Juvenile myoclonic epilepsy
Encyclopedia
Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy
, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus
occurring early in the morning. Most patients also have tonic-clonic seizure
s and many also have absence seizure
s. Linkage studies have demonstrated at least 6 loci for JME, 4 with known causative genes. Most of these genes are ion channel
s with the one non-ion channel gene having been shown to affect ion channel currents.
occurring early in the morning. This rarely results in patients falling, but rather dropping objects. Attacks of myoclonia are more common in the arms than the legs. Other seizure types
such as generalized tonic-clonic and absence seizures can also occur.
Myoclonic seizures can also occur in the later part of the day, and are not limited to the arms and hands. They can also occur in the lower legs, causing sufferers to trip over their own feet. Clusters of myoclonics can lead to absence seizures, and clusters of absence seizures can lead to generalized tonic-clonic seizures. Expression can occur as young as 18 months of age. Males in some families do not survive the crisis point at 24 months of age.
encodes a calcium channel
β subunit. β subunits are important regulators of calcium channel current amplitude, voltage dependence, and also regulate channel trafficking. The β4 isoform encoded by CACNB4 is most prevalent in the cerebellum
. In mice, a naturally occurring null mutation leads to the "lethargic" phenotype, which is similar to JME. There are at least two mutations in the β4 subunit associated with JME, C104F and R482X. When wild-type α1A and β4 subunits are expressed in oocytes they produce large Ba2+
currents that inactivate slowly. Incorporation of either of the mutant β4 subunit into channels instead of wild-type subunits produces currents that are larger by 30-40%. The R482X mutation also increases the rate of fast inactivation of the channel. Since these effects are subtle, it is believed that they are contributory rather than completely causative for JME.
encodes an α subunit of the GABA A receptor
, which encodes one of the major inhibitory neurotransmitter receptors. There is one known mutation in this gene that is associated with JME, A322D, which is located in the third segment of the protein. Expression of the α1β2γ2 combination of subunits in HEK 293 cells produces 6-fold greater current than similar subunits compositions containing mutant α1 subunits. The mutation also results in greatly decreased sensitivity in the receptor for activation by GABA
. This combination of mutant containing receptors also activates far more slowly than wild-type containing receptors. Although originally not reported to result in altered protein trafficking, more recent study has indicated that the A322D mutation reduced α1 subunit trafficking to the membrane by >90%. Heterozygous expression of wild-type and mutant subunits produces current approximately 50% the size of wild-type due to this altered trafficking.
gene encodes a chloride channel
that is heavily expressed in brain regions inhibited by GABA
. It is believed to be important in maintaining a proper chloride
reversal potential
needed in inhibitory neurotransmission by GABA. There are three known mutations in CLCN2 associated with JME, M200fsX231, 74_117del, and G715E. Neither the M200fsX231 nor the 74_117del mutation yield current when expressed in cells. Since these channels are responsible for the removal of intracellular chloride, these mutations are expected to lead to increased chloride concentrations and, thus, altered chloride reversal potential (ECl). As chloride is conducted through the normally inhibitory GABA receptors, this alteration in ECl may lead to either decreased GABAergic currents or GABAergic currents that are actually excitatory. The G715E mutation, on the other hand, produces normal sized currents but has altered voltage dependent activation. For this mutant, activation occurs at more positive potentials compared to wild-type channels. This may cause increased neuronal excitability.
encodes the δ subunit of the GABA receptor
, which is a subunit yielding receptors which do not desensitize
and are localized outside of the synapse
. There are three mutations in this gene associated with JME, E177A, R220C, and R220H, all located in the N-terminus of the protein. The last of these mutations is also present in normal controls. Receptors containing the E177A mutation have greatly decreased current compared to wild-type. This is not the case for the R220C mutation but is similar to the R220H mutation, though to a lesser extent than the E177A mutation. More recent study has found that the E177A mutant also has greatly decreased desensitization
compared to wild-type receptors. Receptors containing only E177A or R220H mutants, versus heterozygotes, had significantly decreased surface expression compared to wild-type or heterozygotic receptors. These mutants also have decreased single-channel open times compared to wild-type. It should be noted, however, that these mutations are very rare as causes of JME.
