Signs and symptoms
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| Autosomal dominant nocturnal frontal lobe epilepsy | |
|---|---|
| Specialty | Neurology |
| Usual onset | Childhood |
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) 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 α and β subunits.
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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 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. [1]
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 nicotinic acetylcholine receptor α4 subunit. [2] Using the numbering based on the human CHRNA4 protein, this mutation is called S280F. [3] 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. [4] These mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine. [5] [6] [7] Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to calcium. [8]
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 acids 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. [9] Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors. [6] [7]
Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. [10] This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors. [3] [7]
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. [11]
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 (15q24) near CHRNA3, CHRNA5, and CHRNB4. Causative genes in this area are still unknown. [12]
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. [13] The V287M mutant displays a higher affinity for acetylcholine when compared to wild-type receptors. [7] [14] As with the mutations in CHRNA4, these mutants lead to receptors less sensitive to calcium. [8]
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. [15]
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. [16]
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An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
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 nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.
Jean-Pierre Changeux is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins, to the early development of the nervous system up to cognitive functions. Although being famous in biological sciences for the MWC model, the identification and purification of the nicotinic acetylcholine receptor and the theory of epigenesis by synapse selection are also notable scientific achievements. Changeux is known by the non-scientific public for his ideas regarding the connection between mind and physical brain. As put forth in his book, Conversations on Mind, Matter and Mathematics, Changeux strongly supports the view that the nervous system functions in a projective rather than reactive style and that interaction with the environment, rather than being instructive, results in the selection amongst a diversity of preexisting internal representations.
Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood. GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravet's syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.
Benign familial neonatal seizures (BFNS), also referred to as benign familial neonatal epilepsy (BFNE), is a rare autosomal dominant inherited form of seizures. This condition manifests in newborns as brief and frequent episodes of tonic-clonic seizures with asymptomatic periods in between. Characteristically, seizure activity spontaneously ends during infancy and does not affect childhood development. However, some studies have reported that a minority of children with BFNS consequently develop intellectual disability. Additionally, BFNS increases lifetime susceptibility to seizures as approximately 14% of those afflicted go on to develop epilepsy later in life. There are three known genetic causes of BFNE, two being the voltage-gated potassium channels KCNQ2 (BFNC1) and KCNQ3 (BFNC2) and the third being a chromosomal inversion (BFNC3). There is no obvious correlation between most of the known mutations and clinical variability seen in BFNE.
Ring chromosome 20, ring-shaped chromosome 20 or r(20) syndrome is a rare human chromosome abnormality where the two arms of chromosome 20 fuse to form a ring chromosome. The syndrome is associated with epileptic seizures, behaviour disorders and intellectual disability.
Gamma-aminobutyric acid receptor subunit gamma-2 is a protein that in humans is encoded by the GABRG2 gene.
Neuronal acetylcholine receptor subunit alpha-7, also known as nAChRα7, is a protein that in humans is encoded by the CHRNA7 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR).
Neuronal acetylcholine receptor subunit alpha-4, also known as nAChRα4, is a protein that in humans is encoded by the CHRNA4 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAChR). Alpha4-containing nAChRs appear to play a crucial role in the addictive response to nicotine.
Neuronal acetylcholine receptor subunit beta-2 is a protein that in humans is encoded by the CHRNB2 gene.
Neuronal acetylcholine receptor subunit alpha-3, also known as nAChRα3, is a protein that in humans is encoded by the CHRNA3 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR). Research with mecamylamine in animals has implicated alpha-3-containing nAChRs in the abusive and addictive properties of ethanol.
Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.
Neuronal acetylcholine receptor subunit alpha-1, also known as nAChRα1, is a protein that in humans is encoded by the CHRNA1 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR).
Neuronal acetylcholine receptor subunit beta-4 is a protein that in humans is encoded by the CHRNB4 gene.
Leucine-rich, glioma inactivated 1, also known as LGI1, is a protein which in humans is encoded by the LGI1 gene. It may be a metastasis suppressor.
Neuronal acetylcholine receptor subunit alpha-2, also known as nAChRα2, is a protein that in humans is encoded by the CHRNA2 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR).
Acetylcholine receptor subunit delta is a protein that in humans is encoded by the CHRND gene.
Acetylcholine receptor subunit gamma is a protein that in humans is encoded by the CHRNG gene.
CHRNA7-FAM7A fusion protein is a protein that in humans is encoded by the CHRFAM7A gene.
Sleep-related hypermotor epilepsy (SHE), previously known as nocturnal frontal lobe epilepsy, is a form of focal epilepsy characterized by seizures which arise during sleep. The seizures are most typically characterized by complex motor behaviors. It is a relatively uncommon form of epilepsy that constitutes approximately 9-13% of cases. This disorder is associated with cognitive impairment in at least half of patients as well as excessive daytime sleepiness due to poor sleep quality. This disorder is sometimes misdiagnosed as a non-epileptic sleep disorder. There are many potential causes of SHE including genetic, acquired injuries and structural abnormalities.