Channelopathies: A ReviewGenevieve Bernard, MD, MSc* and Michael I. Shevell, MD*†
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hannelopathies are a recently delineated, emergingroup of neurologic disorders united by genetically de-ermined defects in ion-channel function. These disordersre characterized by a prominent genetic and phenotypiceterogeneity that can make them challenging and bewil-ering to understand. This systematic review attempts toategorize these disorders according to their predomi-ant clinical manifestations (i.e., myotonia, weakness,igraine, ataxia, epilepsy, and movement disorders)ithin the context of what is presently known about theolecular basis of recognized clinical syndromes. Areas
f both genetic and phenotypic overlap are highlighted.he review is intended to assist clinicians in enhancing
ernard G, Shevell MI. Channelopathies: A review. Pediatreurol 2008;38:73-85.
ntroduction
Channelopathies are disorders caused by inherited muta-ions of ion channels. Channel mutations causing diseaseere first described in inherited neuromuscular disorders [1].hey are now described in many other tissues. Symptomsay represent either an abnormal gain of function (e.g.,
pilepsy, myokymia, and myotonia) or a loss of functione.g., weakness).
Two related concepts are important in these diseases.he first concept is that of phenotypic heterogeneity.ifferent mutations in the same gene can cause differentiseases (e.g., mutations in the same voltage-dependentodium channel in skeletal muscle can result in hyperkale-ic periodic paralysis, hypokalemic periodic paralysis,
otassium-aggravated myotonia, and paramyotonia con-enita). The second concept is that of genetic heterogene-ty. Mutations in different genes can result in the samepparent disease phenotype (e.g., hyperkalemic periodic
rom the Departments of *Neurology/Neurosurgery and †Pediatrics,cGill University, Montreal Children’s Hospital-McGill Universityealth Center, Montreal, Quebec, Canada.
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2008 by Elsevier Inc. All rights reserved.oi:10.1016/j.pediatrneurol.2007.09.007 ● 0887-8994/08/$—see front matter
aralysis is caused by mutations in different genes codingor the skeletal muscle sodium channel).
europhysiology
Ion channels are transmembrane glycoprotein poresmportant in cell excitability, which is mediated by the ionlow in and out of cells. Channels can exist in threeifferent states: open, closed (resting state), or inactivatedrefractory period after opening of the channel, duringhich the channel will not let ions pass through). Channels
re composed of different subunits, with each subunitncoded by a different gene. There are two major classesf ion channels: voltage-gated and ligand-gated.Voltage-gated ion channels are activated and inacti-
ated by changes in transmembrane potential. Channelsre identified according to the principal ion conductedhrough the channel (e.g., sodium, potassium, calcium, orhloride), and are concentrated in different regions ofeurons according to their principal function. Voltage-ated sodium channels are in high concentration in thexon hillock, to generate the action potential. The nodes ofanvier contain a high concentration of both sodium andotassium channels to regenerate the action potential. Thexon terminals contain a large concentration of calciumhannels, to permit the ready release of neurotransmitters.
The different voltage-gated channels contain six trans-embrane regions, S1-S6. The subunits are assembled to
orm a central pore. The specific structure of this centralore determines the selective permeability of the channelo a particular ion. The regions between S5 and S6 of theifferent subunits line the channel pore and determine thiselectivity. The S4 transmembrane domain of the differentubunits forms the voltage sensor.
Voltage-gated channels have several roles. The potas-ium channels are primarily responsible for the establish-ent of resting membrane potential and the repolarization
f cells after an action potential. The sodium channelserve primarily in the generation of the action potential
ommunications should be addressed to:r. Shevell; Department of Pediatrics, Room A-514; Montreal Children’sospital; 2300 Tupper; Montreal, Quebec H3H IP3, Canada.
i.e., fast depolarization). The calcium channels are impli-ated in the generation of the action potential in the heartnd smooth muscles, muscle contraction, neurotransmitterelease, and intracellular signaling (i.e., second messen-er). Certain chloride channels are voltage-gated and arenvolved in the hyperpolarization of cells.
Ligand-gated channels are activated by the binding of theirespective agonists. They are formed by five subunits, eachontaining four transmembrane domains (M1-M4). The M2ransmembrane domain of the different subunits lines theore and determines specific ionic selectivity.
Several ligand-gated channels are evident in the periph-ral and central nervous systems. For example, nicotinicacetylcholine) receptors are located at the neuromuscularunction, and the �-aminobutyric acid (GABAA) andlycine receptors are important for hyperpolarization ofhe cells through the entrance of chloride ions into therain and spinal cord, respectively.Mutations of ion channels can thus theoretically alter
he activation, ion selectivity, or inactivation of the corre-
igure 1. Channelopathies: classification according to defective chypokalemic periodic paralysis; CMS � congenital myasthenic syndroyndrome; EA-1 � episodic ataxia type 1; EA-2 � episodic ataxia tyocturnal frontal lobe epilepsy; BFNC � benign familial neonatal coeneralized epilepsy with febrile seizures-plus; SMEI � severe myoclonbsence epilepsy. Channels/ligands: ACh � acetycholine; GABA � �-amalcium. °Voltage-gated. *Ligand-gated.
ponding mutated channel. g
4 PEDIATRIC NEUROLOGY Vol. 38 No. 2
hannelopathies: An Overview
Channelopathies can be classified according to thebnormal channel or affected organ (muscle or brain).igure 1 classifies different channelopathies according to
he mutated channel. Table 1 classifies channelopathiesccording to the principal organ affected. Table 2 includesll known channelopathies, and summarizes whether orot commercially available genetic testing is available athis time.
