Questions For Dr. Cannon – 2020 Conference

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.

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.

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.

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.

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].

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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)

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

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.

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.

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’m sure they would welcome your participation.  I believe the NHS is a good clearinghouse for the announcements.

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