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In Focus
Dear Readers Fast Facts
This In Focus report is the third in a series of MDAs three-year commitment for all Hypokalemic periodic paralysis
MDA comprehensive reports about the latest in periodic paralysis research as of March Hypokalemic PP can begin anywhere from
neuromuscular disease research and manage- 2009 is $1,938,367. The Associations early childhood to the 30s, with periodic
ment. allocation for research on hyperkalemic attacks of severe weakness lasting hours
This report focuses on the periodic and hypokalemic periodic paralysis to days. The frequency of attacks gener-
paralyses, a group of disorders that result from research since 1950 is $8,125,341. ally lessens in the 40s or 50s. Permanent
malfunctions in so-called ion channels, micro- MDAs allocation for the recently weakness may persist between attacks,
scopic tunnels that make possible high-speed identified Andersen-Tawil syndrome usually beginning in middle age and pro-
movement of electrically charged particles is $515,430 since 2001. MDA is cur- gressing slowly over years.
across barriers inside cells and between cells rently funding 11 grants in the periodic The most common underlying cause
and their surroundings. paralyses. is any of several genetic mutations in
When ion channels fail to open or close The periodic paralyses are gener- a gene on chromosome 1 that carries
according to an exquisitely fine-tuned program, ally divided into hyperkalemic periodic instructions for a calcium channel protein
episodes of paralysis of the skeletal muscles paralysis, hypokalemic periodic paralysis in skeletal muscle fibers. When this chan-
and even temporary irregularities in the heart- and Andersen-Tawil syndrome. The first nel fails to transmit a signal to a calcium
beat can occur. two are caused by genetic defects in storage area inside the cell, the muscle
Throughout history, and unfortunately high-speed tunnels in skeletal muscle fiber cant contract. A minority of people
down to the present day, people who experi- fibers known as ion channels. The last is have sodium channel mutations, but not
ence episodes of paralysis or weakness, inter- due to such defects in both skeletal and the same ones that cause hyperkalemic
spersed with periods of normal functioning, cardiac muscle. periodic paralysis.
have been met with suspicion by their peers All forms of periodic paralysis affect
and even their doctors. Individuals have been both sexes equally and are inherited in Andersen-Tawil syndrome
accused of faking their attacks to gain atten- a dominant manner, meaning only one This syndrome usually begins in child-
tion or shirk their responsibilities, and parents genetic flaw (mutation) from one parent hood or adolescence and is characterized
have been suspected of child abuse when their can cause the disease. by episodes of weakness of the skeletal
children displayed these mysterious symptoms. muscles and irregular heartbeat in the
Today, molecular biology has pinpointed the Hyperkalemic periodic paralysis cardiac muscle. Occasionally people may
precise mechanisms that underlie the periodic Hyperkalemic PP usually begins early develop permanent weakness between
paralyses, and drug trials to treat them are in childhood, with episodes of muscle episodes. Heartbeat irregularities can
under way. There is much work to be done, but weakness or paralysis lasting from 15 be serious enough to warrant treatment
awareness of the diagnosis can provide signifi- minutes to hours or even days. With with medication or electronic devices.
cant reassurance and help in managing these time, some people develop permanent Widely spaced eyes, low-set ears and a
conditions. mild or moderate weakness that persists small chin also are characteristic of this
This special section includes: between bouts of severe weakness. disorder.
Fast Facts about periodic paralysis Some patients also experience episodes The underlying cause of Andersen-
An update on state-of-the-art research and of myotonia, the inability to relax mus- Tawil syndrome is any of a number of
disease management, with first-person cles completely. genetic mutations in a chromosome 17
stories from families affected by periodic The underlying cause is any of sev- gene for a potassium ion channel present
paralysis eral genetic mutations in a gene on chro- in both skeletal and cardiac muscle tissue.
Information about genetic testing mosome 17 that carries instructions for When these channels fail to open, the
To learn more about periodic paralysis, visit a sodium channel protein. The sodium exit of potassium from muscle cells after
www.mda.org or call your local MDA office at channels in skeletal muscle cant close they contract is impaired, and the cells
(800) 572-1717. properly, permitting an excess of sodium cant reset to receive further contraction
ions to enter the muscle fibers. signals.