One characteristic of the channelopathies is a significanthenotypic overlap in clinical presentation, pathophysiol-gy, and treatment. Figure 2 illustrates the phenotypicverlap between the different disorders. For example,atients with episodic ataxia type 2 have episodes oftaxia, but can alternatively have migraines and epilepsy.he overlap observed in pathophysiology is mainly medi-ted through hyperexcitability of the neurons or muscleells, leading to clinical symptoms such as seizures oryotonia. Electrophysiologic investigations (electromyo-
ram, electroencephalogram, and electrocardiogram) are
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seful in this group of diseases for demonstrating cellularyperexcitability and correctly orient a specific diagnosis.ost of these diseases have similar precipitants (stress,
atigue, and dietary factors), and are treated with medica-ions selectively acting on specific ion channels (i.e.,hannel blockers).
uscle Diseases
Muscle diseases under consideration include the periodicaralyses and nondystrophic myotonias (hypokalemic peri-dic paralysis, hyperkalemic periodic paralysis, paramyoto-ia congenita, myotonia congenita, potassium-aggravatedyotonia, and Andersen-Tawil syndrome), malignant hy-
erthermia, central core myopathy, and the congenitalyasthenic syndromes.
eriodic Paralysis and Nondystrophic Myotonias
These rare diseases are all inherited as an autosomal-ominant trait. As a group, they present as episodiceakness or stiffness with an interictal return to an
symptomatic state, which in a few instances may progresso a proximal myopathy. Most of these diseases undergoymptomatic improvement with acetazolamide, a carbonic
able 1. Channelopathies: Classification according to primaryffected organ
ME � Juvenile myoclonic epilepsyMEI � Severe myoclonic epilepsy of infancy
nhydrase inhibitor. t
ypokalemic Periodic Paralysis (OMIM 170400)
Hypokalemic periodic paralysis is the most commoneriodic paralysis, with a prevalence of approximately:100,000 [2]. Inheritance is autosomal-dominant, with aeduced penetrance in females [2,3]. Typically, signs begin inhe first or second decade of life, with attacks of flaccidaralysis. Classically, hypokalemia accompanies the attack,ith or without associated electrocardiogram changes (in-
reased PR and QT intervals, flattening of T waves, androminent U waves). The attacks usually occur upon awak-ning at night or early in the morning. They are rarelybserved by the physician, and must be suspected on theasis of clinical history. Several triggers have been described,ll acting through a lowering of serum potassium concentra-ion: a carbohydrate load on the previous day, high saltntake, stress, certain medications (e.g., beta-agonists, corti-osteroids, or insulin), and rest after strenuous exercise. Therequency, length, and severity of the attacks are variable, butost often the attacks occur weekly to monthly, and can last
p to several hours. Patients may variably report a prodromeonsisting of paresthesias, fatigue, and behavioral or cogni-ive changes the day before the attack. Typically, patientsegain full strength between attacks, and do not developrogressive myopathic features.
In hypokalemic periodic paralysis type 1, four mutations,mplicating the �1 subunit of the skeletal muscle L-typealcium channel gene (CACN1AS) located on chromosomeq, have been described, and account for the majority ofases [2].
In hypokalemic periodic paralysis type 2, more than fiveutations of the �-subunit of the skeletal muscle sodium
hannel (SCN4A) gene on chromosome 17q in the voltageensor have also been described, accounting for approximately0% of cases [3]. Certain authors think that these mutations giveise to a slightly different phenotype [3].
The nine mutations previously discussed in CACNA1Snd SCN4A do not account for about one fifth to one thirdf patients with a clinical diagnosis of hypokalemiceriodic paralysis, indicating additional possible allelic orenetic heterogeneity [3].The goal of treatment is to avoid attacks of weakness, or at
east to decrease their frequency and severity. Lifestyleodifications (i.e., avoidance of carbohydrate load, high salt
ntake, and strenuous exercise) are the first step in theanagement of these patients. Acute pharmacologic inter-
ention consists of correcting the serum potassium level,hich only treats indirectly the overt muscle weakness.hronic pharmacologic intervention consists of administer-
ng acetazolamide or dichlorphenamide, which are botharbonic anhydrase inhibitors. Anesthesia should be per-ormed with caution because of the potential risk of pre- orostanesthetic weakness [4] and malignant hyperthermia [5].he prognosis is usually good, with the rare development of aroximal myopathy, which was found to develop independent of
he actual frequency and severity of documented attacks [6].
