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HOFFMANVOLTAGE-GATED ION CHANNELOPATHIES

0066-4219/95/0401-0431$05.00431

Annu. Rev. Med. 1995. 46:43141

Copyright 1995 by Annual Reviews Inc. All rights reserved

VOLTAGE-GATED ION

CHANNELOPATHIES: Inherited

Disorders Caused by Abnormal Sodium,

Chloride, and Calcium Regulation in

Skeletal Muscle

Eric P. Hoffman, Ph.D.

Departments of Molecular Genetics and Biochemistry, Human Genetics, and Pediatrics,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

KEY WORDS: myotonia, voltage-gated ion channels, sodium channels, chloride channels, cal-

cium channels, genetic disease

ABSTRACT

The pathological genetic defects in the inherited myotonias and periodic pa-

ralyses were recently elucidated using molecular genetic studies. These disor-

ders are usually transmitted as a dominant trait from an affected parent to a

child. The many clinical symptoms include cold-induced uncontrollable con-

traction of muscle, potassium-induced contraction and paralysis, myotonia

with dramatic muscular hypertrophy, muscle stiffness, and insulin-inducedparalysis (in males). Horses afflicted with the disorder can suddenly collapse,

despite an impressive physique. In the past three years, these clinically defined

disorders have been shown to share a common etiology: subtle defects of ion

channels in the muscle-fiber membrane. Although the specific ion channel

involved varies depending on the disease, most patients have single amino acid

changes in the channel proteins, with both normal and mutant channels present

in each muscle fiber. For each patient, we can now establish a precise molecu-

lar diagnosis in the face of overlapping clinical symptoms and begin specific

pharmacological treatment based on the primary problem. These studies have

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THE VOLTAGE-SENSITIVE SODIUM CHANNELOPATHIES

Whereas the acetylcholine receptor sodium channel initiates the action poten-

tial at the neuromuscular junction, the voltage-gated sodium channel carries

the action potential throughout the muscle membrane. The influx of sodium

through this channel results in a cascade of events culminating in muscle fiber

contraction. The channel has a single major polypeptide chain composed of

approximately 1800 amino acids. The polypeptide crosses the lipid bilayer at

least 24 times, resulting in a doughnut shape (Figure 1). The hole of the

doughnut is a regulated pore through which sodium is allowed to flow along

its concentration gradient, from outside the myofiber into its cytoplasm. A

smaller beta subunit has also been identified that appears to regulate the major

Figure 1 Schematic diagram of a small region of a muscle fiber. Some of the major ion channels

involved in generation of action potentials, as well as the genetic disorders associated with these

channels, are depicted. The nerve connects to the muscle at the neuromuscular junction, and

acetylcholine released by the nerve terminal binds the acetylcholine receptor sodium channel in the

muscle fiber. The resulting influx of sodium causes a change in the membrane potential that isdetected by voltage-sensitive sodium channels distributed throughout the myofiber surface mem-

brane and the t-tubules (verticle tubes transversing the myofiber). This change triggers the voltage-

sensitive calcium channel of the muscle membrane [also called the dihydropyridine (DHP) receptor],

which permits calcium influx. The plasma membrane calcium channel is directly connected to the

calcium-release channel of the sarcoplasmic reticulum (ryanodine receptor). The ryanodine receptor

releases calcium, which in turn triggers myofibrillar contraction. Between action potentials, the

muscle fiber must maintain a resting membrane potential of approximately 70 to 90 mV. This

resting membrane potential is regulated by the voltage-sensitive chloride channel.

B924301

K+

Action

Potential

70mV

+60mV

70mV

Na+

Na+

K+

Ca2+

Ca2+

Na+

ACH ACH ACH

Na

+Na

+

Sodium Channel (Na+)Hyperkalemic Periodic Paralysis

Paramyotonia Congenita

ACH Receptor

Na+

Channel

Ca2+

DHPReceptor (Ca

2+)

HypokalemicPeriodic Paralysis

RyanodineReceptor (Ca

2+)

MalignantHyperthermia

Chloride Channel (Cl-)

Congenital Myotonia

Cl-

VOLTAGE-GATED ION CHANNELOPATHIES 433

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alpha subunit. Considerable research on the structure of the channel has re-

sulted in the delineation of subregions of the major alpha subunit. These

subregions seem to control selectivity of the channel for sodium, voltage

sensitivity, and speed of opening and closing (gating).

