Proposed structure of the voltage-gated potassium channel, Kv1.1 (KCNA1), implicated in episodic ataxia type 1. Voltage-dependent potassium channels comprise four subunits that form a channel pore. Each subunit contains six transmembrane domains, with the S4 segment containing positively charged amino acids that act as the voltage sensor. Mutations associated with episodic ataxia type 1 are illustrated. Disease-causing mutations are indicated by the one-letter amino acid representation. Amino acids with circles are wild-type, and the corresponding mutation is indicated by a connecting line with the corresponding position and amino acid.
ChannelopathiesDefinition: A disease caused bymutations of ion channels.Increasingly recognized as important causeof disease (>30 diseases).Numerous mutation sites may causesimilar channelopathy e.g. cystic fibrosiswhere>1000 different mutations of CFTRdescribed
The periodic paralyses—the first group of ion channel disorderscharacterized 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 cellexcitability by regulating ion flow into and out of cells .A channel : It is a macromolecular protein complex, composed of distinct protein subunits, eachencoded 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 restingmembrane 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 ofaccessory subunits ( β, γ, etc.) α-subunits determine ion selectivity and mediate the voltage-sensingfunctions of the channel, accessory subunits act as modulators Channels exist in one of three states: open, closed, or inactivated
Channel FunctionIon channels are not open continuously but open andclose in a stochastic or random fashion. Ion channelfunction may be decreased by decreasing the opentime (o), increasing the closed time (c), decreasingthe single channel current amplitude (i) or decreasingthe 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 inmembrane potential.In the inactivated state, the channels will not conduct current. Inactivation isboth time and voltage dependent, and many channels display both fast and slowinactivation.Depending on the location within the channel, mutations could alter voltage-dependent activation, ion selectivity, or time and voltage dependence ofinactivation.Thus, two different mutations within the same gene can result in dramaticallydifferent physiological defects
Phenotypic heterogeneity : Different mutations in a single gene cause distinct phenotypesGenetic 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 channelEach α-subunit contains six transmembrane segments (S1 to S6) linkedby extracellular and intracellular loopsThe S5-S6 loop penetrates deep into the central part of the channel andlines the pore. The S4 segment contains positively charged amino acids andacts as the voltage sensorThese channels serve many functions, most notably to establish the restingmembrane potential and to repolarize cells following an action potential. A unique class of potassium channel, the inwardly rectifying potassiumchannel, is homologous to the S5 to S6 segment of the VGKC.Because thevoltage-sensing S4 domain is absent, voltage dependence results from avoltage-dependent blockade by magnesium and polyamines.
Proposed structure of the voltage-gated potassium channel
Voltage-gated sodium and calcium channels are highly homologous and sharehomology with VGKCs, from which they evolved. The α-subunits contain fourhighly homologous domains in tandem within a single transcript (DI–DIV)Each domain resembles a VGKC α-subunit, with six transmembrane segmentsThe sodium channel is composed of an α- and a β-subunit, and the calciumchannel is composed of a pore-forming α1- subunit, an intracellular β-subunit, amembrane-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 neurotransmitterrelease and allow the calcium influx that leads to second messenger effects
Channelopathies are further subdivided into:MUSCULARNEURONALNON NEUROLOGICAL
CLINICAL: Prevalence :1 per 100,000 Age : Episodes of limb weakness with hypokalemia usually begin duringadolescence.Time: Attacks usually occur in the morningTrigger: Ingestion of a carbohydrate load ,high salt intake the previous night, or byrest following strenuous exercise.Findings:Generalized muscle weakness Reduced/ absent tendon reflexesLevel of consciousness and sensation are preserved spares the facial &respiratory muscles or only mild weaknessDuration Occur at intervals of weeks or monthsAttack durations vary from minutes to hoursPrognosis: Patients usually recover full strength, although mild weakness may persist forseveral days. Progressive permanent myopathy may develop later.