ing 20 chromosome Ring chromosome 20 20 Clinical (karyotype)
6 PEDIATRIC NEUROLOGY Vol. 38 No. 2
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yperkalemic Periodic Paralysis (OMIM 170500)
Hyperkalemic periodic paralysis was first described inhe 1950s, and is also known as “adynamia episodicaereditaria” [7].The onset is typically at an earlier age than in hypokale-ic periodic paralysis, with the first signs occurring
uring infancy or childhood. Characteristic attacks ofeakness definitively begin by adolescence. These attacks
an occur from several times a day to several times a year,nd are typically relatively brief (i.e., 15-60 minutes). Theerum potassium level is elevated or normal during at-acks. Hyperkalemia is the usual precipitant (because ofest after exercise, intake of food high in potassium, stress,r fatigue). Clinical myotonia can be observed betweenttacks, most readily in the facial, lingual, thenar, andinger extensor muscles. Patients with this condition com-only develop a progressive myopathy over time [8].Hyperkalemic periodic paralysis is an autosomal-
igure 2. Channelopathies: overlap of signs between different diseases.QTS � long QT syndromes; PPS � periodic paralysis syndromes;TS � Andersen/Tawil syndrome; EA-1 � episodic ataxia type 1;A-2 � episodic ataxia type 2; SCA6 � spinocerebellar ataxia type 6;HM � familial hemiplegic migaines; ADFLE � autosomal-dominantocturnal frontal lobe epilepsy; BFNC � benign familial neonatalonvulsions; BFNIS � benign familial neonatal-infantile seizures;EFS� � generalized epilepsy with febrile seizures-plus; SMEI �
ominant disease with high penetrance. Most cases are i
aused by mutations of the voltage-dependant sodiumhannel gene or SCN4A on chromosome 17q [9]. Theseutations were found to cause a hyperpolarizing shift in
he activation curve, and a disruption in slow inactivation10]. These respective changes cause an increased androlonged opening of the sodium channel, leading toncreased depolarization and secondarily to myotonia. Ifhe depolarization is prolonged enough, the sodium chan-els are effectively inactivated and transient cellular inex-itability ensues, causing the transient weakness.
After strenuous exercise, some patients can abort anttack by performing mild but sustained exercise. Attacksan also be aborted with a high sugar load, which reducesxtracellular potassium. Other interventions can also besed to stop an attack, and these include thiazides, inhaled-adrenergic agonists, and intravenous calcium gluconate.he attacks can be prevented by a diet low in potassiumnd high in carbohydrates, and also with the use ofedications, i.e., oral dichlorphenamide, acetazolamide,
nd thiazide [11]. With increasing age, a large proportionf these patients develop progressive proximal myopathy,hich was observed to be independent of the actual
requency of attacks [8].
aramyotonia Congenita (OMIM 168300)
This disease was first described by von Eulenburg in886 [12]. The cardinal symptom is paradoxical myotonia.e., muscle stiffness initiated by activity, rather than rest13]. This can be induced with a simple bedside test bysking patients to close their eyes repeatedly and force-ully. Patients will experience progressive difficulty withelaxation of the eyelids. Myotonia may be more easilylicited, especially in a young child, by asking a patient toorcefully squeeze the examiner’s second and third fin-ers. The onset is typically at birth, with signs of myotoniand weakness that usually remain unchanged throughoutife. Both the myotonia and weakness are enhanced byxposure to cold. During attacks, the serum potassiumevel is variable (i.e., high, low, or relatively normal).
This disease is allelic to hyperkalemic periodic paraly-is. Several mutations of the SCN4A gene on chromosome7q were described in different families [14].Signs are generally mild and infrequent, and typicallyay not need treatment. If cold-induced myotonia is
ignificant, avoidance of cold is recommended. If pharma-ologic treatment is necessary, sodium-channel blockerse.g., mexiletine), chlorothiazide, or acetazolamide can besed.
yotonia Congenita (OMIM 255700 and 160800)
Myotonia congenita was first described by Thomsen in876, who suffered from the disease himself [15]. Thisisease is characterized by the development of myotoniauring childhood that typically improves when the individual
s activating the involved muscle (“warm-up” phenomenon).
here is both an autosomal-recessive (Becker, OMIM55700) and an autosomal-dominant (Thomsen OMIM60800) variant of the disease. Both forms are rare andlinically similar [16]. The few differences between thewo forms are as follows: Thomsen is characterized byarly onset, mild to moderate myotonia, and slight muscleypertrophy. Becker is characterized by later onset, mod-rate to severe myotonia with associated transient weak-ess, moderate muscular hypertrophy, and in some casesermanent muscle weakness and eventual wasting. Thestimated worldwide prevalence of these two forms col-ectively is approximately 1:100,000 [17].
Genetic testing usually confirms the diagnosis, after theiagnosis is clinically suspected. Several mutations of theuscle chloride channel CIC-1 were described in both
orms of the disease. These mutations are thought to affecthloride-channel gating, resulting in decreased chlorideonductance, and causing an electrical instability of thearcolemma with resulting repetitive, sustained electricischarges. The voltage-gated chloride channel (CIC-1) isncoded by the gene CLCN1 on chromosome 7q35. Morehan 80 mutations have been described, most of which areesponsible for the recessive form of the disease. Fifteenutations were reported to result in the autosomal-domi-
ant form of the disease [18]. Ten mutations were found toesult in either the recessive or the dominant form [19].
