Serene Forest

Tuesday, December 16, 2014

325 Members!!

Congratulations to us all at the Periodic Paralysis Network Support, Education and Advocacy Group!!! We now have over 325 members!!!!!!!! Thank you all for your support!!!

Our PPN Forum:

The following are the services and features of our PPN forum:

PPN Support, Education and Advocacy Group:
https://www.facebook.com/groups/periodicparalysisnetworksupportgroup/

PPN Website: www.periodicparalysisnetwork.com

PPN Books: "Living With Periodic Paralysis: The Mystery Unraveled" and "The Periodic Paralysis Guide And Workbook: Be The Best You Can Be Naturally"
(Found on our website http://www.periodicparalysisnetwork.com/books.htm)

PPN Blog: http://livingwithperiodicparalysis.blogspot.com/

PPN Book Discussion Group:
https://www.facebook.com/groups/periodicparalysisnetwork/

PPN Genealogy-Genetic Discussion Group:
https://www.facebook.com/groups/580168915344191/

PPN Website Facebook Page:
https://www.facebook.com/PeriodicParalysisNetwork

PPN Author's Page:
https://www.facebook.com/SusanQKnittleHunterauthor

Email: periodicparalysisnetwork@gmail.com

Please check out our PPN Members World Map: http://www.multiplottr.com/?map_id=55083

Sunday, December 14, 2014

The Survey Results: Part One


Hello All,

I have decided to present the results of the set of surveys in articles on our blog. It may take three or four articles to complete the project. The following is the first, as I wrote it last year when it was first completed.


The Periodic Paralysis Network, Inc (PPNI) Project:

Creating Guidelines/Criteria
For
Diagnosing Various Forms of Periodic Paralysis Clinically
(Without using Genetic Testing)


This project, Creating Guidelines/Criteria For Diagnosing Various Forms of Periodic Paralysis Clinically (Without using Genetic Testing), was created, designed and executed by the Periodic Paralysis Network, Inc. This project was deemed necessary after reports for the past nearly four years of the inability of many individuals throughout the world, with severe and obvious symptoms of the various forms of Periodic Paralysis, to obtain a diagnosis despite the fact that everything else had been ruled out. Also, some medical professionals called “specialists” in the field of Periodic Paralysis have been known to overturn diagnoses already received by patients from other doctors. The excuses given by these medical professionals and specialists for denying a diagnosis or removing a diagnosis indicate a severe lack of up-to-date knowledge and true understanding of Periodic Paralysis.

About 40% of all individuals suffering from the devastating affects of various forms of Periodic Paralysis do not have a known genetic mutation. By the time some one discovers this, many, many years have passed after many misdiagnoses, wrong medications and treatment and more. Most doctors will not diagnose someone without a known genetic code. Other doctors will not diagnose based on a lack of knowledge or by using outdated information.
Without a diagnosis individuals cannot get the medications they need or may be given medications, which may harm or kill them. They may not be able to get disability or they may have to continue to work, which may make them worse. Some may attempt to prove they have PP by provoking symptoms, which can kill them. This does not happen in other medical conditions or diseases. Other conditions and diseases are diagnosed based on their symptoms. This is called a “clinical” diagnosis.
We are attempting to create a set of symptoms and characteristics called criteria, to be used by doctors to make a clinical diagnosis, once everything else has been ruled out. Orginally, this final report or study was to be presented to a team of doctors, who are not related to the PP “specialists”, but a set of fresh eyes, to look at the results. Due to the knowledge that it may not be published, we have decied to present it in this manner, on our blog as a series of articles. It is our hope that this report, in its entirety, will hopefully be used as a guideline for any doctor to diagnose all forms of Periodic Paralysis based strictly on the symptoms of the individuals.
Many members of our on-line Support, Education and Advocacy Group at the Periodic Paralysis Network, Inc who are not diagnosed genetically, display many of the same symptoms and characteristics of Andersen-Tawil Syndrome (ATS) but have many more symptoms, which they share but are out of the ordinary for ATS and seems to have an autoimmune component. We believed at the beginning of this endeavor there may be a type of ATS without a known genetic code, which we called Periodic Paralysis+10 Syndrome. We hoped the data collected may shed some light on this possibly new form. We, in fact, were surprised by what the results actually uncovered. The new information took us in another direction and revealed much more about Periodic Paralysis; how it progresses and how to diagnose it in a very new manner.

The following is our original plan:

The Project Outline
The Goals and Objectives

Goal 1:
The first goal of this project is to provide medical professionals with a means to recognize and diagnose three forms of a medical condition known as Periodic Paralysis to include: Hypokalemic Periodic Paralysis, Hyperkalemic Periodic Paralysis and Normokalemic Periodic Paralysis, which either have no identifiable genetic code, or without the use of genetic testing through a set of criteria to be established with this study.

Objective 1:
Gather data from a group of individuals exhibiting similar symptoms of periodic paralysis, other similar symptoms experienced regularly yet unexplained, potassium levels and affects of potassium, similar co-existing diseases and conditions, similar unique physical characteristics, similar medical history, similar family history, similar results of medical testing and with or without known genetic mutation discovered. This group may include individuals with clinical diagnoses of various forms Periodic Paralysis.

