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Channelopathies
Definition: A disease caused by
mutations of ion channels.

Increasingly recognized as important cause
of disease (>30 diseases).
Numerous mutation sites may cause
similar channelopathy e.g. cystic fibrosis
where
>1000 different mutations of CFTR
described

 The periodic paralyses—the first group of ion channel disorders
characterized at a molecular level—defined the field of Channelopathies

 It now includes disorders of:
Muscle
Neurons
Kidney (Bartter syndrome)
Epithelium (cystic fibrosis)
Heart (long QT syndrome)

 Ion channels are transmembrane glycoprotein pores that underlie cell
excitability by regulating ion flow into and out of cells .

A channel :
It is a macromolecular protein complex, composed of distinct protein subunits, each
encoded by a separate gene

 Classification: depending on their means of activation :
Voltage-gated or Ligand-gated.

Voltage-gated ion channels:
Changes in membrane potentials activate and inactivate them.
They are named according to the physiological ion preferentially conducted
(e.g., Na+, K+, Ca2+, Cl−)

Ligand-gated ion channels:
Respond to specific chemical neurotransmitters;
(e.g., acetylcholine, glutamate, γ-aminobutyric acid [GABA], glycine).

 Voltage-gated ion channels are critical for establishing a resting
membrane potential and generating action potentials

 These channels consist of one or more pore-forming subunits
(generally referred to as α-subunits) and a variable number of
accessory subunits ( β, γ, etc.)

 α-subunits determine ion selectivity and mediate the voltage-sensing
functions of the channel, accessory subunits act as modulators

 Channels exist in one of three states: open, closed, or inactivated

Channel Function
Ion channels are not open continuously but open and
close in a stochastic or random fashion. Ion channel
function may be decreased by decreasing the open
time (o), increasing the closed time (c), decreasing
the single channel current amplitude (i) or decreasing
the number of channels (n).

 Voltage-gated channels open with threshold changes in membrane potential,
and after an interval go to a closed(inactivated) state.

From the closed state, a channel can reopen with an appropriate change in
membrane potential.

In the inactivated state, the channels will not conduct current. Inactivation is
both time and voltage dependent, and many channels display both fast and slow
inactivation.

Depending on the location within the channel, mutations could alter voltage-
dependent activation, ion selectivity, or time and voltage dependence of
inactivation.

Thus, two different mutations within the same gene can result in dramatically
different physiological defects

Phenotypic heterogeneity :
Different mutations in a single gene cause distinct phenotypes

Genetic heterogeneity :
A consistent clinical syndrome results from a variety of underlying mutations

GEFS+, Generalized epilepsy with febrile seizures plus

Voltage-gated potassium channels (VGKC) consist of four homologous α-
subunits that combine to create a complete channel

Each α-subunit contains six transmembrane segments (S1 to S6) linked
by extracellular and intracellular loops

The S5-S6 loop penetrates deep into the central part of the channel and
lines the pore. The S4 segment contains positively charged amino acids and
acts as the voltage sensor

These channels serve many functions, most notably to establish the resting
membrane potential and to repolarize cells following an action potential.

 A unique class of potassium channel, the inwardly rectifying potassium
channel, is homologous to the S5 to S6 segment of the VGKC.Because the
voltage-sensing S4 domain is absent, voltage dependence results from a
voltage-dependent blockade by magnesium and polyamines.

Proposed structure of the voltage-gated potassium channel

Voltage-gated sodium and calcium channels are highly homologous and share
homology with VGKCs, from which they evolved. The α-subunits contain four
highly homologous domains in tandem within a single transcript (DI–DIV)

Each domain resembles a VGKC α-subunit, with six transmembrane segments

The sodium channel is composed of an α- and a β-subunit, and the calcium
channel is composed of a pore-forming α1- subunit, an intracellular β-subunit, a
membrane-spanning γ-subunit, and a membrane-anchoring α2δ-subunit.

Sodium channels mediate fast depolarization and underlie the action potential,
whereas voltage-gated calcium channels (VGCCs) mediate neurotransmitter
release and allow the calcium influx that leads to second messenger effects

Channelopathies are further subdivided into:

MUSCULAR

NEURONAL

NON NEUROLOGICAL

MUSCULAR CHANNELOPATHIES

CLINICAL

PATHOPHYSIOLOGY

DIAGNOSIS

TREATMENT

CLINICAL:
 Prevalence :1 per 100,000

 Age : Episodes of limb weakness with hypokalemia usually begin during
adolescence.

