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 monthsAttack 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 attacks

No Myalgias following attacks

Tubular aggregates in muscle biopsy

Vacuoles in the muscle 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 frequentlonger lastingprecipitated 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

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

DICTUM:

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 childhoodTriggers include rest after vigorous exercise, foods high in potassium, stress, and fatigueNormal 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 TocainidePhenytoinProcainamideQuinine exhibit variable degrees of efficacy

Potassium-Aggravated MyotoniaClinical 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.