Several medications have been used to treat myotoniancluding mexiletine, quinine, lithium carbonate, tocainiderarely used because of potential bone marrow suppres-ion), procainamide, carbamazepine, phenytoin, and acet-zolamide [11].
otassium-Aggravated Myotonia (OMIM 608390)
This disease is subdivided into myotonia fluctuans,yotonia permanens, and acetazolamide-responsive myo-
onia [11]. The typical presentation is that of a painfulyotonia that fluctuates and is aggravated by exercise or
est after exercise, potassium loads, and exposure toepolarizing neuromuscular blocking agents. These pa-ients do not experience episodic weakness or progressive
yopathy. This disease is caused by mutations of theodium channel SCN4A gene on chromosome 17q [20].
ndersen-Tawil Syndrome (OMIM 170390)
This entity was first described in 1971 [21]. Theallmark of this syndrome is the triad of periodic paralysiswith variable serum potassium levels during an attack),ardiac arrhythmias, and dysmorphic features [22]. Dis-inctive physical findings include hypertelorism, micro-nathia, low-set ears, high-arched or cleft palate, shorttature, clinodactyly, syndactyly, and a broad nasal root23]. Phenotypic expressivity is extremely variable, withatients exhibiting clinical evidence of two or three featuresf the triad each, with variable apparent severity. Rarely,
ndividuals are asymptomatic carriers [23]. a
8 PEDIATRIC NEUROLOGY Vol. 38 No. 2
Andersen-Tawil syndrome is thought to be an autoso-al-dominant disease with variable penetrance. Some
ases are sporadic, and are caused by de novo mutations.wo third of cases are caused by mutations of a widelyxpressed potassium channel encoded by the KCNJ2 gene,ocated on chromosome 17q [23]. Complete evaluations ofhese patients require a cardiac assessment, because thisisorder is part of the differential diagnosis of long QTyndrome. The remaining third of patients have an un-nown molecular defect.Treatment of this condition necessitates control of
ardiac arrhythmias. If there is ventricular tachycardia, anmplantable defibrillator was found to improve survival24]. To decrease the frequency, severity, and duration ofttacks, carbonic anhydrase inhibitors can also be used.ral potassium can be used for the acute treatment of
ttacks as well as for prophylaxis, with the advantage ofhortening the observed QT interval.
alignant Hyperthermia Susceptibility
Malignant hyperthermia susceptibility was first recog-ized by Denborough et al. in 1962 [25]. This is aell-known but uncommon condition, characterized by
he development of a hypermetabolic reaction (tachypnea,achycardia, rigidity, acidosis, rhabdomyolysis, and hyper-hermia) when volatile anesthetics and depolarizing neu-omuscular blockers are administered together to a sus-eptible individual.
Malignant hyperthermia susceptibility is an autosomal-ominant condition with multifactorial inheritance. Theondition is subdivided into malignant hyperthermia sus-eptibility 1-6. What is known to date about the genetics ofhese six types is listed in Table 3. Mutations of the RYR1ene on chromosome 19q, encoding for ryanodine recep-or type 1, account for the majority of cases [26]. Thiseceptor is a skeletal muscle calcium channel located inhe sarcoplasmic reticulum, responsible for the release ofalcium in the sarcoplasmic reticulum, allowing muscleontraction. Mutation of this channel then leads to anbnormal sustained increase in myoplasmic calcium con-entration in skeletal muscle, with the resulting potentialor developing malignant hyperthermia [27]. In someamilies with susceptibility to malignant hyperthermia,dditional susceptibility loci on chromosome 3 [28] wereocumented, as was the role of voltage-dependent calciumhannels [29].
Recognition of a family history of this disorder, or ofrevious clinical signs of malignant hyperthermia on expo-ure to an anaesthetic agent in an individual, is essential.revention of the hypermetabolic reaction with dantrolenean inhibitor of calcium release from the sarcoplasmic retic-lum) is the mainstay of management. When the reactionccurs, the use of anesthetics must be discontinued immedi-tely, and active support measures must be undertaken (e.g.,ore cooling or respiratory support) concurrent with an
Central core disease was first described by Shy andagee in 1956 [30]. It is a nonprogressive, congenitalyopathy presenting in infancy with hypotonia, grossotor delay, moderate muscle weakness (maximal in the
roximal lower limbs), and secondary musculoskeletalbnormalities including congenital hip dislocation, footeformities, scoliosis, and joint contracture [31]. Theseatients have a particular susceptibility to malignant hy-erthermia [32]. The diagnosis is usually made by muscleiopsy (amorphous central cores).Central core disease is usually inherited in an autosom-
l-dominant manner [30,32]. In a few families, inheritanceas shown to be autosomal-recessive [33]. Many sporadic
ases have also been described [34]. Several mutations ofhe ryanodine receptor described above were shown toause this congenital myopathy [26].
ongenital Myasthenic Syndromes
Congenital myasthenic syndromes are a rare, heteroge-eous, nonimmune-mediated group of disorders of neuro-
uscular transmission [35]. Some of these disorders may belassified as channelopathies. Congenital myasthenic syn-romes are characterized by fatigable weakness with an onsetypically during infancy to early childhood. Investigationsre negative for circulating acetylcholine receptor antibod-es (i.e., classic myasthenia gravis).