Data to gather:
Description of the paralytic episodes
Other symptoms experienced regularly yet unexplained
Potassium levels and effects of potassium
Diagnosed diseases/conditions co-existing with periodic paralysis
Unique physical characteristics
Unique characteristics regarding medications
Patient medical history
Family medical history
Medical tests completed and results
Clinical diagnosis (if applies)

Objective 2:
Organize data from a group of individuals exhibiting similar symptoms of periodic paralysis, other similar symptoms experienced regularly yet unexplained, potassium levels and effects of potassium, similar co-existing diseases and conditions, similar unique physical characteristics, similar unique characteristics regarding medications, similar medical history, similar family history, similar results of medical testing and with or without known genetic mutation discovered. This group may include individuals with clinical diagnoses of various forms Periodic Paralysis.

Locate:
Matching symptoms accompanying paralytic episodes
Matching symptoms experienced regularly yet unexplained
Matching diagnosed diseases/conditions co-existing
Matching unique physical characteristics
Matching unique characteristics regarding medications
Matching patient medical history
Matching family medical history
Matching medical tests completed and results
Matching clinical diagnosis (if applies)

Objective 3:
Create a set of criteria for making a clinical diagnosis for three forms of a medical condition known as Periodic Paralysis to include: Hypokalemic Periodic Paralysis, Hyperkalemic Periodic Paralysis and Normokalemic Periodic Paralysis, which, either have no identifiable genetic code, or without the use of genetic, based on matching symptoms accompanying paralytic episodes, matching symptoms experienced regularly yet unexplained, potassium levels and effects of potassium, matching diagnosed diseases/conditions co-existing, matching unique physical/other characteristics, matching unique characteristics regarding medications, matching patient medical history, matching family medical history, matching medical tests completed and results and matching clinical diagnosis (if applies).
           
            Set of criteria:
            Symptoms of paralytic attack:
            Symptoms experienced regularly yet unexplained:
            Potassium levels and affects of potassium:
Diagnosed diseases/conditions co-existing:
            Unique physical/other characteristics:
            Unique characteristics regarding medications:
Medical history:
            Family history:
            Medical tests results:
All else ruled out:

Clinical diagnosis of Hypokalemic Periodic Paralysis
Clinical diagnosis of Hyperkalemic Periodic Paralysis
Clinical diagnosis of Normokalemic Periodic Paralysis

Objective 4:
Provide the results of this study to a team of medical professionals who specialize in diagnosing difficult to diagnose conditions, unrelated to any specialists of Periodic Paralysis or Andersen-Tawil Syndrome, with the intention of the acceptance of the criteria as standard for diagnosing Hypokalemic Periodic Paralysis, Hyperkalemic Periodic Paralysis and Normokalemic Periodic Paralysis which have no identifiable genetic code, or without the use of genetic testing.

Goal 2:
The second goal of this project is to provide medical professionals with a means to recognize and diagnose a new form of a medical condition known as Periodic Paralysis to be further known as Periodic Paralysis Plus 10 Syndrome (PP+10) which has no identifiable genetic code, through a set of criteria to be established with this study.
 (This condition has symptoms and characteristics which resemble a form of Periodic Paralysis known as Andersen-Tawil Syndrome. Individuals with this form have no identifiable genetic code and have at least 10 similar symptoms in common, as well as, a myriad of accompanying autoimmune/inflammatory conditions to be described in the final report.)

Objective 1:
Gather data from a group of individuals exhibiting similar symptoms of periodic paralysis, other similar symptoms experienced regularly yet unexplained, potassium levels and affects of potassium, similar co-existing diseases and conditions, similar unique physical characteristics, similar medical history, similar family history, similar results of medical testing and with or without known genetic mutation discovered. This group may include individuals with clinical diagnoses of various forms Periodic Paralysis.

Data to gather:
Description of the paralytic episodes
Other symptoms experienced regularly yet unexplained
Potassium levels and affects of potassium
Diagnosed diseases/conditions co-existing with periodic paralysis
Unique physical characteristics
Unique characteristics regarding medications
Patient medical history
Family medical history
Medical tests completed and results
Clinical diagnosis (if applies)

Objective 2:
Organize data from a group of individuals exhibiting similar symptoms of periodic paralysis, other similar symptoms experienced regularly yet unexplained, potassium levels and affects of potassium, similar co-existing diseases and conditions, similar unique physical characteristics, similar unique characteristics regarding medications, similar medical history, similar family history, similar results of medical testing and with or without known genetic mutation discovered. This group may include individuals with clinical diagnoses of various forms Periodic Paralysis.

Locate:
Matching symptoms accompanying paralytic episodes
Matching symptoms experienced regularly yet unexplained
Matching diagnosed diseases/conditions co-existing
Matching unique physical characteristics
Matching unique characteristics regarding medications
Matching patient medical history
Matching family medical history
Matching medical tests completed and results
Matching clinical diagnosis (if applies)

Objective 3:
Create a set of criteria for making a clinical diagnosis for a new form of a medical condition known as Periodic Paralysis to be further known as Periodic Paralysis Plus 10 Syndrome (PP+10) which has no identifiable genetic code based on matching symptoms accompanying paralytic episodes, matching symptoms experienced regularly yet unexplained, potassium levels and affects of potassium, matching diagnosed diseases/conditions co-existing, matching unique physical/other characteristics, matching unique characteristics regarding medications, matching patient medical history, matching family medical history, matching medical tests completed and results and matching clinical diagnosis (if applies).
           