Time: Attacks usually occur in the morning

Trigger: Ingestion of a carbohydrate load ,high salt intake the previous night, or by
rest following strenuous exercise.

Findings:
Generalized muscle weakness
 Reduced/ absent tendon reflexes
Level of consciousness and sensation are preserved
 spares the facial &respiratory muscles or only mild weakness

Duration
 Occur at intervals of weeks or months
Attack durations vary from minutes to hours

Prognosis:
Patients usually recover full strength, although mild weakness may persist for
several days. Progressive permanent myopathy may develop later.

PATHOPHYSIOLOGY:

In up to 70% of cases, the responsible mutation has been linked to a gene
encoding a VGCC on chromosome.

The gene, CACNA1S, encodes the α1-subunit of the dihydropyridine-sensitive L-
type VGCC found in skeletal muscle.

This channel functions as the voltage sensor of the ryanodine receptor and plays
an important role in excitation-contraction coupling in skeletal muscle

Some 10% to 20% of families with hypoKPP have mutations in the gene
encoding the α-subunit of the skeletal muscle voltage-gated sodium channel
(SCN4A) on chromosome 17q. This is the same channel implicated in
hyperKPP and other disorders described later.

 Evidence suggests that this sodium channel–associated syndrome is
phenotypically different from the more common CACNA1S form

HypoKPP2 CLASSIC HypoKPP
SCN4A on chromosome 17q CACNA1S on chromosome 1q
Myalgias following paralytic No Myalgias following attacks
attacks
Tubular aggregates in muscle Vacuoles in the muscle biopsy
biopsy
older age of onset
shorter duration of attacks
In some patients,
acetazolamide worsens
symptoms

Whether involving SCN4A or CACNA1S, virtually all mutations causing
hypoKPP involve an S4 voltage-sensor domain.

In the case of the sodium channel, these mutations allow a leak current to
pass through the “gating pore” at resting membrane potentials leading to action
potential failure

 Speculation exists that this phenomenon may also occur in mutated VGCCs.

DIAGNOSIS:

 In hypoKPP compared to hyperKPP paralytic attacks are:
 less frequent
longer lasting
precipitated by a carbohydrate load
 often begin during sleep

 Potassium concentrations are usually low during an attack, but <2 mM
suggests a secondary cause

Electrocardiogram (ECG) changes of hypokalemia

Provocative testing can be dangerous and is not routine

EMG, which may show decreased compound muscle action potential
amplitudes during attacks compared with interictal values.

Muscle histology reveals nonspecific myopathic changes of tubular
aggregates or vacuoles within fibers

Thyrotoxic periodic paralysis may be clinically indistinguishable from
hypoKPP, except:

 It is not familial

serum potassium levels are often lower than in familial hypoKPP (<2.5)

Some cases may be associated with a mutation in KCNJ18, the gene
encoding a novel inwardly rectifying potassium channel

DICTUM:

All patients with hypoKPP require screening for hyperthyroidism and
secondary causes of persistent hypokalemia:

Renal, adrenal, and gastrointestinal, thiazide diuretic use or licorice
(glycyrrhizic acid) intoxication are

TREATMENT

Dietary modification to avoid high carbohydrate loads and refraining from
excessive exertion helps prevent attacks.

Oral potassium (5-10 g load) reverses paralysis during an acute attack.
Prophylactic use of acetazolamide decreases the frequency and severity of
attacks. 125 mg daily, titrating as needed up to a maximum daily dose of 1000-
1500 mg, divided bid–qid

 Dichlorphenamide is another carbonic anhydrase inhibitor that effectively
prevents attacks, the average dose was 100 mg daily.

Reducing the frequency of paralytic attacks provides protection against the
development of myopathy.

Hyperkalemic Periodic Paralysis

Clinical
 Episodic weakness precipitated by hyperkalemia.

 Milder than hypoKPP, but may cause flaccid quadriparesis.

 Respiratory ,ocular muscles are unaffected and Consciousness preserved

 Frequency: several per day to several per year.

Duration: Brief, lasting 15 to 60 minutes, but may last up to days.