Hyperkalemic periodic paralysis is a dominantly inherited disorder charac-

terized by attacks of skeletal muscle paralysis associated with high serum

potassium levels. Attacks usually begin in the second decade and vary both in

frequency and in duration. Respiration is rarely affected, and the disorder is

considered benign. Attacks are most often induced by rest after strenuous

exercise, although ingestion of foods high in potassium, such as bananas, can

also induce attacks in some patients. An important discovery was the electrical

inexcitability of muscle during an attack: Affected muscle could not sustain an

action potential, suggesting an abnormality in the regulation of ions and volt-

age in the muscle fibers. Thus, the ion channel proteins became candidates forthe primary biochemical defect.

A similar disorder was described in quarter horses, the most popular breed

of horse in the US (2). The disease appeared to be quite common in the show

or halter class of these horses and was associated with the most successful

breeding line. Affected horses experienced attacks of paralysis (Figure 2) that

were often induced by stimuli analogous to those that provoked attacks in

humans (rest after exercise, or ingestion of feed high in potassium, such as

alfalfa). Some affected horses have substantial interictal myotonia, which

owners often describe as worms under the skin. This myotonia could be aform of autoexercise, which gives the horses an impressive physique that

seems to have increased their success in the show ring (3). Interictal myotonia

has also been seen in most humans with hyperkalemic periodic paralysis,

although it is generally not as dramatic as in horses.

A series of genetic linkage studies in both human and horse pedigrees

(47), followed by gene mutation studies (1a, 8), identified single amino acid

changes in the muscle sodium channel gene that result in hyperkalemic peri-

odic paralysis in both species. The sodium channel gene is comprised of

approximately 30,000 base pairs, with approximately 6000 base pairs of pro-tein coding sequence (9, 10). A single base pair is changed in one of the two

sodium channel genes of each affected species member, resulting in a single

amino acid change in the protein product. This change alters the character of

the channel, such that it does not function correctly. Recent studies have begun

to carefully investigate the electrophysiological features of the mutant chan-

nels, either by examining muscle cells of affected humans and horses or

through expression of mutant channels in experimental systems. These studies

promise to identify the precise effect of the amino acid change on channel

function and will shed light on normal channel function through the study of

dysfunction (1115).

434 HOFFMAN

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Figure 2 Attacks of paralysis in a quarter horse with hyperkalemic periodic paralysis. Shown is a

quarter horse that is a member of the most popular line of halter class horses, with pronounced

musculature thought to be secondary to interictal myotonia (upper panel). Injection of potassium

salt induces an attack of paralysis (lower panel). The muscle cannot sustain an action potential during

an attack. This disease is caused by a single amino acid change (phenylalanine to leucine) in the

1800amino acid voltage-sensitive sodium channel in horse muscle. In both humans and horses,

this change occurs in only half the sodium channels in muscle. The disorder is dominantly inherited

in both species. Reproduced from Ref. 15a.

A

B


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Study of patients and families with different but overlapping phenotypes

have shown that other clinically defined types of myotonia were also caused

by distinct mutations of the sodium channel (1618). Paramyotonia congenitais a benign yet fascinating disorder first described in the late 1800s that

presents with myotonia in muscles exposed to cold temperature (Figure 3).

The myotonia is often associated with residual weakness that eventually re-

covers. Pure myotonia, without sensitivity to cold or attacks of paralysis, has

also been observed with sodium channel mutations and has been termed so-

dium channel myotonia (19, 20). Patients with overlapping symptoms have

also been identified (21).

Patients with sodium channelopathies often cannot be diagnosed by clinical

and electromyograph examination alone. Although myotonia is a frequentfeature of sodium channelopathies, some patients with hyperkalemic periodic

paralysis do not exhibit interictal myotonia (22). A positive family history

facilitates diagnosis; however, isolated cases with new mutations have been

reported (1a). DNA studies are often diagnostic, particularly in hyperkalemic

periodic paralysis, which involves two common mutations (Table 1).

Paramyotonia congenita is much more heterogeneous at the molecular level.