, which is poorly understood. EFHC1 has three DM10 domains (themselves of unknown function) and an EF hand motif, which is known to bind intracellular calcium
. EFHC1 is expressed in many tissues, including the brain, where it is localized to the soma
and dendrite
s of neurons, particularly the hippocampal CA1
region, pyramidal neurons in the cerebral cortex
, and Purkinje cell
s in the cerebellum
. There are 5 mutations in EFHC1 associated with JME; D210N, F229L, D253Y, P77T and R221H. The last two mutations were originally detected as a pair in the same individual. EFHC1 seems to be involved in programmed cell death
as EFHC1 transfected cells have a higher rate of apoptosis
. This rate is decreased by the double mutations P77T + R221H. Wild-type EFHC1 increased the R-type calcium channel
currents in transfected cells. This stimulation is decreased by JME associated mutations. Because of this, programmed cell death is decreased and the pruning of unwanted neurons may be hampered. As with some other loci, mutations in EFHC1 is not a common loci for JME. More recently, R221H has been found without P77T in one JME kindred.
gene on chromosome 6 (6p21) to JME. Causative genes in this region, however, have not been shown.
s, both genetic syndromes
and genetic diseases
, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause
despite the widely-varying set of medical symptoms
that are clinically visible in the disorders. This emerging
class of diseases are called ciliopathies
. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell
, organelle
s which are present in many cellular types throughout the human
body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia
, Bardet-Biedl syndrome
, polycystic kidney
and liver disease
, nephronophthisis
, Alstrom syndrome
, Meckel-Gruber syndrome and some forms of retinal degeneration
. It has been suggested that juvenile myoclonic epilepsy may be a ciliopathy
.
recordings are also sometimes used as confirmation.
Idiopathic generalized epilepsy
Idiopathic generalized epilepsy is a group of epileptic disorders that are believed to have a strong underlying genetic basis. Patients with an IGE subtype are typically otherwise normal and have no anatomical brain abnormalities. Patients also often have a family history of epilepsy and seem to...
, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
occurring early in the morning. Most patients also have tonic-clonic seizure
Tonic-clonic seizure
Tonic–clonic seizures are a type of generalized seizure that affects the entire brain...
s and many also have absence seizure
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....
s. Linkage studies have demonstrated at least 6 loci for JME, 4 with known causative genes. Most of these genes are ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s with the one non-ion channel gene having been shown to affect ion channel currents.
Signs and symptoms
Signs of JME are myoclonusMyoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
occurring early in the morning. This rarely results in patients falling, but rather dropping objects. Attacks of myoclonia are more common in the arms than the legs. Other seizure types
Seizure types
The numerous epileptic seizure types are most commonly defined and grouped according to the scheme proposed by the International League Against Epilepsy in 1981...
such as generalized tonic-clonic and absence seizures can also occur.
Myoclonic seizures can also occur in the later part of the day, and are not limited to the arms and hands. They can also occur in the lower legs, causing sufferers to trip over their own feet. Clusters of myoclonics can lead to absence seizures, and clusters of absence seizures can lead to generalized tonic-clonic seizures. Expression can occur as young as 18 months of age. Males in some families do not survive the crisis point at 24 months of age.
CACNB4
CACNB4CACNB4
Voltage-dependent L-type calcium channel subunit beta-4 is a protein that in humans is encoded by the CACNB4 gene.- Function :This gene encodes a member of the beta subunit family, a protein in the voltage-dependent calcium channel complex...
encodes a calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
β subunit. β subunits are important regulators of calcium channel current amplitude, voltage dependence, and also regulate channel trafficking. The β4 isoform encoded by CACNB4 is most prevalent in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. In mice, a naturally occurring null mutation leads to the "lethargic" phenotype, which is similar to JME. There are at least two mutations in the β4 subunit associated with JME, C104F and R482X. When wild-type α1A and β4 subunits are expressed in oocytes they produce large Ba2+
Barium
Barium is a chemical element with the symbol Ba and atomic number 56. It is the fifth element in Group 2, a soft silvery metallic alkaline earth metal. Barium is never found in nature in its pure form due to its reactivity with air. Its oxide is historically known as baryta but it reacts with...
currents that inactivate slowly. Incorporation of either of the mutant β4 subunit into channels instead of wild-type subunits produces currents that are larger by 30-40%. The R482X mutation also increases the rate of fast inactivation of the channel. Since these effects are subtle, it is believed that they are contributory rather than completely causative for JME.
GABRA1
GABRA1GABRA1
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
encodes an α subunit of the GABA A receptor
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
, which encodes one of the major inhibitory neurotransmitter receptors. There is one known mutation in this gene that is associated with JME, A322D, which is located in the third segment of the protein. Expression of the α1β2γ2 combination of subunits in HEK 293 cells produces 6-fold greater current than similar subunits compositions containing mutant α1 subunits. The mutation also results in greatly decreased sensitivity in the receptor for activation by GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. This combination of mutant containing receptors also activates far more slowly than wild-type containing receptors. Although originally not reported to result in altered protein trafficking, more recent study has indicated that the A322D mutation reduced α1 subunit trafficking to the membrane by >90%. Heterozygous expression of wild-type and mutant subunits produces current approximately 50% the size of wild-type due to this altered trafficking.