Specific:
Myotonia is present between attacks.
Onset is usually in infancy or childhood
Triggers include rest after vigorous exercise, foods high in potassium, stress,
and fatigue
Normal serum potassium concentration during an attack
 Mild weakness may persist afterward, and the later development of a
progressive myopathy is common.

Pathophysiology

HyperKPP is as an autosomal dominant disorder, with some sporadic cases

The disorder links to SCN4A, the same gene responsible for a minority of
hypoKPP cases. Among several identified missense mutations, four account for
about two-thirds of cases

Mutations cause a decrease in the voltage threshold of channel activation or
abnormally prolonged channel opening or both ,effectively increasing the
depolarizing inward current.

If sustained long enough, this would lead to inactivation of the sodium
channels, transitory cellular inexcitability, and weakness

Diagnosis

 Serum potassium is normal between attacks and even during many attacks.

 Potassium administration may precipitate an attack

 Myotonia is present in many patients between attacks
(spontaneously or after muscle percussion)

Electrodiagnostic studies: Subclinical myotonic discharges, Nonspecific
findings such as fibrillation potentials and small polyphasic motor unit potentials
occur during late stages of disease

A potassium-loading test provokes an attack but is not usually necessary and
can be dangerous.

Treatment

Acute attacks are often sufficiently brief and mild so as not to require acute
intervention.

In more severe attacks, aim treatment at lowering extracellular potassium levels.

Mild exercise or eating a high sugar load (juice or a candy bar) may suffice, as
insulin drives extracellular potassium into cells.

Thiazide diuretics and inhaled β-adrenergic agonists , and intravenous calcium
gluconate may be useful in severe weakness .

Prevention: A diet low in potassium and high in carbohydrates. Oral
dichlorphenamide was useful for prophylaxis in one RCT (Tawil et al., 2000).
Acetazolamide and thiazide diuretics.

Myotonic symptoms: sodium channel blockers would seem an effective therapy,
and mexiletine is commonly used for this purpose

Paramyotonia Congenita
Clinical
 Paradoxical myotonia, cold-induced myotonia, and weakness after prolonged
cold exposure.

Exacerbation of myotonia after repeated muscle contraction

 Symptoms at birth and usually remain unchanged throughout life

Myotonia affects all skeletal muscles, although the facial muscles, especially
the orbicularis oris, and muscles of the neck and hands are the most common
sites of myotonia in the winter.

 Onset : during the day, lasts several hours, and is exacerbated by cold,
stress, and rest after exercise.

 Cold-induced stiffness may persist for hours even after the body warms, and
percussion myotonia is present even when the patient is otherwise
asymptomatic

Pathophysiology

Point mutations in the SCN4A gene on chromosome 17q

 Mutations of the gene cause defects in sodium channel deactivation and fast
inactivation.

The resting membrane potential rises from −80 up to −40 mV when intact
muscle fibers cool.

Mild depolarization results in repetitive discharges (myotonia), whereas
greater depolarization results in sodium channel inactivation and muscle
inexcitability (weakness).

Diagnosis
A family history of exercise- and cold-induced myotonia strongly supports the
diagnosis of PMC.

Serum potassium concentration may be high, low, or normal during attacks, and
serum creatine kinase concentrations may be elevated 5 to 10 times normal.

 EMG reveals fibrillation-like potentials and myotonic discharges that muscle
percussion, needle movement, and muscle cooling accentuate.

 Muscle cooling elicits an initial increase in myotonia, then a progressive
decrease in myotonia followed by a decrease in compound muscle action potential
amplitude that correlates with muscle stiffness and weakness.

A reduction in isometric force of 50% or more and a prolongation of the relaxation
time by several seconds after muscle cooling support the diagnosis.

Muscle pathology shows only nonspecific changes, and biopsy is unnecessary

Treatment
Symptoms are generally mild and infrequent.

Sodium channel blockers such as mexiletine are sometimes effective in
reducing the frequency and severity of myotonia.

 Patients with weakness often respond to agents used to treat hyperKPP (e.g.,
thiazides, acetazolamide).

A single case report suggests the possible use of pyridostigmine (Khadilkar et
al., 2010)

Cold avoidance reduces the frequency of attacks

Myotonia Congenita
Clinical

 Either as an autosomal dominant (Thomsen disease) or recessive (Becker
myotonia) trait. The main feature is myotonia .

