Channelopathies

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Chapter 42 Channelopathies

Kelly Knupp, Julie A. Parsons, Amy R. Brooks-Kayal

Introduction

Channelopathies are a group of genetically and phenotypically heterogeneous neurological disorders that result from genetically determined defects in ion-channel function. Channelopathies are considered phenotypically heterogeneous because mutations in the same gene can cause different diseases; they are considered genetically heterogeneous because mutations in different genes can result in the same disease phenotype. Mutations of ion channels can alter the activation, ion selectivity, or inactivation of the mutated channel. Neurological manifestations of channelopathies fall into several clinical phenotypes: epilepsy, pain, migraine, ataxia, movement disorders, and muscle disorders (myotonia and weakness).

Ion channels are transmembrane glycoprotein pores that control the excitability of neurons and muscle cells by mediating the flow of charged ions in and out of cells. Channels are typically composed of different protein subunits, each encoded by a different gene. There are two major classes of ion channels: voltage-gated and ligand-gated. Voltage-gated ion channels are activated and inactivated by changes in membrane voltage and are identified according to the principal ion conducted through the channel (e.g., sodium, potassium, calcium, or chloride). Activation and opening of voltage-gated channels have different effects (depolarization, repolarization, or hyperpolarization of the cell membrane), depending on what ion they gate and its charge, the electrochemical gradient for that ion (which determines which direction the ion flows when the channel is opened), and where the channels are located on the cell. Sodium channel opening results in the generation of the action potential (i.e., depolarization). Opening of potassium channels repolarizes cell membranes after action potential firing and maintains the resting membrane potential. Calcium channels are important for the generation of muscle contraction, neurotransmitter release, and intracellular signaling via second messengers. Opening of voltage-gated chloride channels results in the hyperpolarization of cells.

Ligand-gated channels are heterogeneous complexes composed of multiple protein subunits that are activated by the binding of their respective agonists. Several ligand-gated channels are present in the peripheral and central nervous systems. Gamma-aminobutyric acid (GABA)A receptors mediate most of the fast synaptic inhibition in the brain outside of the fetal and early neonatal periods. They are anion-selective and gate primarily chloride, which flows into the cell, causing hyperpolarization upon GABAA receptor activation. Glutamate is the primary excitatory neurotransmitter in the central nervous system and binds to three types of ligand-gated, cation-selective receptor channels: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate. Glutamate receptors gate either sodium only (most AMPA and all kainate receptors), or sodium and calcium (NMDA receptors and some subtypes of AMPA receptors). Nicotinic acetylcholine receptors are nonselective cation channels permeable to Na+ and K+, and in some subtypes Ca2+; they are located on certain neurons and on the postsynaptic side of the neuromuscular junction. Opening of nicotinic receptors causes depolarization of the plasma membrane and activation of voltage-gated ion channels that can effect the release of neurotransmitters and activate intracellular signaling cascades.

Epilepsy Syndromes

As basic science advances and the etiology of several epilepsy syndromes is discovered, ion channelopathies have been identified involving sodium, potassium, and calcium channels. Ligand-gated channels such as GABA receptors and nicotinic receptors also have been implicated. Identifying these syndromes will likely lead to unique treatments for this group of patients.

Dravet’s Syndrome (Severe Myoclonic Epilepsy of Infancy, Severe Myoclonic Epilepsy of Infancy – Borderline)

Clinical Features

Dravet’s syndrome was described first by Charlotte Dravet in 1978 and then in the publication Advances in Epileptology in 1982 [Dravet et al., 1982]. Dravet described a group of children using the name “severe myoclonic epilepsy of infancy” (SMEI). Over time, it became recognized that some children have an incomplete form of the disease, leading to the terminology of “severe myoclonic epilepsy of infancy – borderline.”

