that EMS personnel have difficult decisions to make in managing people with neurologic issues. This is especially acute with mild traumatic brain injury such as concussion because someone with a concussion could be aggressive but be cogent enough to try to refuse emergency care. The athletic trainer in me sees this often with athletes with concussion.  When I work with the athletic trainers we have worked to benefit the athletes with neurologic issues. As a researcher who has been working on bleeding in the brain for nearly 15 years it is nice to see that concussion and mild brain injury is high up in the public psyche. Sadly it appears that politicians are getting involved and making decisions that are ill advised.

As anyone who has read my blog regularly over the past 6 months knows I have been studying creatine, creatine kinase and creatine transport for about 25 years. It is what I did my Ph.D. on. I have submitted several blogs the creatine transporter deficiency because I am really excited that we have a chance to truly improve the patients with this disease as well as the creatine transporter deficiency syndromes. We have several drug candidates that show promise and will be working to get these to patients as soon as the FDA will allow.

As a person who has been trying to “help” people for an entire career. Being on the cusp of producing a drug that will drastically improve the lives of numerous patients is humbling and daunting. As I said in the beginning of this blog it is my 200th blog, if you have been following my blog for any period of those 200 posts you will have seen how I got here from there.

Thanks for reading this and come back soon.

Concerning appearances, I’ve decided to not advertise when I’m traveling for personal security reasons. I’ll blog on conferences I attend after I have been and gone.

The web site has seen continuous growth since its launch 2 years ago. Yes the site has been live for 2 years. The site gets 10,000 visits a month – not just hits but people on the site. I’m very happy with this number and the overall growth of the site. My blog has been picked up by a couple of others, so the number of reads is harder to estimate.

I know the link to my science site is down. I will be updating it as soon as the new one is ready. Sorry; remember this is my housekeeping blog.

For my EMS friends, please check out www.uc.edu/cas/firescience. This represents a lot of work locally to develop the course and program with multiple disciplines to develop a masters of emergency management, disaster preparedness and homeland security. It has been a ton of fun for me as I get a chance to catch with ambulance and EMS technologies. I’ll be one of the instructors with my course starting in 2012. I blogged on it previously; http://www.josephfclark.com/blog/?p=550.

I’ve started a patient and family support group on facebook; creatine deficiency syndrome support group https://www.facebook.com/?ref=home#!/home.php?sk=group_127389967322193&ap=1. I have been working on diagnostics and treatments for this disease for quite a while and this is a forum for family members to get information on this devastating disease. I hope you will visit it and refer your friends to the site.

If you followed my blog on My Graduate Education, I am almost done with the follow up to be called; My European Education about doing post doctoral work in Paris France and Oxford England. When I’ll start posting it will depend upon how much time I get to work on it.