Autosomal dominant nocturnal frontal lobe epilepsy is an 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 nightmares. 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, ''CHRNA4'', ''CHRNB2'', and ''CHRNA2'', encode various

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

α and β subunits.

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 nightmares,

night terror Night terror, also called sleep terror, is a sleep disorder causing feelings of panic or dread and typically occurring during the first hours of stage 3–4 non-rapid eye movement (NREM) sleep and lasting for 1 to 10 minutes. It can last long ...

parasomnia Parasomnias are a category of sleep disorders that involve abnormal movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep. Parasomnias are dissociat ...

s and various psychiatric disorders.

Causes

While not well understood, it is believed that malfunction in thalamocortical loops plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in

sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...

and the frontal cortex is the origin of ADNFLE seizures. Secondly, both the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

and cortex receive cholinergic inputs and

acetylcholine receptor An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptors are classified according ...

subunits comprise the three known causative genes for ADNFLE. Thirdly,

K-complex A K-complex is a waveform that may be seen on an electroencephalogram (EEG). It 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. K-complexes have two proposed ...

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 α4 subunit could lead to reduced GABA release, causing hyperexcitability.

Pathophysiology

''CHRNA4''

The first mutation associated with ADNFLE is a serine to phenylalanine transition at position 248 (S248F), located in the second transmembrane spanning region of the gene encoding a

α4 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. These mutant receptors also have a decreased single channel conductance than wild-type and have a lower

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for acetylcholine. Also importantly, this mutation along with the others in ''CHRNA4'' produce receptors less sensitive to

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...

. 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 (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

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.

15q24

Some families have been shown to not have mutations in ''CHRNA4'' and, furthermore, to show no linkage around it. Instead some of these families show strong linkage on

chromosome 15 Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DN ...

(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 β2 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 α2 subunit similar to the nAChR α4 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

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...

recordings can be confirmatory if they occur during attacks.

Management

Anti-epileptic drugs are normally used to combat ADNFLE. These drugs are discussed in the main epilepsy article.