Below please find a dialogue that occurred between myself and the parent of a newly diagnosed Creatine Transporter Deficiency boy. I am posting this dialogue with Dan G’s permission so that other parents and care givers can learn from Dan’s experience and to continue to raise awareness of the creatine deficiency syndromes.
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.
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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
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
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
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
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