These diseases have a heterogeneous pathophysiology.hey can be caused by an abnormal release of acetylcho-
ine (presynaptic), a deficiency in acetylcholinesterasesynaptic), or a defect at the postsynaptic level (abnormalecognition of acetylcholine by nicotinic acetycholineeceptors, or a reduction in acetylcholine receptors). Theatter mechanism accounts for the vast majority of cases.pproximately 10% of cases are presynaptic, about 15%
re synaptic, and about 75% are postsynaptic. The major-ty of those that are postsynaptic are caused by ancetylcholine receptor deficiency [35].
Congenital myasthenic syndromes are inherited in anutosomal-recessive or, less frequently, dominant manner.ifferent genes encoding proteins expressed at the neuro-uscular junction were found to cause congenital myas-
henic syndromes. These genes and the mechanisms by
Protein Detection
Ryanodine receptor type 1 25-70%Unknown UnknownDihydropyridine-sensitive L-type calcium
hich they cause observable disease in congenital myas-henic syndromes are presented in Table 4 [36].
The treatment of congenital myasthenic syndromesaries according to subtype (e.g., slow-channel congenitalyasthenic syndrome versus fast-channel congenital my-
sthenic syndrome). Most patients improve on acetylcho-inesterase inhibitors (e.g., pyridostigmine), with the excep-ion of patients with endplate acetylcholinesterase deficiencyCOLQ mutations) and with slow-channel congenital my-sthenic syndrome, who are refractory or actually deteri-rate with these drugs. Other medications can be used,uch as the potassium-channel blocker 3,4-diaminopyri-ine, quinidine, fluoxetine, and ephedrine with or withoutyridostigmine [36].
rain Diseases
Channelopathies involving neurons include disease-ausing migraines (familial hemiplegic migraine), ataxiaepisodic ataxias, or spinocerebellar ataxia type 6), exag-erated responses to exogenous sensory stimuli (heredi-ary hyperekplexia), and epilepsy (e.g., autosomal-domi-ant frontal lobe epilepsy, or benign familial neonatalonvulsions).
amilial Hemiplegic Migraine (OMIM 141500,02481, and 609634)
Familial hemiplegic migraine is an autosomal-dominantondition consisting of migraines with aura and associatedotor deficits (e.g., hemiparesis) that typically resolve
ompletely between attacks. A permanent neurologic def-cit is extremely rare. The diagnosis is based on clinicaliagnostic criteria: (1) at least two attacks fulfill theriteria for migraine with aura; (2) the aura must include aeversible motor deficit; and (3) the family history isositive (first-degree or second-degree relative) [37].Mutations of three genes were found to cause the three
ecognized types of familial hemiplegic migraine. Familialemiplegic migraine type 1 is caused by a mutation of theACNA1 gene (encoding for the voltage-dependent P/Q-
ype calcium channel subunit alpha-1A) on chromosome9 [38]. Some overlap was noted between familial hemi-legic migraine type 1, episodic ataxia type 2, and spino-erebellar ataxia type 6 regarding this mutation site. Inact, �90% of families with familial hemiplegic migrainend cerebellar signs (including nystagmus) have aACNA1A mutation [39]. Familial hemiplegic migraine
ype 2 is caused by a mutation of the ATP1A2 geneencoding for the sodium/potassium-transporting ATPaselpha-2 chain) on chromosome 1 [40]. Several allelicisorders in familial hemiplegic migraine type 2 causeeizures: simple febrile seizures, generalized epilepsy withebrile seizures-plus, severe myoclonic epilepsy of infancyi.e., Dravet syndrome), and intractable childhood epilepsyith generalized tonic-clonic seizures. Seizures were de-
cribed during severe attacks in this condition [41]. Fa- T
0 PEDIATRIC NEUROLOGY Vol. 38 No. 2
ilial hemiplegic migraine type 3 is caused by a mutationf the SCN1A gene (encoding for sodium channel proteinype 1 subunit alpha) on chromosome 2 [42].
Anecdotal evidence and case reports support the use ofcetazolamide as a prophylactic agent [43]. Other caseeports indicate that verapamil may be useful both as ancute treatment and as a prophylactic agent [44].
pisodic Ataxias
The episodic ataxias are a group of autosomal-ominant diseases characterized by episodic attacks oftaxia with or without interictal neurologic symptomse.g., myokymia or cerebellar symptoms). Six typesepisodic ataxia types 1-6) have been described. Theain features of episodic ataxia types 1 and 2, and the
nown features of episodic ataxia types 3-6, are sum-arized in Table 5.
pisodic Ataxia Type 1 (OMIM 160120)
Episodic ataxia type 1 is an autosomal-dominant con-ition characterized by the early onset of brief attacks (i.e.,econds to minutes) of ataxia and dysarthria and interictalyokymia [45]. The attacks can occur several times a day.