People who know me know I lead an visited the MDA clinic at Yale University added to local
extremely active life, says Linda Feld in New Haven, Conn., where a doctor anesthetics,
of Longwood, Fla. People dont see me suggested her condition might be peri- also can cause
as somebody on a scooter. Im Linda, odic paralysis but wasnt sure. problems. If
and I do all these things every day, and She tried to work, but soon it the respiratory
they know me for me. I tell people that became more and more difficult to hold muscles are
periodic paralysis has become my friend. down a job. The weakness episodes affected, respi-
Its along for the ride, but its not going to would come on, and I couldnt get out of ratory insuf-
rule my life. my desk chair at work. Id be sitting there ficiency can
Feld, now 59 and a hospice volunteer, working and couldnt get up to go to the result. Linda Feld didnt get a
says her experience with the genetic copy machine. It became impossible to Felds father definitive diagnosis until she
was 56 years old.
disease she now knows as hypokalemic hold a job. became com-
(low potassium) periodic paralysis As she aged, the paralysis episodes pletely paralyzed after the anesthesia he
goes back to her earliest memories, at ceased, but were replaced by progres- was given for the tracheostomy proce-
age 3 or 4. sive and ultimately permanent weakness. dure and succumbed to a respiratory
I would develop a limp [periodical- (The lack of episodes and the permanent arrest a few days later.
ly], she recalls. Were talking the early weakness made diagnosis even more Feld finally got a definitive diagnosis
1950s, and not much was known about elusive.) She tried breeding dogs, but the when she was 56 years old, through the
periodic paralysis. Even though my father work of maintaining a kennel eventually laboratory of Frank Lehmann-Horn at
was disabled, he didnt have a diagnosis. proved too taxing. Ulm University in Germany.
An orthopedic specialist suspected Felds sister, Sally, nine years younger, Lehmann-Horn, who received several
her legs were of unequal length and pre- began following a similar pattern. When MDA grants in the 1990s to study the
scribed a lift for her shoe and supportive she reached her teenage years, she periodic paralyses, was originally trained
footwear. It was always very important started with terrible episodes of muscle as an engineer, later becoming a medical
to my parents that I wore really sturdy cramping, Feld recalls. Sally was given doctor. Hes widely regarded as an out-
shoes. I wanted to be like the other kids an erroneous diagnosis of limb-girdle standing contributor to the study of ion
and wear sneakers, Feld says. muscular dystrophy. channel physiology, having done more to
I was never good at gym in school. Their father retired at age 55 because describe its behavior in health and dis-
There was teasing by fellow classmates. of continued weakness, including weak- ease and to apply his findings to patient
I couldnt run fast. When I reached ness of his respiratory muscles. A bad care than perhaps any other professional.
my teen years, I started having terrible chest infection when he was 72 caused Feld says the disease has forced many
muscle cramps. There was nothing that his doctor to recommend a tracheostomy, compromises in her life. I had to learn
would alleviate the pain. The muscles a surgical opening in the trachea, through I could not be everything that every-
became rock hard. It was not my whole which mucus would be suctioned out. body else was. I couldnt be the athlete,
body, always just a limb. Those cramps The family was unaware at the couldnt follow the crowd and do what
lasted 24 to 48 hours. Then they would time that certain anesthetics, both gas they did. I couldnt go out and go drink-
start to subside, but the weakness took and local, and muscle relaxants called ing with them. Alcohol was a big trigger.
weeks to come back from. I missed big depolarizing agents, frequently used I wish I had known earlier in life some of
segments of school. during surgery, can cause long-lasting the things that work for people.
Feld finished high school and went on and severe weakness in people with Today, she manages her disease with
to college. When she was about 20, she periodic paralysis. Epinephrine, often a medication called eplerenone (Inspra),
Acetylcholine leaves the nerve fiber and docks on receptors in the muscle Sodium channels open in response to this small depolarization, permitting
membrane, causing that area of the muscle fiber to become slightly more a huge flow of positively charged sodium ions to enter the muscle fiber. The
positive (depolarized). depolarization is greatly amplified, and a brief electrical impulse (action
potential) spreads throughout the fiber.
In the early 2000s, Rabi Tawil at the not on the X chromosome and that one environment, such as when foods high
University of Rochester (N.Y.) led an defect, inherited from one parent, is suf- in potassium are ingested or when a
effort to collect a large cohort of patients ficient to cause the disease. But in many person rests after exercising. Under these
and refine the diagnostic criteria. Tawil cases, the person with periodic paralysis circumstances, the sodium channels fail
is co-director of the MDA clinic at the knows of no family history of the condi- to close right away, allowing sodium to
University of Rochester Medical Center, tion. In these cases, its believed to be continue leaking into the muscle fiber and
where he conducted MDA-supported caused by a new genetic mutation, not keeping the muscle fiber (muscle cell)
research on what would later become one thats been seen before in the family. membrane depolarized.
known as Andersen-Tawil syndrome. (From that point on, however, it can be This depolarization may cause pro-
Ptacek and colleagues identified the inherited by future generations.) longed muscle contraction temporarily.
underlying genetic and biochemical However, weakness or paralysis soon
mechanisms. A long and winding occur, because a depolarized muscle fiber
Andersen-Tawil syndrome is inter- cant receive new signals from a nerve
road led to hyperkalemic
esting and different, Ptacek says. Its cell.