CLCN2
The CLCN2CLCN2
Chloride channel protein 2 is a protein that in humans is encoded by the CLCN2 gene. Mutations of this gene have been found to cause Idiopathic generalised epilepsy . CLCN2 contains a transmembrane region that is involved in chloride ion transport as well two intracellular copies of the CBS domain....
gene encodes a chloride channel
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
that is heavily expressed in brain regions inhibited by GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. It is believed to be important in maintaining a proper chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
reversal potential
Reversal potential
In a biological membrane, the reversal potential of an ion is the membrane potential at which there is no net flow of that particular ion from one side of the membrane to the other...
needed in inhibitory neurotransmission by GABA. There are three known mutations in CLCN2 associated with JME, M200fsX231, 74_117del, and G715E. Neither the M200fsX231 nor the 74_117del mutation yield current when expressed in cells. Since these channels are responsible for the removal of intracellular chloride, these mutations are expected to lead to increased chloride concentrations and, thus, altered chloride reversal potential (ECl). As chloride is conducted through the normally inhibitory GABA receptors, this alteration in ECl may lead to either decreased GABAergic currents or GABAergic currents that are actually excitatory. The G715E mutation, on the other hand, produces normal sized currents but has altered voltage dependent activation. For this mutant, activation occurs at more positive potentials compared to wild-type channels. This may cause increased neuronal excitability.
GABRD
GABRDGABRD
Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene....
encodes the δ subunit of the GABA receptor
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
, which is a subunit yielding receptors which do not desensitize
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
and are localized outside of the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. There are three mutations in this gene associated with JME, E177A, R220C, and R220H, all located in the N-terminus of the protein. The last of these mutations is also present in normal controls. Receptors containing the E177A mutation have greatly decreased current compared to wild-type. This is not the case for the R220C mutation but is similar to the R220H mutation, though to a lesser extent than the E177A mutation. More recent study has found that the E177A mutant also has greatly decreased desensitization
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
compared to wild-type receptors. Receptors containing only E177A or R220H mutants, versus heterozygotes, had significantly decreased surface expression compared to wild-type or heterozygotic receptors. These mutants also have decreased single-channel open times compared to wild-type. It should be noted, however, that these mutations are very rare as causes of JME.
EFHC1
The final known associated gene is EFHC1EFHC1
EF-hand domain-containing protein 1 is a protein that in humans is encoded by the EFHC1 gene.-Further reading:...
, which is poorly understood. EFHC1 has three DM10 domains (themselves of unknown function) and an EF hand motif, which is known to bind intracellular calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
. EFHC1 is expressed in many tissues, including the brain, where it is localized to the soma
Soma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
and dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
s of neurons, particularly the hippocampal CA1
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
region, pyramidal neurons in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, and Purkinje cell
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. There are 5 mutations in EFHC1 associated with JME; D210N, F229L, D253Y, P77T and R221H. The last two mutations were originally detected as a pair in the same individual. EFHC1 seems to be involved in programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
as EFHC1 transfected cells have a higher rate of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. This rate is decreased by the double mutations P77T + R221H. Wild-type EFHC1 increased the R-type calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
currents in transfected cells. This stimulation is decreased by JME associated mutations. Because of this, programmed cell death is decreased and the pruning of unwanted neurons may be hampered. As with some other loci, mutations in EFHC1 is not a common loci for JME. More recently, R221H has been found without P77T in one JME kindred.
Other loci
There is also evidence linking a gene or genes on chromosome 15 (15q14) as well as the BRD2BRD2
Bromodomain-containing protein 2 is a protein that in humans is encoded by the BRD2 gene.-Further reading:...
gene on chromosome 6 (6p21) to JME. Causative genes in this region, however, have not been shown.
Relation to other rare disorders
Until recently, the medical literature did not indicate a connection among many genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s, both genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
despite the widely-varying set of medical symptoms
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
that are clinically visible in the disorders. This emerging
Emergence
In philosophy, systems theory, science, and art, emergence is the way complex systems and patterns arise out of a multiplicity of relatively simple interactions. Emergence is central to the theories of integrative levels and of complex systems....
class of diseases are called ciliopathies
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s which are present in many cellular types throughout the human
Human
Humans are the only living species in the Homo genus...
body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, Bardet-Biedl syndrome
Bardet-Biedl syndrome
The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.-Summary of the...
, polycystic kidney
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
and liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Alstrom syndrome
Alstrom syndrome
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in...
, Meckel-Gruber syndrome and some forms of retinal degeneration
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
. It has been suggested that juvenile myoclonic epilepsy may be a ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
.
Diagnosis
Diagnosis is typically made based on patient history. EEGEEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
recordings are also sometimes used as confirmation.