            Set of criteria:
            Symptoms of paralytic attack:
            Symptoms experienced regularly yet unexplained:
            Potassium levels and affects of potassium:
Diagnosed diseases/conditions co-existing:
            Unique physical/other characteristics:
            Unique characteristics regarding medications:
Medical history:
            Family history:
            Medical tests results:
All else ruled out:

Clinical diagnosis of Periodic Paralysis Plus 10 Syndrome (PP+10)

Objective 4:
Provide the results of this study to a team of medical professionals who specialize in diagnosing difficult to diagnose conditions, unrelated to any specialists of Periodic Paralysis or Andersen-Tawil Syndrome with the intention of the acceptance of Periodic Paralysis Plus 10 Syndrome (PP+10) as a form of Periodic Paralysis and the acceptance of the criteria as standard for diagnosing Periodic Paralysis Plus 10 Syndrome (PP+10) clinically; without using genetic testing.


The Results :

The Execution



The information and data obtained for this study was gathered through a series of four surveys presented to the on-line Support and Educational Group at the Periodic Paralysis Network. Sixty-one members of the eighty members at the time of the study participated in the survey. The sixty-one members included:



23% (14) males ages 13 to 67

77% (47) females ages 9 to 82


Average age of members 50 years


18% (11) had genetic diagnoses

  8 = Hypokalemic Periodic Paralysis

  1 = Hyperkalemic Periodic Paralysis

  2 = Andersen-Tawil Syndrome



51% (31) had clinical diagnoses

24 = Hypokalemic Periodic Paralysis

  1 = Hyperkalemic Periodic Paralysis

  3 = Andersen-Tawil Syndrome



31% (19) had no diagnosis

  9 suspect Hypokalemic Periodic Paralysis

  2 suspect Normokalemic Periodic Paralysis

  1 suspect Hyperkalemic Periodic Paralysis

  4 suspect Andersen-Tawil Syndrome


First signs of Periodic Paralysis range from birth to 55 years of age



Number of years presently waiting for a diagnosis range from 2 years to 61 years



100% experience periods of muscle weakness

  75% (46) experience full body paralysis

  25% (15) experience no full body paralysis (2 with genetic diagnoses)



The Description of Paralytic Episodes (Despite the form of Periodic Paralysis or if they were diagnosed clinically, genetically or still waiting for a diagnosis)
 

Description of the Paralytic Episodes
Full body Paralysis 75% (46)
Partial body paralysis 85% (52)
Periods of muscle weakness 97% (59)
Blood pressure issues 49% (30)
Heart issues 79% (48)
Breathing issues 70% (43)
Choking issues 5% (3)
Swallowing issues 20% (12)
Pain  (before, during or after) 85% (52)
Falls/drops 8% (5)
Eyes closed 26% (16)


Until Later...

Saturday, December 6, 2014

The Connection Between Mitochondria and Autoimmune Disease in Periodic Paralysis


The Connection Between Mitochondria and Autoimmune Disease

I wrote about the connection between mitochondrial issues and autoimmune dysfunction in the new book, “The Periodic Paralysis Guide And Workbook: Be All You Can Be Naturally.” I did not go into the research and the infromation that led me to my findings. Although I had written about this for the members in our PPNI Support Group, I felt it was important to add that information to our blog for others to read about and understand.

I am now posting what I wrote last year.


November 3, 2013

Yesterday I spent a great deal of time researching the connections between Periodic Paralysis and lactic acidosis. I did this because of several reasons, but mostly due to the results of a set of tests done a few years ago, that no doctor seems to know what it means or what to do about it. 
           
I posted these a few weeks ago but I am posting it again in order to further explain what I discovered yesterday which may be a major break through for us all !

The following is the results of the Amino Acid Plasma Quantitative Test :

Aspartic Acid (<2, 0-6) and 3 Methylhistidine (<;6, 0-64) were low and Proline Plasma (501, 110-360), Alanine Plasma (744, 230-510), Valine (331, 150-310) Plasma, Tyrosine Plasma (107, 45-74), Homcysteine Plasma (11.9, 4.0-12.0), and Pyruvic Acid (0.146, 0.030-0.107) were all high. Lactic Acid was high also (1.8, .5-1.6)

"The high Alanine Plasma indicates: Primary or Secondary Lactic Acidosis or Hyperammonemic Syndrome. Clinical findings may be episodic. Further workup may be warranted."

"Hyperprolinemia is consistent with Mitochondrial Dysfunction or may indicate Type 1 or Type 2 Hyperprolinemia. Further analysis may be warranted."

"Recommend measurement of blood lactate and repeat of the Plasma Amino Acid Analysis."

These test results indicate "primary or secondary lactic acidosis" and Mitochondrial Dysfunction.

My real eye opener came when I read this:

"Metabolic dysregulation can also cause mitochondrial dysfunction. Vitamins, minerals, and other metabolites act as necessary cofactors So, wanting to understand how I could have Periodic Paralysis, over 10 autoimmune condition diagnoses AND Mitochondrial Dysfunction, I set out to find some answers. The discovery I made was unbelievable. Karen Carr has mentioned mitochondrial issues on this board for as long as I can remember. I have read through the complicated articles, etc. and I never quite understood the connection. I will try to put this in an easy to understand format, though it may be a little difficult to follow.