able 5. Episodic ataxias
Type 1 Type 2
MIM 160120 108500nheritance AD ADene KCNA1 CACNA1Aocus 12p13 19p13nset Late childhood to
early adolescenceChildhood or early
adolescenceharacteristicsof attacks
Brief attacks of ataxiaand dysarthria
Longer attacks (hours todays) of ataxia, vertigo,nausea
nterictalsymptoms
Myokymia (face,arms, legs)
About 50% have migrainesWith time, nystagmus andataxia
MG/NCS Myokymiamaging Normal MRI Atrophy of cerebellar vermisreatment Phenytoin
AcetazolamideAcetazolamide
rognosis Resolution in seconddecade
Development of cerebellarsymptoms
ot mentioned: Type 3 (OMIM 606554), AD; linked to 1q42; variableage of onset; brief attacks of vestibular ataxia, vertigo, tinnitus;interictal myokymia; treated with acetazolamide. Type 4 (OMIM606552), AD; onset, early adulthood; attacks of vertigo, diplopia,tinnitus, ataxia; no interictal myokymia; no response toacetazolamide; development of slowly progressive cerebellar ataxiain some patients. Type 5, CACNB4 mutation; locus, 2q22-q23. Type6, SLC1A3 mutation; locus, 5p13.
bbreviations:D � Autosomal-dominantMG/NCS � Electromyography and nerve conduction studiesRI � Magnetic resonance imaging
hey can occur spontaneously, or may be precipitated by
tartle, emotion, fatigue, illness, or exercise. Episodic ataxiaype 1 is caused by a mutation of the potassium channel geneCNA1 on chromosome 12 [46]. Treatment includes thevoidance of triggering factors, phenytoin, or acetazolamide45]. Most patients experience a spontaneous resolution ofheir symptoms in the second or third decade of life.
pisodic Ataxia Type 2 (OMIM 108500)
Episodic ataxia type 2 was first described in 1946 and isharacterized by the onset in childhood or young adult-ood of paroxysmal attacks of ataxia, dysarthria, vertigo,nd nausea lasting hours or days, triggered by stress,xertion, caffeine, alcohol, a high carbohydrate meal,ever, or heat [47]. The frequency of the attacks can rangerom two per year to 3-4 per week. Interictally, someatients will develop gaze-evoked nystagmus, ataxia, andigraines. Episodic ataxia type 2 is caused by a mutation
f the sodium channel CACNA1 gene on chromosome 19i.e., this is an allelic disease, along with familial hemi-legic migraine and spinocerebellar atxia type 6) [48].cetazolamide was shown to decrease the frequency of
ttacks [49]. Some patients develop atrophy of the cere-ellum, best seen on serial brain magnetic resonancemaging studies over time [50].
pinocerebellar Ataxia Type 6 (OMIM 183086)
Spinocerebellar ataxia type 6 is an autosomal-dominantisorder characterized by adult-onset, slowly progressiveerebellar gait ataxia, dysmetria, dysarthria, and nystag-us. The condition does not cause cognitive decline, and
he overall lifespan is not shortened [51]. Magnetic reso-ance imaging of the brain indicates isolated cerebellartrophy [52]. Neuropathologic studies reveal selective Pur-inje-cell degeneration or combined degeneration of bothurkinje and granule cells [53]. Spinocerebellar ataxia type 6
s caused by an expansion of the trinucleotide CAG repeat inhe sodium channel CACNA1A gene on chromosome 19p51]. The normal allele has 18 repeats, and the fullyenetrant disease allele has between 20-33 [54]. Nonticipation has been reported, but an inverse correlationetween the number of repeats and the age of disease onsetas been consistently observed [51].
ereditary Hyperekplexia (OMIM 149400)
Hereditary hyperekplexia is a rare hereditary conditionith both autosomal-dominant and autosomal-recessive
nheritance. Sporadic cases were also reported. The disor-er is characterized by an exaggerated response to unex-ected stimuli (startle), causing marked muscle hypertoniaith preserved consciousness [55]. The onset can be as
arly as the neonatal period. Hereditary hyperekplexia isaused by mutations of the (a) GLRA1 gene, encoding forhe alpha-1 subunit of the glycine receptor located on
hromosome 5q [56]; (b) the GLRB gene, encoding for the c
eta-subunit of the glycine receptor [57]; (c) the SLC6A5ene, encoding for presynaptic glycine transporter-2 [58];nd (d) other postsynaptic glycinergic proteins, includingephyrin [59]. The neurologic signs are usually well-ontrolled with benzodiazepines. Clonazepam is the agentost often utilized and investigated [60].
utosomal-Dominant Nocturnal Frontal Lobe Epilepsy
This epileptic syndrome has its onset typically duringhildhood, and is characterized by clusters of brief frontalobe motor seizures during sleep [61]. These seizures areharacterized by hyperkinetic movements (e.g., bicycling,allism, or pelvic thrusting), tonic stiffening, or clonicerking movements, often preceded by gasping, grunting,r vocaliztion. They may occur several times per night anday be preceded by an aura, which may be that of
mpending fear, shivering, vertigo, or a feeling of fallingr of being pushed. Patients often have the impression ofreathing difficulties, and they may hyperventilate. Theecondary generalization of these seizures is unusual. Thelectroencephalogram is characteristically normal interic-ally, and indicates bifrontal epileptiform discharges dur-ng a seizure. Mutations of three genes are known to causehis condition: (a) CHRNA4 (causing autosomal-dominantocturnal frontal lobe epilepsy type 1, OMIM 600513),ncoding for the neuronal nicotinic acetylcholine receptorlpha-4 subunit, on chromosome 20q [62]; (b) CHRNB2causing autosomal-dominant nocturnal frontal lobe epi-epsy type 3, OMIM-605375), encoding for the beta-2ubunit of the same receptor on chromosome 1 [63]; andc) CHRNA2 (causing autosomal-dominant nocturnal fron-al lobe epilepsy type 4, OMIM 610353), encoding for thelpha-2 subunit of the same receptor located on chromo-ome 8p [64]. Autosomal-dominant nocturnal frontal lobepilepsy type 2 was linked to chromosome 15q24, andhe mutation is thought to affect the neighboring genesHRNA3, CHRNA5, or CHRNB4 [65]. Several authors
eported the particular efficacy of carbamazepine for theanagement of this condition [62].
