2020 Webinar :: Questions and Answers

2020 Webinar :: Questions and Answers

Questions at the 2020 Webinar for Dr Cannon

 

Housekeeping genes and PP? How G6PD with absent enzyme activity could impact CACNA1S? sulfa drugs are on avoid list with G6PD. How to treat PP in situation like this?
G6PD deficiency is most commonly associated with blood disorders (anemia, jaundice). Very rarely, it has been associated with muscle breakdown (rhabdomyolysis). There is no known impact of G6PD deficiency on periodic paralysis. Carbonic anhydrase inhibitors are derivatives of sulfonamides and therefore you should check with your primary care physician before going on CAIs. To my knowledge, there is no absolute contra-indication, but it would be prudent to follow the hematologic profile.
For us lay people are Episodic Ataxia and Periodic Paralysis two distinct diagnoses? does the differencial lay in EA: calcium channelopathy & PP is an Potassium channelopathy?

 

One form of EA is caused by Ca channel mutations (the other by a K channel gene), but it is a completely different Ca channel than the one affected in HypoPP. There is no genetic overlap between HypoPP and EA.

Have other ion channels genes been researched and linked to PP, like IP3 receptors (specifically IP3R3/ITPR3)?

Research studies in periodic paralysis has used unbiased gene linkage and whole exome sequencing. These approaches have not identified a defect of IP3 receptors in periodic paralysis. Some early studies also focus on ion channel genes, in general, to search for novel causes of PP. I am not aware of any studies specifically targeted on screening IP3 receptors.

More of a commentary... our family - myself included- have paralysis even with a normal potassium. In fact- my potassium level aim is 4,6 to 5,2. I paralyse under 4,3. We are a large family, not yet having found our defect. But the few that are getting help for PP besides me, need to keep their potassium very high. So high the doctors do not believe it.

Changes in serum potassium levels are clearly associated with triggering an episode of PP, but individuals may have their own threshold, and that threshold may vary with time. In practical terms, it’s important to keep a diary to log the events and identify trigger factors. A “normal” potassium level does not exclude a diagnosis of PP.

Dr. Jerath - Is the alternating myotonia and paralysis that you are talking about the same as mcyclonic jerking? This happens to me and I've learned in the ER that the treatment for it is to be wrapped in heated blankets.

Myoclonus is a rapid, brief jerking movement, often of the digits or limbs. The cause is neurological, not a muscle disorder [Steve Cannon].

Can Normokalemic include muscle stiffness up to entire body for the duration of the attack?

Yes. Most experts view normokalemic PP as a variant along the paramyotonia congenita <-> hyperkalemic periodic paralysis spectrum. Myotonia is part of the clinical presentation [Steve Cannon].

What is meant by extreme cold....below what sort of temp?...

I am not aware of careful studies where skin or muscle temperature was accurately measured. It is clear, however, that immersion of hands in cold water (does not need to be ice cold), drinking a milkshake, or being outside on a winter day can all worsen myotonia.

Can you recommend target values for potassium in hypo patients? In general, can we safely target 5.0 to 6.0

The best approach is to keep a record of what levels are needed to optimize your health. Many individuals with HypoPP are asymptomatic when K >= 4.0. Even for a specific individual, there is not a fixed threshold level of K that triggers an attack of weakness. The general trend is usually consistent; namely lower K increases the likelihood of an episode, but it is not like an all or none switch. Another important feature is that the threshold can shift over time (hours to days, not years). With normal kidney function, it will likely be difficult to keep potassium > 5.0

Can you please explain how you can get hypokpp when there is no one else in the family that has it

It has been well documented that new mutations occur spontaneously. Another possibility is the diagnosis might not be recognized for some individuals. Many women with HypoPP do not have episodic attacks of weakness, but still develop fixed weakness later in life.

I am 23 years old from Australia and have been living with Periodic Paralysis since I was 15-16. I still have not been properly diagnosed and was wondering if there is any help I can get in Australia or should I organise a video appointment with someone in America?

Most academic neuromuscular centers around the world are familiar with periodic paralysis and are equipped to make a diagnosis. Many specialists are also offering telemedicine sessions. I no longer have a clinical practice, perhaps Dr. Jerath can offer some suggestions.