Intuition suggests that myotonia (hyperexcitability) and paralysis are re-

sponses to distinct electrical abnormalities of the muscle fiber. However, myo-

tonia and paralysis share a common etiology in perturbations of the resting

membrane potential of the muscle. If the resting membrane potential becomes

Figure 3 Cold-induced myotonia in a relative of Dr. Ezra Clark Rich, a Utah physician who

described the disease (paramyotonia congenita) in his own family. Shown is an aunt of Dr. Rich,who exhibits no symptoms of a muscular abnormality unless exposed to cold temperatures (left

panel), whereupon the muscle shows dramatic myotonia. Upon warming, muscle function returns

to normal (right panel). This disorder is caused by many different single amino acid changes of the

voltage-sensitive sodium channel of muscle. Reproduced from Ref. 15b.

A B

436 HOFFMAN

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Disorder

Hyperk

alemicperi-

odicpa

ralysis(hu-

mans)

Hyperk

alemicperi-

odicpa

ralysis

(horses

)

Paramyotonia

congen

ita

Sodium

channel

myoton

ia

Thoms

ensmyo-

tonia

Becker

smyotonia

Hypokalemicperi-

odicpa

ralysis

Table1

Summaryofclinicalfeaturesandmoleculardataforthemusclev

oltage-sensitiveionchannelopath

ies

Clinicalfeatures

Episodesofparaly

sisin-

ducedbyrestafterexer-

cise,intakeofpotassium

Episodesofparaly

sisin-

ducedbyrestafterexer-

cise,alfalfahay.

Clinicalvariability

:

manyhorsesasym

pto-

matic,othersmaygo

intoshockanddie

.

Cold-inducedmyo

tonia

Constantmyotonia

Constantmyotonia,stiff-

ness

Constantmyotonia,stiff-

ness,muscularhypertro-

phyAttacksofparalysispre-

cipitated.Mostwo

men

whocarrythedise

ase

genedonotshowsymp-

toms.

Electromyograph

Interictalmyotonia.

Duringattacks,

muscleisinexci-

table.

Dramaticinterictal

myotonia.Oftende-

scribedasworms

undertheskin

Cold-inducedmyo-

tonia

Myotonia

Myotonia

Myotonia

Negative

Gene

Skeletalmuscleso-

di

umchannelalpha

su

bunit

Skeletalmuscleso-

di

umchannelalpha

su

bunit

Skeletalmuscleso-

di

umchannelalpha

su

bunit

Skeletalmuscleso-

di

umchannelalpha

su

bunit

Skeletalmuscle

ch

loridechannel

(C

lCl)

Skeletalmuscle

ch

loridechannel

(C

lCl)

Skeletalmusclecal-

ciumchannel

(D

HPreceptor),al-

ph

a-1subunit

Inheritancep

attern

Dominant

Dominant;descen-

dantsfromacom-

monsire

Dominant

Dominant

Dominant

Recessive

Dominant

Typeofmutation

Singleaminoacid

changesinone

genecopy

Singleaminoacid

changeinonegene

copy

Singleaminoacid

changesinone

genecopy

Singleaminoacid

changesinone

genecopy

Singleaminoacid

changesinone

genecopy

Alterationsinboth

genecopies

Singleaminoacid

changesinone

genecopy

M

utations

5mutations,2

ca

use80%ofcases

1mutationcauses

al

lcases

7mutations,most

in

individualpa-

tients

3mutations,most

in

individualpa-

tients

4mutations,1

ca

uses70%of

ca

ses

5mutations,most

in

individualpa-

tients

3mutations,2

ca

use~70%of

ca

ses


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slightly more positive (i.e. changes from 70 to 60 mV), the myofiber can

more easily reach the threshold for the triggering of an action potential, and the

muscle becomes hyperexcitable. Hyperexcitability is probably synonymous

with myotonia. If, however, the resting membrane potential becomes even

more positive (i.e. changes from

60 to

40 mV), the fiber cannot fire anaction potential owing to loss of a sufficient membrane potential. This inability

to fire is synonymous with paralysis. Thus, the dramatic clinical differences

among patients with sodium channelopathies may reflect relatively minor

differences in abnormalities of the membrane potential (23). Prophylactic

treatment with potassium-wasting diuretics is often successful in reducing

frequency and severity of attacks.