enign Familial Neonatal Convulsions
This entity was first described by Rett and Teubel in964 [66] as an autosomal-dominant form of neonataleizures occurring in otherwise healthy newborns. Sincehen, it was described by several other authors. The typicalresentation is the onset of multifocal tonic-clonic seizuresfter the third day of life in the absence of any obviousausable factors (i.e., intrapartum asphyxia, central ner-ous system infection, or hemorrhage), which is usuallyell-controlled with antiepileptic medications. Patientsave a normal neurologic examination and typically aormal eventual neurodevelopmental outcome. Three mu-ations have been described, with two implicating theoltage-gated potassium channel. The KCNO2 gene, en-
oding for the voltage-gated potassium channel KQT-like
ubfamily member 2, causes benign familial neonatalonvulsions type 1 (OMIM 121200), and is located onhromosome 20q. Mutations of this gene account for theajority of cases [67]. In benign familial neonatal convul-
ions type 2, the mutated gene is KCNO3, located onhromosome 8q [68]. Concolino et al. reported on a familyith the typical clinical features of benign familial neo-atal convulsions and an inversion of chromosome 5benign familial neonatal convulsions type 3) [69].
Benign familial neonatal-infantile seizures are autoso-al-dominant and are characterized by the development of
febrile seizures during the first year of life. The seizuresypically occur in clusters, and the affected children do notave any neurologic sequelae. The disorder is caused byutations of the sodium channel SCN2A gene, located on
hromosome 2q [70].
eneralized Epilepsy With Febrile Seizures-PlusOMIM 604233)
Generalized epilepsy with febrile seizures-plus is aroup of five epilepsy syndromes of variable phenotypesut typically including simple febrile seizures, generalizedeizures usually precipitated by fever after age 6 years, andartial seizures [71]. In generalized epilepsy with febrileeizures-plus type 1, the mutated gene is SCN1B, locatedn chromosome 19q, encoding for the voltage-gated so-ium channel beta-1 subunit [72]. Generalized epilepsyith febrile seizures-plus type 2 is caused by mutations of
he SCN1A gene located on chromosome 2q, encoding forhe alpha-1 subunit of the same sodium channel [73].eneralized epilepsy with febrile seizures-plus type 3 andeneralized epilepsy with febrile seizures-plus type 5 areaused by mutations of either the GABRG2 gene onhromosome 5q [74] or the GABRD gene on chromosome[75], respectively. Both genes encode subunits of theABAA receptor, which is associated with the chloride
hannel. The specific age for this subtype has not yet beendentified. Generalized epilepsy with febrile seizures-plusype 4 was linked to chromosome 2p24, but the underlyingene or channel has not been identified [76].
evere Myoclonic Epilepsy of Infancy (OMIM 607208)
Severe myoclonic epilepsy of infancy (Dravet syn-rome) is the most severe form of generalized epilepsyith febrile seizures-plus [77]. Patients typically present in
he first year of life with generalized tonic, clonic, oronic-clonic seizures, frequently associated with fever, andubsequently these infants develop myoclonic seizures andccasionally partial seizures. The seizures are frequentlyefractory to medication. The disorder is associated with
ventual neurologic deterioration including ataxia, pyra- s
2 PEDIATRIC NEUROLOGY Vol. 38 No. 2
idal signs, and developmental delay or arrest [78]. Thismalignant” epileptic syndrome is thought to be caused bye novo mutations. It can be caused by mutations in eitherhe SCN1A gene (sodium channel) [78] or by mutations ofhe GABRG2 gene (GABAA receptor) [79]. The prognosiss poor, with intractable seizures and severe developmentalelay. Factors modulating the expression of the particularevere myoclonic epilepsy of infancy phenotype are notet known.
uvenile Myoclonic Epilepsy (OMIM 606904)
Juvenile myoclonic epilepsy was first described byerpin in 1867. It is now a very well-delineated epilepsy
yndrome [80], characterized by an onset in adolescencef myoclonic seizures (100% of patients), generalizedonic-clonic seizures (70% of patients), and absenceeizures (30%). Electroencephalograms are character-zed by high-frequency last (3-6 Hz) generalized polyspikend waves discharges, typically triggered by intermittenthotic stimulation. These patients have a relatively benignourse, with excellent response to valproic acid. However,he necessity of long-term treatment is frequently evident.uvenile myoclonic epilepsy is a genetically heteroge-eous disorder, and its precise mode of inheritance is stillnder debate [81]. Mutations of the GABRA1 gene (GABAeceptor) on chromosome 5q [81], the CACNB4 genecalcium channel) on chromosome 2q [82], the CLCN2ene (chloride channel) on chromosome 3q [83], and theABRD gene (GABAA receptor) on chromosome 1p [84]ere all found in some cases to cause this epileptic
yndrome. Linkage analysis also indicated that a geneocated on chromosome 6p is associated with juvenileyoclonic epilepsy [85].