First of all...a biology lesson: There are many mitochondria in a cell. Mitochondria can became damaged for many reasons and then mutate or change. When this happens we can then have "Mitochondrial Dysfunction", leading to things such as lactic acidosis.

There are of course, Mitochondrial Disorders that can be present at birth also which I knew. I had no idea that we can "develop" them.

“…..for the synthesis and function of mitochondrial enzymes and other compounds that support mitochondrial function (see Table 4 ), and diets deficient in micronutrients can accelerate mitochondrial decay and contribute to neurodegeneration (Ames, 2004)"

However, since symptoms vary from case to case, age of onset, and rate of progression, mitochondrial dysfunction can be difficult to diagnose when it first appears. According to Cohen, who wrote a July 2001 article in the Cleveland Clinic Journal of Medicine, “The early phase can be mild and may not resemble any known mitochondrial disease. In addition, symptoms such as fatigue, muscle pain, shortness of breath, and abdominal pain can easily be mistaken for collagen vascular disease, chronic fatigue syndrome, fibromyalgia, or psychosomatic illness”

http://www.nbihealth.com/publications/Mitochondrial_dysfunction.pdf

Periodic Paralysis is a 4th Class Metabolic Dysregulation (Disorder)!!!!!! Periodic Paralysis can cause Mitochondrial Dysfunction!!!!!!!!! Obviously the potassium shifting can cause the damage to the mitochondria in the cells!!!!!! We already know there seems to be an issue with autoimmune issues....Here is the connection!!!!

"…diets deficient in micronutrients can accelerate mitochondrial decay"

THIS IS WHY THE BALANCED DIET IS SO IMPORTANT TO US AND WE SEE DIFFERENCES WHEN WE CUT OUT THE JUNK AND ADD SUPPLEMENTS!!!!!!!

"…symptoms such as fatigue, muscle pain, shortness of breath, and abdominal pain can easily be mistaken for collagen vascular disease, chronic fatigue syndrome, fibromyalgia, or psychosomatic illness”  (MUSCLE PAIN, SHORTNESS OF BREATH, FIBROMYALGIA, CONVERSION DISORDER??????)

"Mitochondrial dysfunction is at the core of a surprising range of very common illnesses and conditions...Even autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus and rheumatoid arthritis appear to have a mitochondrial basis to illness.

Mitochondrial dysfunction has been associated with a wide range of solid tumors, proposed to be central to the aging process, and found to be a common factor in the toxicity of a variety of physical and chemical agents."

http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934637

"EVEN AUTOIMMUNE DISEASES"!!!!!!!!!!!!!

"…toxicity of a variety of physical and chemical agents"    (The ISSUES WE HAVE WITH ALLERGIES AND PROBLEMS ITH MEDICATIONS????)

Table 1
Signs, symptoms, and diseases associated with mitochondrial dysfunction
(Cohen and Gold, 2001)

Organ system: Possible symptom or disease

Muscles: Hypotonia, weakness, cramping, muscle pain,
ptosis, opthalmoplegia

Brain: Developmental delay, mental retardation, autism, dementia, seizures, neuropsychiatric disturbances, atypical cerebral palsy, atypical migraines, stroke, and stroke-like events

Nerves: Neuropathic pain and weakness (which may be intermittent), acute and chronic inflammatory demyelinating
polyneuropathy, absent deep tendon reflexes, neuropathic

gastrointestinal problems (gastroesophageal reflux,
constipation, bowel pseudoobstruction), fainting, absent
or excessive sweating, aberrant temperature regulation

Kidneys: Proximal renal tubular dysfunction (Fanconi syndrome); possible loss of protein (amino acids), magnesium, phosphorus, calcium, and other electrolytes

Heart: Cardiac conduction defects {(electrical system)} (heart blocks), cardiomyopathy

Liver: Hypoglycemia, gluconeogenic defects, nonalcoholic
liver failure

Eyes: Optic neuropathy and retinitis pigmentosa

Ears: Sensorineural hearing loss, aminoglycoside sensitivity

Pancreas: Diabetes and exocrine pancreatic failure

Systemic: Failure to gain weight, short stature, fatigue, and respiratoryproblems including intermittent air hunger

http://www.nbihealth.com/publications/Mitochondrial_dysfunction.pdf

"Exercise intolerance is a well recognized clinical feature of mitochondrial respiratory chain defects due to pathogenic mutations of mitochondrial or nuclear DNA. Severely impaired muscle oxidative phosphorylation results in disabling exercise limitations in which trivial exertion produces muscle fatigue and lactic acidosis. In such patients, low levels of exercise cause prominent tachycardia and dyspnoea (shortness of breath) due to increases in cardiac output and ventilation that exceed the capacity of skeletal muscle to utilize the increase in oxygen delivery mediated by these physiological responses"

".....results in disabling exercise limitations in which trivial exertion produces muscle fatigue and LACTIC ACIDOSIS."
EXERCISE INTOLERANCE and LACTIC ACIDOSIS!!!!! from the Mitochondrial Dysfunction!!!!!

"Oxygen utilization and Lactic Acidosis”

“Latic acidosis has often been used as an indicator of impaired oxidative metabolism and as a clinical marker for mitochondrial disorders…elevated lactate values at rest strengthen the possibility of a mitochondrial disorder."

http://ghr.nlm.nih.gov/mitochondrial-dna

LACTIC ACIDOSIS a cause of low oxygen levels.....