What about DNA testing for those of us with somewhat unusual symptoms. I have been tested for CACNA1S, RYR1, KCNJ2, SCN4A and 105 other gene defects. No match. I have many common Hypo symptoms but also have high cpk most of the time, muscle swelling especially in my thighs, muscle pain and rarely tea colored urine (Rhabdomyolysis) after bad attacks. Are researchers looking to expand the list of gene defects?

The list of candidate genes you mention includes all of the common genetic causes for PP. The CPK and rhabdomyolysis certainly implicates a muscle problem. Up to 20% of patients with a clinical diagnosis of PP do not have an identified gene defect. Commercial labs typically have a panel of genes to be screen (as you describe). Unbiased screens of the entire genome requires much more effort and is usually performed by a research lab. If there is a large family with affected / unaffected members, or special clinical features; these attributes may encourage a research team to look for new mutations.

For people with chloride dysregulation, what can be used for anxiety other than a benzodiazepine.

I’m not sure what you mean by “chloride dysregulation”. Chloride transport problems occur in cystic fibrosis or in a neurological disorder with impaired inhibitory synaptic transmission (stiff-person syndrome). While we strongly believe the chloride distribution across a muscle cell has a strong impact on the risk of PP, periodic paralysis does not have a “chloride dysregulation”, per se.

Can you explain what's going on in the muscle when exercise is causing fluid retention that leads to weakness?
For example: ironing, making a sauce, ... everything goes well in the beginning. Then a part of my hand starts to swell. This swelling leads to weakness of the hand followed by weakness of the wrist. Furosemide takes away the swelling and brings back the strength.
Same feeling with weakness by waking up; furosemide always helps after some time.

While studies of Drs. Weber and Lehmann-Horn have shown swelling (edema) of muscle by MRI scan that is worsening during an attack of PP, I am not familiar with visibly apparent muscle swelling during an episode of PP. Interestingly, furosemide is effective at preventing weakness in our HypoPP mouse (for the same reasons I discussed in regard to bumetanide), but in our mouse model it does not help for HyperPP.

Trying to convince doctors this is not 'functional'.

There are several ways to show “objective” evidence of periodic paralysis. (1) genetic screen, (2) CMAP exercise test (false positive results are extremely rare, so an abnormal response is very meaningful). (3) Needle EMG if you also have myotonia.

What does a muscle biopsy look like for someone with PMW

Muscle fibers are often replaced by fat or fibrous connective tissue, individual muscle fibers have large clear “holes” or vacuoles, ultrastructural studies (electron microscope) may show dilation or redundancy of the transverse tubules and sarcoplasmic reticulum.

If no Myotonia is seen on an EMG, but a person has all the symptoms of Myotonia and HypoKPP (RYR1) should they even mention their Myotonia symptoms?

When discussing your symptoms with healthcare members, it’s always best to use familiar words that describe what you experience, rather than medical terms.There are other conditions that cause inappropriate muscle contraction in the absence of electrical activity, and therefore is not myotonia (for example Brody disease, which is caused by mutations in a calcium pump). It’s conceivable that a RYR1 defect is causing inappropriate Ca release (and therefore producing contraction) without electrical activity of the muscle fiber.

I've taken Adderrall for three days and have not had any weakness and triggers are no longer effecting me. I was weak from Dec 2019 until this past Thursday. I stopped Adderall two weeks before a five hour paralysis episode, I did not fully recover from. What effects can a stimulant such as Adderall have on this issue? I have taken the medication for 4 years for ADHD before I gradually weaned off.

To my knowledge there is no established connection between Adderall usage and periodic paralysis. That said, I would never argue with personal experience.

Do people who have acquired toxicity pass these mutations to their children?

Some “acquired” conditions have a component that is heritable. For example red hair and fair skin are heritable and increase the risk of an “acquired” condition, namely sunburn. So, without more specifics it is difficult to answer your question. The only known “acquired” form of periodic paralysis is from thyrotoxicosis.

Since these mutant ion channels involve amino acids, is that why my serine levels are gradually pooling?

There is no connection between the ion channel mutations in periodic paralysis and amino acid metabolism.

This as after having the Strongbridge / Invitae testing done to rule out the 4 known variants.

The definition of “variant of unknown significance” evolves are we learn more about specific variations in DNA. At present, there is no available commercial service to perform functional testing of a genetic variant.

So when will there be anyone who has any more than a passing reference to ATS? The first speaker couldnt even spell it, this speaker (Dr Cannon) has dismissed it & chosen to concentrate on other things... I understand its the rarest thing, but if it doesnt get discussed here (other than to say this is the definition of ATS, and thats great, but we know that info) where will it ever get discussed?.... the answer is... no where. Bit disappointed.