enign Adult Familial Myoclonic Epilepsy (OMIM01068 and 607876)
Benign adult familial myoclonic epilepsy is an autoso-al-dominant epileptic syndrome with high penetrance,
haracterized by adult onset of myoclonus of the limbs,are and generalized tonic-clonic seizures, and a benignourse [86]. This epileptic syndrome was linked to chro-osome 8q (benign adult familial myoclonic epilepsy type
) [87] and 2p (benign adult familial myoclonic epilepsyype 2) [88]. This epileptic syndrome has been tradition-lly classified as a potential channelopathy, although noon-channel mutation has yet been found.
Childhood absence epilepsy accounts for 5-15% ofediatric generalized epilepsy [89]. This is another veryell-described childhood epilepsy syndrome, character-
zed by a peak onset in mid-childhood of typical absence
eizures occurring multiple times per day with an abrupt
nset and end, without an apparent postictal phase. Elec-roencephalograms reveal bilateral, synchronous, general-zed 3-Hz spikes and waves, typically triggered by hyper-entilation. The response to medication (ethosuximide oralproic acid) is usually excellent, and most patientsxperience an eventual resolution of their absence sei-ures, whereas approximately 30-40% will develop gen-ralized tonic-clonic seizures in adolescence [89]. Theisorder is inherited as an autosomal-dominant trait and isinked to chromosome 8q (childhood absence epilepsyype 1) [89]. Mutations of the GABRG2 gene (GABAeceptor) on chromosome 5q (childhood absence epilepsyype 2) were also shown to cause childhood absencepilepsy [90], as were mutations of the CLCN2 genechloride channel) on chromosome 3q (childhood absencepilepsy type 3) [91]. Mutations of the CACNA1H (cal-ium channel) gene on chromosome 16p may also beesponsible for some cases [92].
aroxysmal Kinesiogenic Dyskinesia
Familial paroxysmal kinesigenic dyskinesia is an auto-omal-dominant condition characterized by frequent at-acks of choreic, ballistic, dystonic, or athetotic move-ents lasting seconds to minutes, induced by movements
r even by anticipation of movements, associated with aormal level of consciousness and a good response tontiepileptic medication (phenytoin or carbamazepine)93]. Linkage analysis of certain families suggests a locusn chromosome 16q, but no gene has yet been found [94].
aroxysmal Nonkinesiogenic Dyskinesia
Familial paroxysmal nonkinesigenic dyskinesia (OMIM18800) is an autosomal-dominant disorder with highenetrance [95]. It is characterized by attacks, lasting frominutes to hours, of dystonia, chorea, ballismus, or athe-
osis, with a preserved level of consciousness [96]. Attacksan be precipitated by alcohol, caffeine, stress, and fa-igue, but not by sudden movement. Both the interictallectroencephalogram and magnetic resonance imaging ofhe brain produce normal results. One gene was found toe mutated in some patients i.e., myofibrillogenesis regu-ator 1 (MR1), which is located on chromosome 2q [97].
Management of these patients is usually difficult andncludes avoidance of precipitants, with or without clon-zepam. Anticonvulsants are not thought to be useful.
ing Chromosome 20
This catastrophic epileptic syndrome was first describedy Atkins et al. in 1972 [98]. The clinical presentation isharacterized by mental retardation, behavioral disorders,nd epilepsy. The absence of (or only minimal) dysmor-hic features usually delay accurate diagnosis. The sei-ures typically start around age 5 years, are of several
ypes, and are refractory to therapy. However, nocturnal N
rontal lobe seizures are frequently encountered, as well asonconvulsive status epilepticus and prolonged confu-ional states. The electroencephalogram is characterizedy a slow background and fronto-temporal interictal epi-eptiform activity, and ictally by generalized spikes andaves, subtle frontal seizures, or nonconvulsive status
pilepticus [99]. Several pathophysiologic mechanismsere suggested to explain this intractable epilepsy. Among
hese, the possibility of a channelopathy involving theelection of two known epilepsy genes during chromo-ome ring formation has been raised: the CHRNA4 geneacetylcholine receptor), known to cause autosomal-dom-nant nocturnal frontal lobe epilepsy, and the KCNQ2potassium channel) gene, known to cause benign familialeonatal convulsions, both located at 20qter [100].
onclusion
It is apparent that the scope of channelopathies ineurologic disorders is both broad and continually expand-ng. It is reasonable to expect that increasing clinicalecognition and sensitivity to this class of disorders,ogether with the application of molecular genetic ap-roaches to explaining their pathogenesis, will expand thepectrum of these disorders and increase what is knownegarding their intrinsic heterogeneity. It may also bexpected that the delineation of the pathogenesis of rela-ively rare, single-gene channelopathies may provide in-ights into the mechanisms underlying more commonisorders (e.g., migraines or epilepsies) that possess ap-arent polygenic familial influences that are not distrib-ted in a classic Mendelian pattern.
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