"In such patients, low levels of exercise cause prominent tachycardia and dyspnoea (shortness of breath) due to increases in cardiac output and ventilation that exceed the capacity of skeletal muscle to utilize the increase in oxygen delivery mediated by these physiological responses"...........

So...could this be abortive attacks or what we may be mistaking for PP episodes in normal ranges or it just happens and we wonder why...we cannot figure out a trigger????? We take potassium when we do not need to and it causes side effects, hyperkalemia???

"In conclusion, this study reveals a wide spectrum of oxidative limitations and exercise capacities........It illuminates the relationship between severity of muscle oxidative defects and symptoms of exercise intolerance in MM patients. Furthermore, it provides insight into the regulatory mechanisms responsible for characteristic physiological responses to exercise in these patients,"

http://ghr.nlm.nih.gov/mitochondrial-dna

"oxidative limitations" problems with oxygen...fluctuating oxygen levels....going down upon exertion....... 

Most of the body's cells contain thousands of mitochondria, each with one or more copies of mitochondrial DNA. These cells can have a mix of mitochondria containing mutated and unmutated DNA (heteroplasmy). The severity of many mitochondrial disorders is thought to be associated with the percentage of mitochondria with a particular genetic change.

http://ghr.nlm.nih.gov/mitochondrial-dna

So there may be varying degrees and severity among us and I suspect that, of course, as we age the symptoms worsen such as the permanent muscle weakness, breathing issues, etc....Thus the importance of stopping the attacks with diet, avoiding triggers, etc as soon as possible when we are young...hopefully avoiding the damage to the mitochondria over a long period of time.....

MY THEORY: Periodic Paralysis, a mineral metabolic disorder, can cause damage to the mitochondria in the cells due to the atypical shifting of potassium. This damage to the DNA of the mitochondria, in turn contributes to the development of autoimmune disorders.

The longer a person with Periodic Paralysis goes with out a diagnosis and without proper treatment and continual atypical potassium shifting, the more chance there is for damage to the mitochndria, which then creates autoimmune diseases.

Periodic Paralysis is difficult to diagnose. Mitochondrial dysfunction is difficult to diagnose. Symptoms of both appear similar to "conversion disorders".  More time passes. Autoimmune diseases develop further clouding the picture of the basic disease...Periodic Paralysis. Damage is irreversible and becomes progressive causing permanent muscle weakness, oxygen issues, cardiac issues...etc.

November 5, 2013
Good Morning Everyone!

This is about Exercise Intolerance......

When I wrote about my discovery yesterday, I forgot to mention how our exercise intolerance may play into this. So, today I will discuss that connection with:

"MY THEORY: Periodic Paralysis, a mineral metabolic disorder, can cause damage to the mitochondria in the cells due to the atypical shifting of potassium. This damage to the DNA of the mitochondria, in turn contributes to the development of autoimmune disorders."

This is based on the fact that metabolic disorders and other issues can cause damage to the mitochondria in cells (probably due to the atypical shifting of potassium). The DNA of the mitochondria gets damaged. Damaged mitochondria then may begin to develop autoimmune disorders. This is all factual except what is in the parentheses...I am not sure of the process for the damage.

This is all related to how the complicated oxygen cycle works in our cells and bodies. That being said, this is the part forgot:

"Exercise intolerance is a well recognized clinical feature of mitochondrial respiratory chain defects due to pathogenic mutations of mitochondrial or nuclear DNA. Severely impaired muscle oxidative phosphorylation results in disabling exercise limitations in which trivial exertion produces muscle fatigue and lactic acidosis. In such patients, low levels of exercise cause prominent tachycardia and dyspnoea due to increases in cardiac output and ventilation that exceed the capacity of skeletal muscle to utilize the increase in oxygen delivery mediated by these physiological responses (Haller and Bertocci, 1994). "

This says that exercise intolerance is related to mutations of the mitochondria. The oxygen cycle does not work properly and then we are unable to do anything in which we must exert ourselves, even the smallest amount of exertion causes muscle weakness and lactic acidosis and then tachycardia and shortness of breath set in. This is because the heart must work harder to try to keep up with a lack of oxygen the muscles are receiving and (our body is not expelling the carbon dioxide as it should).
 
"......in patients .......peak oxygen uptake and mitochondrial capacity for oxidative phosphorylation decreased in proportion to increasing mutation load in muscle. "

"This study is the first to relate the severity of the skeletal muscle oxidative defect to the severity of mismatch between the exercise increase in cardiac output and oxygen uptake."

As we exert ourselves and need more oxygen, we do not get it. The more exertion, the less amount of oxygen.

"This study demonstrates for the first time that exaggerated ventilation relative to oxygen utilization ........ is related to the degree of oxidative impairment. Hyperventilation was more pronounced in patients with more severe oxidative defects, consistent with symptoms of exertional dyspnoea experienced by many patients. The mechanism underlying this hyperventilatory exercise response may relate to excess carbon dioxide production due to lactate buffering, as suggested by the finding of a correspondingly exaggerated respiratory exchange ratio..."

http://brain.oxfordjournals.org/content/126/2/413.long

The more we exert ourselves the more carbon dioxide builds up.

This may be the reason for our exercise intolerance.

This may be why also, when you go to the doctor and they take your blood oxygen level with the finger oximeter it is just fine, because you are sitting and have been for awhile, but you know you are having problems with your breathing, etc they do not think you need oxygen. They need to test you with an overnight or 24 hour recording oximeter. It should show oxygen level decreases during exercise and episodes of paralysis, etc....any exertion.