PATHOPHYSIOLOGY:In up to 70% of cases, the responsible mutation has been linked to a geneencoding 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 playsan important role in excitation-contraction coupling in skeletal muscleSome 10% to 20% of families with hypoKPP have mutations in the geneencoding the α-subunit of the skeletal muscle voltage-gated sodium channel(SCN4A) on chromosome 17q. This is the same channel implicated inhyperKPP and other disorders described later. Evidence suggests that this sodium channel–associated syndrome isphenotypically different from the more common CACNA1S form
HypoKPP2 CLASSIC HypoKPPSCN4A on chromosome 17q CACNA1S on chromosome 1qMyalgias following paralytic No Myalgias following attacksattacksTubular aggregates in muscle Vacuoles in the muscle biopsybiopsyolder age of onsetshorter duration of attacksIn some patients,acetazolamide worsenssymptoms
Whether involving SCN4A or CACNA1S, virtually all mutations causinghypoKPP involve an S4 voltage-sensor domain.In the case of the sodium channel, these mutations allow a leak current topass through the “gating pore” at resting membrane potentials leading to actionpotential 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 mMsuggests a secondary causeElectrocardiogram (ECG) changes of hypokalemiaProvocative testing can be dangerous and is not routineEMG, which may show decreased compound muscle action potentialamplitudes during attacks compared with interictal values.Muscle histology reveals nonspecific myopathic changes of tubularaggregates or vacuoles within fibers
Thyrotoxic periodic paralysis may be clinically indistinguishable fromhypoKPP, except: It is not familialserum potassium levels are often lower than in familial hypoKPP (<2.5)Some cases may be associated with a mutation in KCNJ18, the geneencoding a novel inwardly rectifying potassium channel DICTUM:All patients with hypoKPP require screening for hyperthyroidism andsecondary causes of persistent hypokalemia:Renal, adrenal, and gastrointestinal, thiazide diuretic use or licorice(glycyrrhizic acid) intoxication are
TREATMENTDietary modification to avoid high carbohydrate loads and refraining fromexcessive 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 ofattacks. 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 effectivelyprevents attacks, the average dose was 100 mg daily.Reducing the frequency of paralytic attacks provides protection against thedevelopment of myopathy.
Hyperkalemic Periodic ParalysisClinical 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 aprogressive myopathy is common.
PathophysiologyHyperKPP is as an autosomal dominant disorder, with some sporadic casesThe disorder links to SCN4A, the same gene responsible for a minority ofhypoKPP cases. Among several identified missense mutations, four account forabout two-thirds of casesMutations cause a decrease in the voltage threshold of channel activation orabnormally prolonged channel opening or both ,effectively increasing thedepolarizing inward current.If sustained long enough, this would lead to inactivation of the sodiumchannels, 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, Nonspecificfindings such as fibrillation potentials and small polyphasic motor unit potentialsoccur during late stages of diseaseA potassium-loading test provokes an attack but is not usually necessary andcan be dangerous.
TreatmentAcute attacks are often sufficiently brief and mild so as not to require acuteintervention.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, asinsulin drives extracellular potassium into cells.Thiazide diuretics and inhaled β-adrenergic agonists , and intravenous calciumgluconate may be useful in severe weakness .Prevention: A diet low in potassium and high in carbohydrates. Oraldichlorphenamide 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 CongenitaClinical Paradoxical myotonia, cold-induced myotonia, and weakness after prolongedcold exposure.Exacerbation of myotonia after repeated muscle contraction Symptoms at birth and usually remain unchanged throughout lifeMyotonia affects all skeletal muscles, although the facial muscles, especiallythe orbicularis oris, and muscles of the neck and hands are the most commonsites 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, andpercussion myotonia is present even when the patient is otherwiseasymptomatic
PathophysiologyPoint mutations in the SCN4A gene on chromosome 17q Mutations of the gene cause defects in sodium channel deactivation and fastinactivation.The resting membrane potential rises from −80 up to −40 mV when intactmuscle fibers cool.Mild depolarization results in repetitive discharges (myotonia), whereasgreater depolarization results in sodium channel inactivation and muscleinexcitability (weakness).