These children classically begin to have seizures in the first year of life, typically in the setting of fever and usually characterized by prolonged seizures with hemiconvulsions. The laterality of seizures can alternate with each individual seizure and often evolve into status epilepticus. In the second year of life, other seizure types may begin to emerge, including absence, myoclonic, and generalized tonic–clonic seizures, as well as partial seizures typically occurring without fever. Tonic seizures are rare and, if they do occur, tend to be brief and nocturnal. Myoclonus can be either generalized, focal, or both. Photo-induced seizures occur in some of these children and self-induced seizures have been reported. Throughout childhood, fever continues to be a common provoker of seizures and these seizures are often very difficult to control.

An interesting feature of Dravet’s syndrome is the presence of “obtundation status.” This involves episodes of nonconvulsive status with intermixed myoclonus, at times building up to rhythmic bilateral jerking resembling a generalized clonic seizure. The duration can be hours to days, with slowed responsiveness or waxing and waning alertness. The electroencephalogram (EEG) will often demonstrate diffuse delta activity with intermixed focal and diffuse spikes. Myoclonus may not correlate with spike discharges, except with larger more generalized rhythmic myoclonic jerks. Hospitalization may be required for effective treatment. Some children may have several characteristics of localization-related epilepsy and occasionally have undergone surgical treatment of seizures before the syndrome has been identified.

Development is universally normal in the first year of life. As seizure types become more varied and more frequent, there is often developmental regression or cessation of developmental progress. Severe mental retardation is present in many children with Dravet’s syndrome, but the degree of cognitive impairment is associated with seizure control in many patients [Wolff et al., 2006]. Behavioral issues seem to become more of a concern after age 2. Hyperactivity and autistic traits can be present and very prominent. As children enter into adolescence, hyperkinetic behavior tends to improve and is replaced with overall slowed behavior. Ataxia may also become prominent.

Not all children with Dravet’s syndrome present with what are now considered the classical features, as described above. Some children may not have all of the varied seizure types and have little developmental regression. Myoclonic seizures need not be present for a diagnosis to be made. These seemingly less affected children continue to be exquisitely sensitive to seizure exacerbation due to elevated body temperature, as well as to anticonvulsants that are sodium channel blockers (e.g., carbamazepine, phenytoin, fosphenytoin, oxcarbazepine, lamotrigine, and zonisamide). In some cases these features may suggest the diagnosis. Recently, this syndrome was recognized in a large percentage of children (11 of 14) presenting with seizures and encephalopathy after receiving vaccines (vaccine encephalopathy) [Berkovic et al., 2006]. Logically, it would seem that, for many children, their first fever likely occurs with the first or second set of immunizations. A child was reported to have “hemiconvulsion-hemiplegia syndrome” after a prolonged episode of hemiconvulsion, and subsequently was identified to have the genetic mutation associated with Dravet’s syndrome [Sakakibara et al., 2009].

Since gene testing has become available for this syndrome, it appears that the phenotype is broader than initially appreciated. The diagnosis of severe myoclonic epilepsy of infancy no longer seems to be an appropriate label; therefore the eponym “Dravet’s syndrome” is now the preferred name, encompassing both groups of children. As more children are found to have a similar gene mutation, the true phenotype of this syndrome will likely evolve.

Genetics/Pathophysiology

Mutations in a sodium channel, SCN1A, were initially identified in 7 of 7 children with severe myoclonic infantile epilepsy [Claes et al., 2001]. Approximately 80 percent of children with a clinical diagnosis of Dravet’s syndrome have a mutation in this gene. This channel was initially implicated in generalized epilepsy with febrile seizures plus (GEFS+; see below). The sensitivity to body temperature in both of these syndromes led investigators to evaluate for mutations in the SMEI population. The majority of the children with Dravet’s syndrome have a de novo mutation, although some of the families have a higher than expected history of febrile seizures. The phenotype of patients can be predicted by mutation in most cases, as the majority of patients have a truncation mutation or a mutation that affects the function of the channel pore. Patients with less severe phenotypes often have point mutations that do not result in as severe an effect on the function of the sodium channel, although the correlation of specific SCN1A mutation to phenotype is not a tight one.