 Warm-up phenomenon: Myotonia decreases or vanishes completely when
repeating the same movement several times

Thomsen myotonia : within the first decade

 Becker myotonia:10 to 14 years

 Myotonia is prominent in the legs, where it is occasionally severe enough to
impede a patient’s ability to walk or run

 In recessive disease(Becker):

 There are transitory bouts of weakness after periods of disuse and may
develop progressive myopathy
 Muscle hypertrophy and disease severity are greater than dominant form.
 Becker myotonia is more common than Thomsen disease.

Pathophysiology

Electrical instability of the sarcolemma leads to muscle stiffness by causing
repetitive electric discharges of affected muscle fibers

Early in vivo studies in myotonic goats revealed greatly diminished sarcolemmal
chloride conductance in affected muscle fibers

Genetic linkage analysis for both recessive and dominant forms of MC pointed to
a locus on chromosome 7q, where the responsible gene, CLCN1, encodes the
major skeletal muscle chloride channel.

More than 70 mutations have been identified within CLCN1, and interestingly,
some of these mutations are recognized to cause both dominant and recessive
forms

Diagnosis:
 Myotonia is a nonspecific sign found in several other diseases including
myotonic dystrophy 1, 2, PMC, and hyperKPP

 Cardiac abnormalities, cataracts, skeletal deformities, and glucose intolerance
are not components of MC, and their presence suggests dystrophic myotonias
.
Muscle strength and tendon reflexes are normal, but patients may have muscle
hypertrophy, often giving these patients an athletic appearance.

 The finding of decremental compound muscle action potential amplitudes with
muscle cooling on EMG distinguishes PMC from MC.

 EMG in MC typically reveals bursts of repetitive action potentials with
amplitude (10 μV to 1 mV) and frequency (50-150 Hz) modulation, so-called
dive-bombers, in the EMG loudspeaker.

Biopsy is usually nonspecific, showing enlarged fibers in hypertrophied muscle,
increased numbers of internalized nuclei, and decreased type 2B fibers

Treatment

Many patients experience only mild symptoms and do not require treatment.

 For those with more severe myotonia, sodium channel blocking (Mexiletine) is
used .

Other sodium channel blockers such as
Tocainide
Phenytoin
Procainamide
Quinine
exhibit variable degrees of efficacy

Potassium-Aggravated Myotonia
Clinical
 Autosomal dominant disorder with clinical features similar to MC, except that
the myotonia fluctuates and worsens with potassium administration.

Distinguishing PAM from other nondystrophic myopathies is important because
PAM patients respond to carbonic anhydrase inhibitors

Episodic weakness and progressive myopathy do not occur

Symptom severity varies, with some patients experiencing only mild fluctuating
stiffness, and others a more protracted painful myotonia.

 PAM now encompasses the conditions previously known as myotonia
fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia.

Exercise or rest after exercise, potassium loads, and depolarizing
neuromuscular blocking agents aggravate myotonia

 Cold exposure has no effect

Prominent myotonia of the orbicularis oculi and painful myotonia suggest the
diagnosis.

Pathophysiology

PAM links to chromosome 17q, where mutations in the SCN4A gene cause the
disease

 Disease-causing mutations lead to a large persistent sodium current secondary
to an increased rate of recovery from inactivation and an increased frequency of
late channel openings .

 The cause of myotonia is this enhanced inward current, which leads to
prolonged depolarization and subsequent membrane hyperexcitability.

DIAGNOSIS:

Diagnosis is clinical because screening for the mutated gene is not widely
available.

 Unlike hyperKPP and PMC, PAM patients do not experience weakness.

Another distinction between PAM and PMC is the lack of response to
muscle cooling, either clinically or on EMG.

Furthermore, the myotonia with PAM improves with carbonic anhydrase
inhibitors, whereas mexiletine is more effective in alleviating the myotonia in
MC and PMC.

TREATMENT:

Carbonic anhydrase inhibitors markedly reduce the severity and frequency
of attacks of myotonia. Acetazolamide is most commonly used

Channelopathies- general characteristics

• Although mutation is continuous the
disease may be episodic such as periodic
paralysis or progressive like
spinocerebellar ataxia.
• Abnormalities in same channel may
present with different disease states.
• Lesions in different channels may lead to
same disease eg periodic paralysis.

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