DiagnosisA family history of exercise- and cold-induced myotonia strongly supports thediagnosis of PMC.Serum potassium concentration may be high, low, or normal during attacks, andserum creatine kinase concentrations may be elevated 5 to 10 times normal. EMG reveals fibrillation-like potentials and myotonic discharges that musclepercussion, needle movement, and muscle cooling accentuate. Muscle cooling elicits an initial increase in myotonia, then a progressivedecrease in myotonia followed by a decrease in compound muscle action potentialamplitude that correlates with muscle stiffness and weakness.A reduction in isometric force of 50% or more and a prolongation of the relaxationtime by several seconds after muscle cooling support the diagnosis.Muscle pathology shows only nonspecific changes, and biopsy is unnecessary
TreatmentSymptoms are generally mild and infrequent.Sodium channel blockers such as mexiletine are sometimes effective inreducing 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 etal., 2010)Cold avoidance reduces the frequency of attacks
Myotonia CongenitaClinical Either as an autosomal dominant (Thomsen disease) or recessive (Beckermyotonia) trait. The main feature is myotonia . Warm-up phenomenon: Myotonia decreases or vanishes completely whenrepeating the same movement several timesThomsen myotonia : within the first decade Becker myotonia:10 to 14 years Myotonia is prominent in the legs, where it is occasionally severe enough toimpede a patient’s ability to walk or run In recessive disease(Becker): There are transitory bouts of weakness after periods of disuse and maydevelop progressive myopathy Muscle hypertrophy and disease severity are greater than dominant form. Becker myotonia is more common than Thomsen disease.
PathophysiologyElectrical instability of the sarcolemma leads to muscle stiffness by causingrepetitive electric discharges of affected muscle fibersEarly in vivo studies in myotonic goats revealed greatly diminished sarcolemmalchloride conductance in affected muscle fibersGenetic linkage analysis for both recessive and dominant forms of MC pointed toa locus on chromosome 7q, where the responsible gene, CLCN1, encodes themajor 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 recessiveforms
Diagnosis: Myotonia is a nonspecific sign found in several other diseases includingmyotonic dystrophy 1, 2, PMC, and hyperKPP Cardiac abnormalities, cataracts, skeletal deformities, and glucose intoleranceare not components of MC, and their presence suggests dystrophic myotonias.Muscle strength and tendon reflexes are normal, but patients may have musclehypertrophy, often giving these patients an athletic appearance. The finding of decremental compound muscle action potential amplitudes withmuscle cooling on EMG distinguishes PMC from MC. EMG in MC typically reveals bursts of repetitive action potentials withamplitude (10 μV to 1 mV) and frequency (50-150 Hz) modulation, so-calleddive-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
TreatmentMany patients experience only mild symptoms and do not require treatment. For those with more severe myotonia, sodium channel blocking (Mexiletine) isused .Other sodium channel blockers such asTocainidePhenytoinProcainamideQuinineexhibit variable degrees of efficacy
Potassium-Aggravated MyotoniaClinical Autosomal dominant disorder with clinical features similar to MC, except thatthe myotonia fluctuates and worsens with potassium administration.Distinguishing PAM from other nondystrophic myopathies is important becausePAM patients respond to carbonic anhydrase inhibitorsEpisodic weakness and progressive myopathy do not occurSymptom severity varies, with some patients experiencing only mild fluctuatingstiffness, and others a more protracted painful myotonia. PAM now encompasses the conditions previously known as myotoniafluctuans, myotonia permanens, and acetazolamide-sensitive myotonia.Exercise or rest after exercise, potassium loads, and depolarizingneuromuscular blocking agents aggravate myotonia Cold exposure has no effectProminent myotonia of the orbicularis oculi and painful myotonia suggest thediagnosis.
PathophysiologyPAM links to chromosome 17q, where mutations in the SCN4A gene cause thedisease Disease-causing mutations lead to a large persistent sodium current secondaryto an increased rate of recovery from inactivation and an increased frequency oflate channel openings . The cause of myotonia is this enhanced inward current, which leads toprolonged depolarization and subsequent membrane hyperexcitability.
DIAGNOSIS:Diagnosis is clinical because screening for the mutated gene is not widelyavailable. Unlike hyperKPP and PMC, PAM patients do not experience weakness.Another distinction between PAM and PMC is the lack of response tomuscle cooling, either clinically or on EMG.Furthermore, the myotonia with PAM improves with carbonic anhydraseinhibitors, whereas mexiletine is more effective in alleviating the myotonia inMC and PMC.TREATMENT:Carbonic anhydrase inhibitors markedly reduce the severity and frequencyof 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.