Recent discoveries related to the cell type-specific localization of SCN1A added to our understanding of how loss of function of a sodium channel, logically a cause of hypoexcitablity of individual neurons, could lead to network hyperexcitabilty and, consequently, seizures. This seeming contradiction can be explained by the finding that the loss of SCN1A function leads to selective loss of sodium channel function in inhibitory interneurons [Yu et al., 2006], causing inhibitory dysfunction and secondary hyperexcitability.

Clinical Laboratory Tests

EEG findings are typically normal in the first year of life, but evolve to demonstrate generalized and multifocal abnormalities. A photoconvulsive response can be seen, and diffuse background slowing can become more prominent as children age. No characteristic pattern is diagnostic of Dravet’s syndrome, as is seen in Lennox–Gastaut or Doose’s syndrome; in fact, there can be some overlap between these syndromes and Dravet’s syndrome, making accurate diagnosis challenging. EEG findings can fluctuate, and a small percentage of patients may continue to have normal EEGs; over time, a decrease in epileptiform abnormalities has been reported in older patients.

Magnetic resonance imaging (MRI) in patients with Dravet’s syndrome is usually without any focal abnormalities. In one study that evaluated 58 children with Dravet’s syndrome, 60 percent had SCN1a mutations and 22 percent had abnormal MRI findings, the majority with cortical atrophy and others with cerebellar atrophy, white matter hyperintensity, mesial temporal sclerosis, and focal cortical dysplasia. Abnormal findings were more likely in patients without a genetic mutation [Striano et al., 2007]. Other studies have suggested that mild, diffuse atrophy and ventriculomegaly may develop over time.

Genetic testing is appropriate in patients suspected to have Dravet’s syndrome. Early diagnosis may avoid extensive and expensive metabolic testing and inadvertent exacerbation of seizures by certain medications, as well as providing prognostic information for the family. However, as the phenotype expands, using genotype to provide an accurate prognosis may become more problematic.

Treatment

Seizure control is the primary treatment goal in this disorder. Medications that are known to block the sodium channel often will exacerbate seizures and should be avoided [Guerrini et al., 1998]. Prior to clinical diagnosis, a worsening of seizures while being treated with one of these medications should raise suspicion of Dravet’s syndrome. Topiramate, valproic acid, benzodiazepines, and levetiracetam have been helpful. Nonpharmacologic treatments, such as vagal nerve stimulation or the ketogenic diet [Caraballo and Fejeman, 2006], have been useful in some patients. Combination therapy with stiripentol, clobazam, and either depakote or topiramate has been reported to be more effective than other combinations of medication. In an initial report by Chiron et al., 15 of 21 patients responded to stiripentol [Chiron et al., 2000]. Acetazolamide has not been shown to be beneficial. A recent report with the calcium channel blocker, verapamil, has suggested that this may be helpful, but more research is required [Iannetti et al., 2009].

Avoidance of hot temperatures, both environmental and elevated body temperature, has been used by many families to reduce seizures. Antipyretics, such as acetaminophen, have been helpful, although there is a recent report of four children with transient liver abnormalities that may be associated with use of this medication [Nicolai et al., 2008]. Helmets may be indicated in some patients. Due to the severity of the cognitive impairment, appropriate support must be initiated for the family [Nolan et al., 2008]. Medications for behavioral issues may also be necessary (see Chapter 49).

Generalized Epilepsy with Febrile Seizures Plus (GEFS+)

Clinical Features

This is a familial epilepsy syndrome characterized by febrile seizures in childhood in several generations of family members, often with continuation of febrile seizures into adulthood. Some seizures related to fever may be prolonged. Some family members may also have generalized epilepsies, such as absence epilepsy, myoclonic astatic epilepsy, or, rarely, Dravet’s syndrome. Seizure types include generalized tonic clonic, myoclonic, absence, and atonic seizures. There is variable penetrance of seizures in these familial cohorts. Phenotype also varies among family members. Many family members may have resolution of seizures by age 12. The majority of these patients have normal development and intelligence. There has also been a report of temporal lobe epilepsy with mesial temporal sclerosis associated with the SCN1A mutation [Mantegazza et al., 2005].