I am on oxygen 24/7 because my oxygen drops any time I exert myself, even talking on the telephone, going to the bathroom, etc at the same time, my heart rate increases and breathing gets difficult. This is happening even with my oxygen. I can only imagine how bad it would be without my oxygen.

Before I was on it, I could not even sit up to a meal at the table. It was too much exertion. Even now, sitting up straight for any length of time is too taxing...why I have a reclining feature on my power wheelchair.

I hope this information is helpful to you. It explains a lot of what we are all experiencing everyday and not fully understanding it or how it relates to Periodic Paralysis.

I do not know if anyone has put this together like this. I did it quite accidentally. It does seem to make sense. I forgot to mention that the lactic acidosis thing is also something that would be intermittent and may not show up on tests each time. It also needs to be tested using a very rare test: Amino Acid Plasma Quantitative Test it is only interpreted at a few places in the country. One is: Duke Children's Hospital and Health Center in North Carolina

A thought.....If our body is in stress from the lack of appropriate oxygen to the muscles and build up of lactic acidosis and carbon dioxide...would the STRESS be the CAUSE of the paralysis from exercise or exertion and why it happens after we begin to rest after our running around, walking, shopping, cooking dinner, doing dishes, etc?? As we begin to rest, the adrenaline will be released from the stress?? The adrenaline causes paralysis for most of us. 



Until later...

Monday, December 1, 2014

Genetic Mutation Overview



                 
Hello All,
Several months ago I posted this and then removed it. I have decided to post it once again to demonstrate the need for clinical diagnosing and Whole Genome Sequencing (WES) (DNA/Genetic Testing) if possible.
                

Genetic Mutation Overview for Susan Q. Knittle-Hunter
From:

 Ancestry DNA Ethnic DNA Testing

Through:

GEDmatch DNA and Genealogy Research

Rare SNP (Minor Allele) Search Utility


May 2014

(This is in a smaller font so the charts can post correctly)

According to the American Heart Association, ”The approach to genetic studies of complex traits entails candidate gene or genome-wide association studies. Genome-wide association studies provide an unbiased survey of the effects of common genetic variants (common disease–common variant hypothesis).”

“Based on today’s knowledge, only 1% of the human genome is transcribed into mRNA and translated into proteins. An additional 0.5% serves as a template for noncoding RNA and the regulatory regions that control gene expression.5 The functions of the remaining 98.5% of the genome including functional conserved noncoding elements, which comprise at least 6% of the genome,6 remain unknown. Hence, this large segment of the genome is referred to as the dark matter of the genome.”

This would indicate that genome-wide genetic testing would be the best way to test for the various forms of Periodic Paralysis (PP), but since only 1% of human genome has actually been transcribed, it also indicates why less that half of those tested get negative results. The research labs run testing only for the tests requested by the doctors ordering them. If testing for only one form of Periodic Paralysis is requested, that is all that will be checked. If blood is sent overseas for testing for Periodic Paralysis, only the known mutations are searched for and they are either found or not found. There is no research done on what mutations on the same gene in the same exons or locations mean nor do they report those findings on the results if they are found in the denial letter sent. 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.

 I know that the testing overseas does not test for every known variant of PP. How do I know? Because I have a copy of the letter from them telling me which genes were tested. I also have a copy of my own genetic mutation make-up from Ancestry, which includes all of my known genetic mutations.

Overseas, they sequenced:  KCNJ2 (ATS), CACNA1S (4, 11, 21,30), SCN4A (exons 5, 6, 9, 12, 13, 14, 18, 19, 21, 22, 23, 2. These are not the only gene mutations associated with the many forms of Periodic Paralysis 4), Kir2.1, (potassium channels), Nav1.4 (sodium channels), Cav1.1 (calcium channels).

It was added in the letter that my “type of channelopathy is caused by either a mutation located in an exon that was “not” part of the screening program or by a mutation in a new gene still to be indentified.”  That is exactly the case.

SCN4A 

Searching my own DNA mutations and researching as I went along (not an easy task it has taken months of research and study), I discovered that I have five mutations in the SCN4A gene as follows. Three of the mutations were found on exon 8 which was not included in the testing and the others were not mentioned to me, though they were found in SCN4A which is the “sodium channel, voltage-gated, type IV, alpha subunit” and “mutations in this gene have been linked to several myotonia and periodic paralysis disorders”:
Mutation shown in red
RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs16947296
17
59397269
aG
2.22617
 Exon 8
rs2008896
17
59396947
aG
2.58377
 Exon 8 & 9
rs7218917
17
59399287
Ag
3.30962
 Exon 6
Rs2302236
17
59402199
Ag
12.087
 Exon 5
rs11079516
17
59396573
Ag
13.5948
 Exon 8 & 9

All five mutations are identified as *603967.