a complicated, multisystem disease.
periodic paralysis Too much potassium narrows the
Like other periodic paralyses, its highly diagnosis
penetrant, which means that if you have Hyperkalemic PP stems from mutations
the genetic mutation, you get the dis- in the sodium channels that sit on the
ease. But the variability of the disease is surface of muscle fiber membranes.
extremely high. Its very different from These channels normally respond to
one patient to another, even within the a signal from a nerve cell by opening
same family. briefly and allowing sodium ions to flow
Although doctors and patients have into the fiber.
long noted that periodic paralysis could Sodium ions carry a positive electrical
run in families, scientists did not begin to charge, and when they enter a cell, they
identify the precise genetic abnormalities make it more positive, a phenomenon
involved until the 1990s. referred to as depolarization.
All forms of periodic paralysis are But mutations in the sodium channel Before her periodic paralysis was diagnosed, the
parents of Faith Couture (in front) were told their
inherited in an autosomal dominant fash- gene cause these channels to malfunc- daughter might have seizures, growing pains, arthritis
ion, which means the genetic defects are tion when theyre in a high-potassium or multiple sclerosis.
calcium
channel
calcium
ions
cholride channel
thick filament
thin filament
Depolarization of the muscle fiber is sensed by calcium channels and trig- The sodium channels spontaneously close, potassium channels open, and pos-
gers the release of calcium ions from internal storage areas. This flood of itively charged potassium ions exit the fiber. Chloride channels also stay open,
released internal calcium is the chemical signal that causes the thick and and negatively charged chloride ions enter the fiber. All these actions cause
thin filaments of the muscle fiber to slide past each another (contract). the inside of the fiber to become more negative (repolarized). The muscle
fiber returns to its resting state, calcium is pumped back into the internal stor-
age vesicles, and the fiber is now ready to accept another surge of positively
charged ions in response to stimulation from a nerve fiber. (When several
muscle fibers are at rest, a muscle can relax.)
safety margin, and people with hyper- Its in your daughters head. Get over it. Faith is in the extremely unusual situ-
kalemic periodic paralysis have less of Faiths father was in the Air Force at ation of being steered away from most
a safety margin to begin with, Ptacek the time, and the frequent moves around fruits and vegetables, which are high in
says. When you increase the extracel- the country added complications to the potassium, and toward sugar, which can
lular potassium, it pushes them over a diagnostic process. ward off an attack of paralysis. For now
threshold where the cell remains depo- Weve had so many misdiagnoses we try to manage her diet and watch how
larized. that if we hadnt taken the initiative and much she has in fruits and vegetables,
Thats what began happening to Faith been guided by two or three doctors, we her mother says. The only problem
Couture of Dayton, Ohio, when she was 2 probably would have gone with whatever we have with her is tomatoes. Shes a
years old. Shes now 9. we heard. We were told 19 times this was Southern child and loves tomatoes.
It looked like she would play pos- seizures. Because some kidney diseases
sum when anybody would get her out of When Faith was 7, the family received require a potassium-restricted diet, a
the car, says her mother, Enola. But we orders to go to Ohio and ended up at good reference for the potassium content
started thinking, shes too young to do Childrens Hospital in Dayton. There, a of foods, and a method to reduce the
that. We watched how she reacted when geneticist who had worked with Robert potassium in vegetables, is the National
we set her on the ground. She was like a Griggs, a longtime MDA grantee at the Kidney Foundation Web site at www.
blob of Jello. She would just collapse and University of Rochester, thought he knew kidney.org. (There are, however, marked
start crying. what the problem was and recommended differences between the management of
Soon after the car episodes, Faith DNA testing. kidney disease and periodic paralysis,
began waking up from naps unable to They took her blood two days before even if they overlap in one area.) The
move, sweating and screaming. There her eighth birthday, Enola recalls. When potassium fact sheet can be found at
was no family history of anything like it came back a month later, it was like www.kidney.org/news/newsroom/fs_new/
what Faith was experiencing. Christmas. The diagnosis hyperkale- potassiumCKD.cfm; or you can contact
The pediatrician suggested the prob- mic periodic paralysis wasnt some- the Foundation at (800) 622-9010.
lem was growing pains, later revising thing we were extremely excited about, Giving Faith some sugar to take to
his diagnoses to juvenile arthritis or mul- Enola says, but we were excited to know school has helped somewhat as well,
tiple sclerosis. A referral to one neurolo- that we werent crazy. says Enola. A Coke around 11 a.m.
gist resulted in a diagnosis of learning Faiths episodes still arent well con- seems to have helped a little bit. Shes
disability and speech impairment, while trolled, but her mother says theyre still not having [attacks] as frequently. We
another neurologist told the Coutures, testing everything. keep an eye on her.
