Autosomal dominant nocturnal frontal lobe epilepsy
Encyclopedia
Autosomal dominant nocturnal frontal lobe
epilepsy
(ADNFLE) is a rare epileptic disorder that causes frequent violent seizures during sleep. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmare
s. Attacks often occur in clusters and typically first manifest in childhood. There are four known loci for ADNFLE, three with known causative genes. These genes encode various nicotinic acetylcholine receptor
α and β subunits CHRNA4, CHRNB2, and CHRNA2.
s, night terror
s, parasomnia
s and various psychiatric disorders.
s plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in sleep
and the frontal cortex is the origin of ADNFLE seizures. Secondly, both the thalamus
and cortex receive cholinergic inputs and acetylcholine receptor
subunits comprise the three known causative genes for ADNFLE. Thirdly, K-complex
are almost invariably present at the start of seizures.
It is thought that epilepsy is caused because these receptor subunits are expressed presynaptically by neurons that release the inhibitory transmitter GABA. Therefore, the mutation in the alpha-4 sunubit could lead to reduced GABA release, causing hyperexcitability.
to phenylalanine
transition at position 248 (S248F) according to the Pacific electric ray
Torpedo californica protein numbering, located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor
α subunit. Using the numbering based on the human CHRNA4 protein, this mutation is called S280F. Receptors containing this mutant subunit are functional, but desensitize
at a much faster pace compared to wild-type only receptors. These mutant containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. Interestingly, these mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine
. Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to calcium
.
The second discovered ADNFLE mutation was also in CHRNA4. This mutation, L259_I260insL, is caused by the insertion of three nucleotides (GCT) between a stretch of leucine
amino acid
s and an isoleucine
. As with the S248F mutation, the L259_I260insL mutation is located in the second transmembrane spanning region. Electrophysiological experiments have shown that this mutant is tenfold more sensitive to acetylcholine
than wild-type. Calcium permeability, however is notably decreased in mutant compared to wild-type containing receptors. Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.
Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.
The most recently discovered mutation in CHRNA4 associated with ADNFLE is T265M, again located in the second transmembrane spanning segment. This mutation has been little studied and all that is known is that it produces receptors with increased sensitivity to acetylcholine and has a low penetrance.
around it. Instead some of these families show strong linkage on chromosome 15 (15q24) near CHRNA3, CHRNA5, and CHRNB4. Causative genes in this area are still unknown.
The other known mutation in CHRNB2 is I312M, located in the third membrane-spanning region. Receptors containing these mutant subunits display much larger currents and a higher sensitivity to acetylcholine than wild-type receptors.
recordings can be confirmatory if they occur during attacks.
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
(ADNFLE) is a rare epileptic disorder that causes frequent violent seizures during sleep. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmare
Nightmare
A nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...
s. Attacks often occur in clusters and typically first manifest in childhood. There are four known loci for ADNFLE, three with known causative genes. These genes encode various nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
α and β subunits CHRNA4, CHRNB2, and CHRNA2.
Signs and symptoms
ADNFLE is a partial epilepsy disorder characterized by brief violent seizures during sleep. Seizures are complex, consisting of arm and leg movements, fist clenching, and vocalizations such as yelling and moaning. These seizures often occur in clusters and can first manifest in childhood. Diagnosis is often initially incorrectly made as nightmareNightmare
A nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...
s, night terror
Night terror
A night terror, also known as a sleep terror, incubus attack, or pavor nocturnus, is a parasomnia disorder that predominantly affects children, causing feelings of terror or dread, typically occur in the first few hours of sleep during stage 3 or 4 NREM sleep...
s, parasomnia
Parasomnia
For the 2008 horror film, see Parasomnia Parasomnias are a category of sleep disorders that involve abnormal and unnatural movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep...
s and various psychiatric disorders.
Causes
While not well understood, it is believed that malfunction in thalamocortical loopThalamocortical loop
Thalamocortical radiations are the fibers between the thalamus and the cerebral cortex.The "thalamocortical loop" is the functional loop between these two structures. The loop consists of projections from thalamus to cortex and from cortex back to thalamus. These projections usually remain within...
s plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
and the frontal cortex is the origin of ADNFLE seizures. Secondly, both the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
and cortex receive cholinergic inputs and acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
subunits comprise the three known causative genes for ADNFLE. Thirdly, K-complex
K-complex
A K-complex is an electroencephalography waveform that occurs during stage 2 of NREM sleep. It is the "largest event in healthy human EEG". They are more frequent in the first sleep cycles of sleep.K-complexes have two proposed functions...
are almost invariably present at the start of seizures.
It is thought that epilepsy is caused because these receptor subunits are expressed presynaptically by neurons that release the inhibitory transmitter GABA. Therefore, the mutation in the alpha-4 sunubit could lead to reduced GABA release, causing hyperexcitability.
CHRNA4
The first mutation associated with ADNFLE is a serineSerine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
to phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
transition at position 248 (S248F) according to the Pacific electric ray
Pacific electric ray
The Pacific electric ray is a species of electric ray in the family Torpedinidae, endemic to the coastal waters of the northeastern Pacific Ocean from Baja California to British Columbia. It generally inhabits sandy flats, rocky reefs, and kelp forests from the surface to a depth of , but has also...
Torpedo californica protein numbering, located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
α subunit. Using the numbering based on the human CHRNA4 protein, this mutation is called S280F. Receptors containing this mutant subunit are functional, but desensitize
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
at a much faster pace compared to wild-type only receptors. These mutant containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. Interestingly, these mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to 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...
.
The second discovered ADNFLE mutation was also in CHRNA4. This mutation, L259_I260insL, is caused by the insertion of three nucleotides (GCT) between a stretch of leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and an isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
. As with the S248F mutation, the L259_I260insL mutation is located in the second transmembrane spanning region. Electrophysiological experiments have shown that this mutant is tenfold more sensitive to acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
than wild-type. Calcium permeability, however is notably decreased in mutant compared to wild-type containing receptors. Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.
Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.
The most recently discovered mutation in CHRNA4 associated with ADNFLE is T265M, again located in the second transmembrane spanning segment. This mutation has been little studied and all that is known is that it produces receptors with increased sensitivity to acetylcholine and has a low penetrance.
15q24
Some families have been shown to not have mutations in CHRNA4 and, furthermore, to show no linkageGenetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
around it. Instead some of these families show strong linkage on chromosome 15 (15q24) near CHRNA3, CHRNA5, and CHRNB4. Causative genes in this area are still unknown.
CHRNB2
Three mutations have been found in the gene CHRNB2, which encodes an acetylcholine receptor β subunit. Two of these mutations, V287L and V287M, occur at the same amino acid, again in the second transmembrane spanning region. The V287L mutation results in receptors that desensitize at a much slower rate compared to wild-type. The V287M mutant displays a higher affinity for acetylcholine when compared to wild-type receptors. As with the mutations in CHRNA4, these mutants lead to receptors less sensitive to calcium.The other known mutation in CHRNB2 is I312M, located in the third membrane-spanning region. Receptors containing these mutant subunits display much larger currents and a higher sensitivity to acetylcholine than wild-type receptors.
CHRNA2
Recently, the I279N mutation has been discovered in the first transmembrane spanning segment of CHRNA2, which encodes a nicotinic acetylcholine receptor α subunit similar to that encoded by CHRNA4. This mutant shows a higher sensitivity to acetylcholine and unchanged desensitization compared to wild-type.Diagnosis
Diagnosis is typically made upon patient history, although 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 can be confirmatory if they occur during attacks.