I discussed new findings in our mouse model of ATS at the 2019 PPA Conference. The talk is available on-line at the PPA site.

In the lodocane study with repeated electrocution which lowered seizure threshold, would that create the sodium mutation.

No, electric shock is not associated with causing ion channel mutations.

As you mentioned, the channels SCN4A and CACNA1S have no appearance in the heart muscle. Is there an explanation for tachycardia and cumulative ventriclar extrasysoles in hypokalemic PP-patients with mutations in these two channels?

Furthermore I have some specific questions about the replacement of Arginin in CACNA1S but it's hard to write them just in time here as we're from Germany. Is it possible to write a mail to you afterwards.

The PPA has an “ask the experts” forum on the web site. This is the best way to submit a question (so that others can also benefit from the answer). I frequently answer questions on this forum.

With regard to the heart issues, there are two thoughts on this. First, SCN4A is expressed at low levels in the heart. Second, skeletal muscle is a huge reservoir for ions in the body (especially potassium). During episodes of PP, ions redistribute into the skeletal muscle and this can have secondary changes on heart electrical properties.

I remember that in the past, insulin was used as a test for PP. Many of my episodes seem to be triggered by a low blood sugar trigger, especially when I am in a hospital situation where I cannot control my diet. Will you explain chemically how this becomes a trigger?

Carbohydrate ingestion (sugar or starch), causes insulin release. Insulin binds to receptors on many tissues, but especially muscle and liver, which causes glucose (sugar) uptake in these tissues. This movement of sugar is couple to movement of potassium and so blood potassium levels can decrease substantially.cc

I believe I am more confused now than before tuning in to hear David Griffin. I have been told I do have hypokalemic periodic paralysis and I was diagnosed at Henry Ford Hospital in Detroit. The endocrinologist at Henry Ford referred me to The children's hospital in Detroit and the specialist there did confirm I have hypokalemic periodic paralysis. Will you please confirm with me that there is such a thing as secondary hypokalemic periodic paralysis which is caused by something else causing the symptoms of hypokalemic periodic paralysis? Is this even possible.

Primary periodic paralysis occurs when there is an inherited defect in the muscle (ion channel dysfunction). Secondary periodic paralysis is weakness that will occur in normal muscle when there is “external” cause, for example an extreme change of ions in the blood. These severe changes tend to occur in certain forms of kidney disease or if there is an unusual fluid loss (eg very severe diarrhea)

Do you know of a lecture similar to yours (that describes for example how acidity affects muscle function) but for myotonia congenita? Perhaps presented in one of those vimeo presentations.

Acidosis may aggravate myotonia. It is well known that acidosis causes reduced function of chloride channels in muscle (the same ones that are defective in myotonia congenita). In our HyperPP mouse model (SCN4A M1592V), acidosis clearly worsens myotonia. Sorry, I’m not aware of a video presentation on this topic

Is there anything to report in ATS research over the last year or two

See the PPA Conference from 2019

Bumetanide seems to be as effective as warm down.... but he didnt show them against eachother.. obviously its better not to take medication. Is that correct?

We have found synergistic benefits from using simultaneous approaches to reduce the risk of HypoPP. For example, being both well hydrated and keeping K higher is better than either alone for protection against post-acidosis loss of force. Bumetanide is not yet approved for symptomatic treatment in HypoPP (or ATS). As you say, lifestyle changes are preferred over medication if the result is effective. 

You mentioned this year and last how valuable input from patience has been directing his research. Has though been given to leveraging the PPA's network to survey patients in mass on symptoms, triggers, and/or treatment/management?

Hi J,

Thanks for suggesting surveys to assist research efforts. This topic has come up at many prior PPA meetings, and some informal surveys were done. Jake Levitt wrote up the results and published it. I always welcome information on personal experience with PP.

I'm in the UK but I'm happy to help with research in any way at all. How can I help you help me?

Dr. Michael Hanna’s group at Univ College London / Queen’s Square Neurological Institute is very active in muscle channelopathy research in the UK. They intermittently have clinical trials and natural history studies. I am sure they would welcome your participation. I believe the NHS is a good clearinghouse for the announcements.

How can I help a patient who is recently diagnosed with PPP?

Education and community engagement are two effective approaches. The PPA is a great place to start!