THE VOLTAGE-GATED CALCIUM CHANNELOPATHIES

The ion channel primarily responsible for translating the plasma membrane

voltage changes (induced by the sodium channel) to the intracellular calcium

storage compartment (sarcoplasmic reticulum) is the plasma membrane cal-

cium channel. This voltage-gated calcium channel, also called the dihydro-

pyridine (DHP) receptor (Figure 1), opens in response to the voltage changes

caused by the sodium channel and permits calcium to enter the myofiber. It

forms physical and functional associations with a very large calcium channel

in the intracellular membrane of the sarcoplasmic reticulum known as theryanodine receptor. The ryanodine receptor is a calcium-gated, calcium-re-

lease channel that releases large amounts of calcium contained in the sarco-

plasmic reticulum. The calcium released by the sarcoplasmic reticulum binds

to the myofibrillar apparatus and causes the myofiber to contract. The transla-

tion of electrical signaling at the surface membrane into intracellular calcium

release from the sarcoplasmic reticulum is known as excitation-contraction

coupling.

Hypokalemic periodic paralysis is a dominantly inherited disorder associ-

ated with a low serum potassium level during attacks. This disorder differsfrom hyperkalemic periodic paralysis in several additional respects: The at-

tacks can be very severe in certain patients; women with the same mutation are

much less severely affected than men; attacks are often triggered by high

carbohydrate intake or insulin challenge; and this condition can lead to a

progressive disabling myopathy.

Family genetic studies using experimental strategies similar to those em-

ployed for the sodium channelopathies recently identified single amino acid

changes in the voltage-gated calcium channel as the cause of the majority of

cases of hypokalemic periodic paralysis (2426). Two common mutations are

involved, making molecular diagnosis of the disease relatively straightfor-

438 HOFFMAN

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ward. Symptomatic treatment of severe attacks entails ingestion of high levels

of potassium. Prophylactic treatment with acetazolamide is also successful.

THE VOLTAGE-GATED CHLORIDE CHANNELOPATHIES

The myofiber must maintain relatively tight control over the resting membrane

potential. If the membrane becomes hypopolarized to less negative potentials,

the fiber becomes first hyperexcitable (myotonia), then paralyzed. If the cell

becomes too hyperpolarized, the fiber becomes refractory to nerve impulses

(hypoexcitability). The voltage-sensitive chloride channel traffics chloride ion

to stabilize the membrane potential to the correct level (Figure 1).

Patients with pure myotonia have been described in families with both

dominant and recessive inheritance of the condition. The myotonia presents

clinically as muscular stiffness, with many patients showing marked muscularhypertrophy. The severity of the stiffness varies tremendously, and in many

patients the myotonia is subclinical and can only be detected by electromyo-

graphy (P Koty & EP Hoffman, unpublished results). The recessively inherited

condition (Beckers myotonia or myotonia congenita) is often more clinically

severe than the dominantly inherited disorder (Thomsens myotonia).

A mouse model for myotonia was identified through its delayed ability to

return to an upright position after being turned on its side. A mutation of the

voltage-sensitive chloride channel was found to be responsible for this disease

in the mouse (27). The human chloride channel therefore became a candidategene for the pure myotonias. The discovery of many different mutations of the

human chloride channel gene in patients, both in dominantly and recessively

inherited forms of the disease, validated this hypothesis (28, 29). It is very

unusual to find a similar clinical disease caused by both dominant and reces-

sive mutations of the same gene. Both calcium channels and sodium channels

have a single polypeptide chain that forms the pore through the membrane,

whereas chloride channels require four subunits to form a single pore (Figure

1). Thus, a patient can have a dominantly inherited mutation in a single

chloride channel gene, but the mutant protein can reduce the function of allchannels in the myofiber through multimeric interactions with the normal

subunits encoded by the normal gene (30, 31).

CONCLUSION

A new category of human disease, voltage-sensitive ion channelopathies, has

been elucidated over a very short period of time. The sodium channelopathies

and calcium channelopathies are dominantly inherited and are caused by a

change of function of the mutant protein, resulting in a variety of clinical

syndromes, including myotonia and paralysis. The chloride channelopathies


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exhibit both dominant and recessive inheritance, but all mutations result in a

loss of function of the myofiber chloride conductance and in pure myotonia. It

is tempting to speculate as to whether analogous disorders of ion channels in

neurons could cause clinical disease. For example, could epilepsy be a myo-

tonia of the brain?

Any Annual Review chapter, as well as any article cited in an Annual Review chapter,may be purchased from the Annual Reviews Preprints and Reprints service.

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