Genetics/Pathophysiology

SCN1B was a mutation first reported in a large family with this syndrome [Wallace et al., 1998]. Mutations in other sodium channels – SCN1A [Escayg et al., 2000a] and SCN2A [Sugawara et al., 2001] – have been found subsequently. The majority of these mutations have been point mutations. In patients with SCN1A mutations, a difference in phenotype from GEFS+ and Dravet’s syndrome can often be predicted, given the location of the mutation (distance from the pore), as well as alteration in transcription of the gene. Nonsense and truncation mutations are more likely to be associated with Dravet’s syndrome. Sodium channel mutations do not account for all of the mutations in GEFS+; there also have been reports of mutations identified in GABAA receptor subunit genes,GABRG2 and GABRD (gamma 2 and delta subunits) [Harkin et al., 2002]. GABAA receptors are ligand-gated chloride channels that provide the majority of inhibition in brain beyond the neonatal period, and mutations resulting in GABAA receptor dysfunction result in increased central nervous system excitability that has been associated with a number of genetic epilepsies.

Treatment

There has been little published discussion of the treatment of these syndromes. For patients with sodium channel mutations, avoidance of sodium channel blockers is wise. Treatment when necessary with broad-spectrum anticonvulsants is thought to be useful. Avoidance of temperature changes and routine use of fever control measures may be of some benefit.

Benign Familial Neonatal Seizures

Clinical Features

Benign familial neonatal seizures are an autosomal-dominant epilepsy presenting with seizures in the first or second week of life, most commonly starting on day of life 2 or 3, resolving within weeks to months. Most seizures have stopped at 4–5 months of life. Seizures are usually multifocal clonic seizures or focal seizures. The feature suggesting this entity is the presence of similar seizures in parents and first-degree relatives, occurring at the same age. Development is characteristically normal during this time period, as well as after seizures stop. Fifteen percent of children will develop epilepsy later in life, usually in childhood or as a young adult. There are some children who progress to medically refractory epilepsy with encephalopathy [Steinlein et al., 2007].

Genetics/Pathophysiology

Mutations in potassium channels KCNQ2 [Singh et al., 1998; Biervert et al., 1998] and KCNQ3 [Charlier et al., 1998] (found on chromosomes 20 and 8 respectively) have been reported in families with benign neonatal seizures. These mutations also have been reported in some families with benign rolandic epilepsy [Hahn and Neubauer, 2009]. Recently, mutations in these genes also have been reported in a small percentage of patients with idiopathic generalized epilepsy, suggesting it may play some role in the etiology of these epilepsies. Mutations can cause alteration in function or complete loss of function of the potassium channel. Approximately 50 percent of mutations lead to shortening of expressed protein [Heron et al., 2007]. The age specificity of the seizures in this disorder is thought to emanate from brain developmental changes during the neonatal period. GABA, which acts as an inhibitory neurotransmitter later in life, can be excitatory in the early neonatal period due to developmental changes in the chloride gradient that result in opening of GABAA receptor chloride channels, producing membrane depolarization in early development rather than membrane hyperpolarization, as it does in mature neurons. In contrast, opening of potassium channels is hyperpolarizing throughout development, and due to the paucity of GABAergic inhibition, potassium channel-mediated inhibition is uniquely critical in the newborn. This may explain why impairment or absence of potassium channel inhibition results in seizures specifically at this time and why only a small fraction of patients with KCNQ2/3 mutations have seizures later in life.

Clinical Laboratory Tests

EEG generally demonstrates normal interictal features, although at the time of seizure there is an electrographic correlate. MRI is expected to be normal. Other causes of seizures, such as neonatal infection and metabolic abnormalities, should be excluded.