Location of problem sodium channel calcium channel (most common) potassium channel
sodium channel
Functional defect channel does not close properly; calcium channel on cell surface channel does not open properly;
prolonged sodium leak into cell does not transmit signal for inte- potassium cant leave cell
rior calcium release
Development of may occur; increases with age may occur; increases with age may occur; increases with age
permanent weakness
Muscle pain may occur in exercised muscles may occur in exercised muscles may occur in exercised muscles
Episode triggers high blood potassium; high low blood potassium; high car- high or low blood potassium,
potassium intake; fasting; cold bohydrate intake; rest after exer- depending on exact genetic
temperatures; certain anesthetics; cise; cold temperatures; certain mutation; certain anesthetics;
depolarizing muscle relaxants anesthetics; depolarizing muscle depolarizing muscle relaxants;
relaxants other triggers consistent with
either hyper- or hypokalemic PP
would fall down for no apparent reason. had pulled the door shut on my room that sodium and by cold temperatures.
They tried high-top shoes. We went to night. I was trying to yell, but I couldnt, Until about 25, it was very rough. I
different doctors, but they didnt under- and I couldnt reach the buzzer. had a lot of attacks. I always had a rough
stand the problem. Parker was finally taken to Ohio State time holding jobs. Its hard to explain to
Then, at age 12, Parker experienced by ambulance, where they started treating people. Im 6 feet 2, 290 pounds. I could
his first true attack of periodic paralysis. him with oral potassium. Several hours tear the barn doors off a barn, but some
My parents were out for the evening, later, his serum potassium level was back days I cant get out of bed.
he remembers. I was sitting on the up, and the diagnosis became clear. Parker has the type of hypokalemic
couch, eating popcorn and drinking a They did a lot of tests. They finally PP caused by a mutation in a cell-sur-
pop. I went to get up and I couldnt. got me medicated and got me going. face calcium channel gene. (A minority
Parkers parents arrived home, and his Parker began taking oral potassium and of patients have hypokalemic PP caused
father tried unsuccessfully to get him up acetazolamide. by sodium channel mutations that are
and walking. My legs didnt work, and my Ptacek admits that the mechanism by different from those that cause hyperka-
arms were weak. I could still move them a which acetazolamide and other diuret- lemic PP.)
little bit. I could wrap my arms around my ics in the carbonic anhydrase inhibitor The surface calcium channels, unlike
dads neck, he remembers. family actually work in periodic paralysis the other ion channels, dont play an
At Childrens Hospital, Parkers serum remains uncertain. Some experts believe important role in the movement of calcium
potassium level was 1.8, which is very they interact directly with ion channels, into and out of the muscle fiber. Instead,
low, and he was started on potassium he says, while others believe their effects their role is to sense changes in the
supplements. That started a whole pro- on the acidity of the serum are involved. electrical state (voltage) in the fiber and
cess of doctoring. We went through a The teenage years were very rough transmit signals to storage areas inside
whole gamut of potassium [types] to find for me, Parker says. He had paralysis the fiber, from which calcium ions are then
the one that worked for me. Although attacks every few days, often requiring a released, causing contraction of the fiber.
Parker still didnt have a diagnosis, at hospital stay. When the surface calcium channels
least he had something that seemed Like other periodic paralysis patients, malfunction in hypokalemic PP, this sig-
treatable, if imperfectly. he soon learned that high-carbohydrate naling doesnt happen, and the muscle
Then, at 15, he experienced a major meals (such as the popcorn and soda he fiber doesnt contract.
attack of paralysis. He was already in the ingested the night of his first full-blown In 2002, Parkers DNA was tested at
local hospital undergoing intravenous episode) trigger attacks. (Like intrave- Lehmann-Horns laboratory in Germany,
treatment for an extremely low serum nous glucose, these carbohydrates cause the same lab that would later pinpoint
potassium level. Unfortunately, in addi- potassium to migrate from the serum Linda Felds genetic abnormality, and he
tion to potassium, the IV contained into the cells, lowering serum potassium learned the precise mutation that affects
glucose (sugar), which drives potassium levels.) But the paralysis was still unpre- his calcium channel gene.
from the bloodstream into cells. dictable. Although his own attacks of paralysis
When treating potassium deficiency in I could eat almost anything and not have become less frequent, he now has a
other conditions, that would be the goal. have an attack and then three days later son and a daughter with the disease.
But in hypokalemic periodic paralysis, have an attack, he says. He also found From what we were told [in the
which Parker would soon learn was his attacks could be triggered by excess 1980s], we thought it couldnt be geneti-