*603967 =
SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4A
Alternative titles; symbols

NAV1.4

HGNC Approved Gene Symbol: SCN4A
Location
Phenotype
Phenotype
MIM number



Hyperkalemic periodic paralysis, type 2



Hypokalemic periodic paralysis, type 2



Myasthenic syndrome, acetazolamide-responsive



Myotonia congenita, atypical, acetazolamide-responsive



Paramyotonia congenita




Cytogenetic location: 17q23.3     Genomic coordinates (GRCh37): 17:62,015,913 - 62,066,875 (from NCBI)






SCN4A is a Voltage-gated sodium channel.
SCN4A sodium channel, voltage-gated, type IV, alpha subunit

Also known as: HYPP; SkM1; HYKPP; NAC1A; HOKPP2; Nav1.4; Na(V)1.4
The mutations above are directly related to:

“Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]”

The following are the mutations I discovered. Each one is a definite mutation, which causes Paramyotonia Congenita (PMC) a form of Periodic Paralysis. I have a combination of the three of them:

08 c.1167T>C
c.703+55C>T, c.864C>T,
Tyr389Tyr SCN4A_00012 DNA SEQ - - paramyotonia congenita (OMIM168300)

http://chromium.liacs.nl/LOVD2/variants.php?select_db=SCN4A&action=search_all&search_Variant%2FDNA=c.1167T%3EC

05i c.703+55C>T - r.(?) p.(=) (LDGA)
06 c.864C>T - r.(?) p.(Asn288Asn) (LDGA)
08 c.1167T>C Tyr389Tyr r.(?) p.(=) (LDGA)

According to Pt├ícek, LJ, et al., “Mutations 1, 4, 6, 7, 8, and 18 are associated with PAM; mutations 2, 9, 12, 13, 14, 15, and 16 are associated with PC; and mutations 3, 5, 10, 11, 17, and 19 are associated with HyperKPP.”  And some double mutations on exon 5 are now known to cause Hyperkalemic Periodic Paralysis.
                       
As listed above for SCN4A, exon 8 was not tested in the overseas testing. These mutations were not seen. I am not sure why they did not show up in exon 5 and 6, or if they were disregarded.  Apparently, by themselves, each of these does not cause it, but the combination does. So it would not be found based on their testing.

I also discovered that one of those mutations above is responsible for what is called "enhanced slow inactivation. This is related to how long the episode of paralysis/weakness may last. If one has "enhanced slow inactivation", it causes their episodes to last longer. My research also led me to the knowledge that a lower pH will help shorten the length of weakness or prevent it.

There is no doubt that I have Paramyotonia Congenita. The specific mutations I have at exons 6 and 8 have been found to be associated with PMC and research indicates that mutations at exon 5 are associated with Hyperkalemic Periodic Paralysis.

 KCNJ5

 With the discovery of a new journal article indicating that mutations at the KCNJ5 gene on Chromosome 11 is now linked to Andersen-Tawil Syndrome, I searched through my DNA data. Much to my surprise I discovered I have three mutations on KCNJ5:

Mutation shown in red
RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs7118824
11
128287188
gT
17.1178
 Exon 2
rs1317470
11
128287424
aG
17.6794
 Exon 2
rs11221503
11
128277662
cT
19.5168
KCNJ5 Ex 2&3

“CONCLUSIONS:

Our findings indicate that rs6590357 and rs7118824 [G810T] in KCNJ5 are associated
with early-onset lone AF in Caucasians.
The risk of stroke is increased fivefold in individuals with AF. The degree of increased risk
may be substantial, depending on the presence of additional risk factors (such as

This would indicate that I have the mutation responsible for early onset Atrial Fibrillation.
 It has obviously been aggravated by the potassium shifting from the Periodic Paralysis. This
has been evident since my young adulthood. It is now probably responsible for the TIAs
that I have experienced in the past few months.

The following is also related to these mutations:

The C11orf45 indicates 3 mutations within the sequence. All three mutations
are identified as *600734.

*600734
POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
Alternative titles; symbols
CARDIAC INWARD RECTIFIER; CIR
G PROTEIN-ACTIVATED INWARDLY RECTIFYING POTASSIUM CHANNEL 4; GIRK4
INWARDLY RECTIFYING POTASSIUM CHANNEL KIR3.4
KATP1
HGNC Approved Gene Symbol: KCNJ5
Cytogenetic location: 11q24.3   Genomic coordinates (GRCh37):
Location
Phenotype
Phenotype
MIM number

Long QT syndrome 13

#613485


LONG QT SYNDROME 13; LQT13


Phenotype-Gene Relationships


Location
Phenotype
Phenotype
MIM number

Gene/Locus
Gene/Locus
MIM number
Long QT syndrome 13

KCNJ5


TEXT


A number sign (#) is used with this entry because long QT syndrome-13
is caused by heterozygous mutation in the KCNJ5 gene (600734) on
chromosome 11q24.




According toYosuke Kokunai, MD, PhD, et al…”We identified a mutation in the KCNJ5 gene, which encodes the G-proteinactivated inwardly rectifying potassium channel 4 (Kir3.4).
We propose that
KCNJ5 is a second gene causing AndersenTawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.
http://www.neurology.org/content/early/2014/02/26/WNL.0000000000000239.abstract
 Mutations in
Kv1.4 and Kir3.4 channels are also related to potassium and pH balance.

http://www.ncbi.nlm.nih.gov/pubmed/15454439

The information above regarding mutations at SCN4A indicates I have issues with sodium Channel, voltage-gated, type IV, alpha subnit and mutations KCNJ5 indicate strong evidence that I have a variant of Andersen-Tawil Syndrome. But I was not told of these mutations and their implications. My researches lead me to even more mutations in my genes related to calcium channels also involved with potassium shifting, periodic paralysis and pH balance.