Developmental Delay, Epilepsy and Neonatal Diabetes (DEND)

This is a rare syndrome, presenting with neonatal diabetes, developmental delay, seizures and mild dysmorphic features, which has been associated with a mutation in the KCNJ11 gene that encodes for a subunit of the adenosine triphosphate (ATP)-sensitive potassium channel. This channel is found on pancreatic islet cells, as well as neurons, and neonates with this disorder usually present with diabetes and subsequently develop seizures and global developmental delay [Gloyn et al., 2004]. Dysmorphic features, including downturned mouth, bilateral ptosis, prominent metopic suture, and contractures, have also been described [Gloyn et al., 2004]. There have been reports of infantile spasms in some of these children [Bahi-Buisson et al., 2007], as well as others with tonic-clonic and myoclonic seizures. Seizures have been very refractory to traditional antiepileptic medications. In contrast, patients are very responsive to treatment with sulfonylurea medications such as glibenclamide, leading to improvement in diabetes as well as developmental outcomes and seizures.

Other “Idiopathic” Epilepsies

Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal-dominant nocturnal frontal lobe epilepsy is a familial epilepsy characterized by frontal lobe seizures that typically occur at night and usually present as arousal from sleep with bizarre hypermotor behaviors, such as spinning, thrashing and rocking. Seizures can occur several times per night. Nicotinic receptor mutations have been found in many of these familial cohorts [Steinlein et al., 1995], although there are several families for which no gene mutation has been identified. These ligand-gated receptors allow sodium and potassium to cross the cell membrane. Many patients are responsive to carbamazepine and phenytoin.

Benign Familial Infantile–Neonatal Seizures

Benign familial infantile–neonatal seizures is an epilepsy syndrome that has been described as being similar to benign neonatal seizures but occurs at a slightly older age. Mutations have been found in a sodium channel, SCN2A1, in some cohorts [Herlenius et al., 2007].

Childhood Absence Epilepsy

Childhood absence epilepsy has been linked to mutations in GABA receptors (GABRA1 and GABRG2) [Baulac et al., 2001; Wallace et al., 2001] and chloride channels (CLCN2). Mutations have also been described in a calcium channel, CACNA1H, but this mutation may represent an ethnic variant present in Chinese Han patients, as these findings were not present in a large European cohort [Chen et al., 2003]. The families with CLCN2 also had members with generalized tonic-clonic seizures on awakening and juvenile myoclonic epilepsy [Baykan et al., 2004].

Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy is a seizure disorder that usually presents in adolescents with myoclonic seizures that are more likely to occur in the early morning after awakening, as well as generalized tonic-clonic seizures that also tend to occur in the morning hours. Several gene mutations have been found in these patients, although the majority of patients have yet to have an underlying etiology determined. It appears that, similar to childhood absence epilepsy, this is likely a polygenic disorder. Channels that have been identified include GABA receptors (GABRA1 and GABRD) [Cossette et al., 2002], calcium channels (CACNB4) [Escayg et al., 2000b], and chloride channels (CLCN2) [Baykan et al., 2004]. In addition, a gene that is not a direct channel gene but enhances calcium influx into the cell and can stimulate programmed cell death (EFHC1) [Suzuki et al., 2004] has also been identified as being involved in this epilepsy syndrome.

Familial Pain Syndromes

Several pain syndromes have been associated with sodium channel mutations. This is not surprising, as sodium channels are located on spinal sensory neurons in the dorsal root ganglion.

Clinical Features

Inherited erythromelalgia, primary erythermalgia

Inherited erythromelalgia (IEM), or primary erythermalgia, is a pain syndrome characterized by episodes of redness and swelling of the hands and feet, associated with burning pain. These episodes can be triggered by mild warmth or exercise. Many patients prefer to avoid or are unable to wear socks and shoes due to heat inducing an episode. Some patients also report involvement of the ears, nose, and other parts of their face, as well as the upper legs. Erythema can become constant, and edema may be associated [Drenth and Waxman, 2007]. Families have reported symptoms starting in the first year of life. Age of onset can vary from childhood to adulthood, and can be familial or sporadic [Drenth et al., 2008; Han et al., 2009]. About 15 percent of cases are familial, and in these cases onset is often in the first decade of life.

Paroxysmal extreme pain disorder

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