Serene Forest

Sunday, September 28, 2014

GeneticTesting Should Be For Any Mutation Close To The Relevant Gene


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Hello All,

Today one of our extremely conscientious members, who is always researching about all aspects of Periodic Paralysis and sharing the articles she finds with us, posted an article about DNA and genetic testing. The article, which was thirty-five pages long, was filled with a great deal of technical information. I know a lot great deal about DNA and genetic testing from my own study, but it is always very difficult for me to understand when I do read that kind of article. This article was one of those, but as I was reading along, something jumped off the page to me. The following is my response to the article:

Thank you for sharing this with us. As usual when I read about DNA genetic testing I get confused and lost.  Although I feel I understand quite a bit about it, the articles always seem to be difficult to understand. However, in this article, one thing popped out to me; the following statement:

"For the great majority of diseases there is extensive allelic heterogeneity, and genetic testing requires a search for any mutation anywhere within or near the relevant gene. The biggest current problem in laboratory genetic diagnosis is the lack of any quick, cheap and reliable method for doing this."

This is exactly what I have been trying to say for quite awhile about our testing for Periodic Paralysis....."GENETIC TESTING REQUIRES A SEARCH FOR ANY MUTATION ANYWHERE WITHIN OR NEAR THE RELEVANT GENE"!!!!!!!!!!

That is what has been missing for most of us whether our genetic testing was done in Germany, or from a doctor's orders somewhere else in the world. The testing was and is too narrow, specific and biased; only looking for specific alleles. The mutations “anywhere within or near the relevant gene” are either ignored or overlooked or not even looked for to begin with. That is why so many people got/get a letter saying they do not have a "known" genetic mutation for Periodic Paralysis. This is definite “bias” in the testing. One is left to believe there is no reason for their symptoms and to wonder about their own sanity. An individual’s doctors, not understanding the above information, believe that the person does not have Periodic Paralysis.

But in reality, I was lucky enough to have a chance to see all of my mutations. Some of my mutations were on different, but recognized exons known to cause PP but were not looked at in the German study. They were not even looked for and some were seen but because they were not the exact allele but right next to it, they were ignored and dismissed. No mention of them was included in the testing result letter. A better way to handle it would have been, first to look at ALL of the known mutations/alleles and then in the letter sent with the results, it should have been stated that similar to my sample letter:

"The results to your DNA testing for Periodic Paralysis are as follows. You have the symptoms of Hyperkalemic Periodic Paralysis. We searched for ALL of the KNOWN mutations for ALL forms of Periodic Paralysis. You do not have the exact and known mutations, but you do have mutations on Exon 7 near the ones that cause Hyperkalemic Periodic Paralysis. Therefore it is likely that you (and possibly your family) have a new or original or unique mutation for Hyperkalemic Periodic Paralysis. This will be documented for your family and for others that may have the same mutation. We need to notify your doctors so that you will be treated from this point on as probably having a form Hyperkalemic Periodic Paralysis. You also need to notify your family members and share this letter with them."

Because this has not happened and I do not expect it to see it happening anytime in the near future and because genetic testing is no longer being done in Germany, and all other testing besides whole genome testing is extremely narrow, diagnosing for Periodic Paralysis must be done by doctors based on the symptoms and characteristics of the individual. This should be done once testing for any other condition in which periods of paralysis or muscle weakness have been ruled out.

The article posted:
http://www.ncbi.nlm.nih.gov/books/NBK7586/?report=reader (no longer available)
Three more related articles:

https://www.nature.com/articles/gim200597
"This is because 
most conditions demonstrate extensive allelic heterogeneity, so a search for a mutation anywhere within or near the relevant gene (or locus) is required and not all variants are known or detectable."

https://www.nature.com/articles/gim200597 (Found in: 'Individuals and families')
"A related problem here is that mutation-scanning tests appear not to perform as well as direct gene tests. This is because most conditions demonstrate extensive allelic heterogeneity, so a search for a mutation anywhere within or near the relevant gene (or locus) is required and not all variants are known or detectable."

https://www.ncbi.nlm.nih.gov/books/NBK19932/
"These genetic diseases often exhibit a genetic phenomenon known as allelic heterogeneity, in which multiple mutations within the same gene (i.e., alleles) are found to be associated with the same disease." 



Until later…..

6 comments:

  1. "Genetic testing is no longer being done in Germany". ? Do you mean that in common or that they don´t search gene mutations from your blood anymore there?

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  2. As of June 30th 2014, there is no more genetic testing for Periodic Paralysis being done in Ulm Germany due to staff cuts and budget cuts.

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  3. I didn´t know that, thank you for telling. Do you know what happens to old samples? I thought that Professor L-H worked as a voluntary basic, so I am surprised that "staff cuts" has an effect to this issue. Very bad thing for many that they can´t send their blood there anymore.

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  4. This is the message they put out:

    "Here is some very recent news from the PPA about the genetic testing in Germany. Dear PPA Members, Due to cuts in both funding and staff at the Department of Neurophysiology in Ulm, Germany, Dr. Frank Lehmann-Horn will no longer be able to conduct genetic testing for the PPA. He will do his best to complete testing on samples he has received up to and including June 30, 2014. The lab will not be accepting new samples. We know many of you have not found your mutation through the initial testing for KNOWN mutations. There will be no further work done on any of these samples. It is unclear what the disposition will be of the DNA currently stored in the lab at this time. The PPA is extremely grateful to Dr. Lehmann-Horn for the thousands of samples he and his lab have processed free of charge for our members over the past 15 years. His work has been an extraordinary gift to the members of the Periodic Paralysis Association. We are exploring new options for genetic testing at a U.S.-based facility, including technology and sample transfer from Dr. Lehmann-Horn's lab to the new lab. No specimens will be transferred without the consent of the individuals who gave them. Please know that your PPA Board is here to offer support if you need questions answered. Please address any questions or concerns to our website at: http://www.periodicparalysis.org/english/inquiries.asp?x=1 Thank you for your understanding and patience during this difficult time. Sincerely, Linda Feld, Vice President and Genetic Testing Liaison "

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  5. Oh! That is terrible that he will not research unknown mutations. A very bad thing for many people. I didn´t get any message from Ulm or PPA about this, wonder why. Hopefully old blood samples will be transfered to someone else. Thank you for this information Susan.

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  6. Luckily others continue to do research to continue to identify further new mutations for Ion Channel disorders as they are considered excellent targets for medical (read pharmacuetical intervention) I continue to try to learn how best to handle by avoiding dangerous medications as I can and also by changing what behaviours I can to improve my state of health. I do believe dietery and life style choices continue our best bet along with supplementaton of our deficient vitamins and minerals.

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