CACNA1C

I have mutations on the CACNA1C gene, which are related to the SCN5A gene. The CACNA1C gene was not tested in the overseas research. New information has been published to relate mutations on the CACNAIC gene, also known as Cav1.1, is the first calcium channel related to Normokalemic Periodic Paralysis. I have 24 mutations on this gene!

Mutation shown in red
RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs2283284
12
2104022
cT
2.5786

rs2270371
12
2656118
Ag
4.48034

rs12230535
12
2117693
aG
6.29314

rs2302727
12
2644862
Ac
6.77245

rs2239126
12
2622948
Ag
7.29738

rs215976
12
2564899
cT
8.81847

rs4765970
12
2662922
aG
9.31559

rs11831557
12
2385250
Gt
9.37356

rs7957163
12
2675893
Ac
9.68454

rs3794288
12
2659482
aG
9.96197

rs2238096
12
2620174
aC
10.311

rs2239093
12
2479823
Ag
11.1857

rs216009
12
2592794
CC
11.5033

rs1076346
12
2424539
Ct
11.8242

rs16929471
12
2472004
Ag
13.1292

rs216013
12
2599893
GG
16.2705

rs11831085
12
2385119
aG
16.3592

rs2370515
12
2381423
Ag
16.4472

rs10848666
12
2479535
Ag
16.4819

rs1076390
12
2602980
AA
16.4989

rs2370602
12
2546944
Ct
16.5967

rs7301013
12
2378832
aG
17.0857

rs98545
12
2607556
TT
17.3897

rs215986
12
2580141
cT
19.9388

 According to Lehman-Horn F. et al, This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Ca(v)1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis. http://www.ncbi.nlm.nih.gov/pubmed/24240197/

*114205
CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C, also known as Long QT 8
Alternative titles; symbols
CALCIUM CHANNEL, L TYPE, ALPHA-1 POLYPEPTIDE, ISOFORM 1, CARDIAC MUSCLE; CACNL1A1
CCHL1A1
CaV1.2
CALCIUM CHANNEL, CARDIAC DIHYDROPYRIDINE-SENSITIVE, ALPHA-1 SUBUNIT
DHPR, ALPHA-1 SUBUNIT
CACH2
HGNC Approved Gene Symbol: CACNA1C
Cytogenetic location: 12p13.33     Genomic coordinates (GRCh37): 12:2,079,951 - 2,807,114 (from NCBI)
http://omim.org/entry/114205

CACNA1C is an important paralog of the gene SCN5A. This means the genes are related by duplication and they evolve into a new functions.
http://homepage.usask.ca/~ctl271/857/def_homolog.shtml
http://www.genecards.org/cgi-bin/carddisp.pl?gene=CACNA1C

KCNJ16 and KCNJ2

Although I do not have KCNJ2 (ATS) mutations, I have mutations at KCNJ16 on chromosome 17 at 17q23.1-q24.2. KCNJ16 and KCNJ2 (ATS) are separated by only 34 kb, which is extremely close and there is interaction and interplay between these two genes.

Mutation shown in red
RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs8072022
17
65606151
Ct
9.80244




RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs2836251
21
38555062
Gt
18.8342


***http://www.ncbi.nlm.nih.gov/clinvar/RCV000051047/


There are more mutations related to the above mutations, which I also have. But will not add them to this list.
KCNQ1

I also know that for sure I have the mutation for Long QT 1:

Mutation shown in red
RSID
Chr
Position (B36)
Genotype
%Occurrence
Gene
Matching Origins
rs12418076
11
2645676
Ct
8.77465

rs231887
11
2695756
cT
12.6968

rs9666604
11
2654171
aG
12.7112

rs12576239
11
2458895
cT
14.8241

rs1057128
11
2753813
Ag
19.2399



KCNQ1 : rs1057128 c.1638G>A (p.Ser546=) AND AllHighlyPenetrant

"AllHighlyPenetrant"
Term used to represent disorders for which a pathogenic allele would be expected to be expressed as the disorder."

This means if you have this mutation...you have a very high chance of having or developing the disease.

So it would seem I have PMC and Long QT 1 and the possibility of HyperPP and/or Normo PP and/or ATS.

No wonder I am sick!!

The reason I am sharing all of this is to let you know that the testing done on one or two genes, ordered by your doctor, is useless and the testing done overseas is not testing for every possibility. Many gene mutations work together to create illness/disease in our bodies. This is explained below.

”SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of non-coding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and may be upstream or downstream from the gene.

Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, chemicals, drugs, vaccines, and other agents. SNPs are also critical for personalized medicine.[5] However, their greatest importance in biomedical research is for comparing regions of the genome between cohorts (such as with matched cohorts with and without a disease) in genome-wide association studies.

SNPs are usually biallelic and thus easily assayed.[6] A single SNP may cause a Mendelian disease. For complex diseases, SNPs do not usually function individually, rather, they work in coordination with other SNPs to manifest a disease condition as has been seen in Osteoporosis.[7]
http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism

Unless someone can take to time, and hours, days, weeks and months...even years of research like I am doing for myself...these things can and will be missed and overlooked.

Based on all of the above information, we need to be diagnosed clinically, based on our symptoms and whole genome testing needs to be done with the hope that whoever is doing the research understands the workings among and between the genes.


I would like to conclude this article with another article posted recently:

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



 

Until later...