Autosomal dominant nocturnal frontal lobe epilepsy

Last updated
Autosomal dominant nocturnal frontal lobe epilepsy
Other namesADNFLE
Specialty Neurology

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 α and β subunits.

Contents

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 terrors, parasomnias and various psychiatric disorders.[ citation needed ]

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 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] 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.[ citation needed ]

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 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]

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 (15q24) near CHRNA3, CHRNA5, and CHRNB4. Causative genes in this area are still unknown. [12]

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. [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]

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. [16]

Diagnosis

Diagnosis is typically made upon patient history, although EEG recordings can be confirmatory if they occur during attacks.[ citation needed ]

Management

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

Footnotes

  1. ↑ El Helou J, Navarro V, Depienne C, Fedirko E, LeGuern E, Baulac M, An-Gourfinkel I, Adam C (2008). "K-complex-induced seizures in autosomal dominant nocturnal frontal lobe epilepsy". Clin Neurophysiol. 119 (10): 2201–4. doi:10.1016/j.clinph.2008.07.212. PMID   18762450. S2CID   26640365.
  2. ↑ Steinlein O, Mulley J, Propping P, Wallace R, Phillips H, Sutherland G, Scheffer I, Berkovic S (1995). "A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy". Nat Genet. 11 (2): 201–3. doi:10.1038/ng1095-201. PMID   7550350. S2CID   210163.
  3. 1 2 Matsushima N, Hirose S, Iwata H, Fukuma G, Yonetani M, Nagayama C, Hamanaka W, Matsunaka Y, Ito M, Kaneko S, Mitsudome A, Sugiyama H (2002). "Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes". Epilepsy Res. 48 (3): 181–6. doi:10.1016/S0920-1211(01)00336-9. PMID   11904236. S2CID   36484761.
  4. ↑ Weiland S, Witzemann V, Villarroel A, Propping P, Steinlein O (1996). "An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics". FEBS Lett. 398 (1): 91–6. doi: 10.1016/S0014-5793(96)01215-X . PMID   8946959.
  5. ↑ Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J (1997). "Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors". J Neurosci. 17 (23): 9035–47. doi: 10.1523/JNEUROSCI.17-23-09035.1997 . PMC   6573611 . PMID   9364050.
  6. 1 2 Bertrand S, Weiland S, Berkovic S, Steinlein O, Bertrand D (1998). "Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy". Br J Pharmacol. 125 (4): 751–60. doi:10.1038/sj.bjp.0702154. PMC   1571006 . PMID   9831911.
  7. 1 2 3 4 Bertrand D, Picard F, Le Hellard S, Weiland S, Favre I, Phillips H, Bertrand S, Berkovic S, Malafosse A, Mulley J (2002). "How mutations in the nAChRs can cause ADNFLE epilepsy". Epilepsia. 43 (Suppl 5): 112–22. doi: 10.1046/j.1528-1157.43.s.5.16.x . PMID   12121305.
  8. 1 2 Rodrigues-Pinguet N, Jia L, Li M, Figl A, Klaassen A, Truong A, Lester H, Cohen B (2003). "Five ADNFLE mutations reduce the Ca2+ dependence of the mammalian alpha4beta2 acetylcholine response". J Physiol. 550 (Pt 1): 11–26. doi:10.1113/jphysiol.2003.036681. PMC   2343021 . PMID   12754307.
  9. ↑ Steinlein O, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic S, Nakken K, Propping P, Bertrand D (1997). "An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy". Hum Mol Genet. 6 (6): 943–7. doi:10.1093/hmg/6.6.943. PMID   9175743.
  10. ↑ Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K, Kaneko S, Mitsudome A (1999). "A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy". Neurology. 53 (8): 1749–53. doi:10.1212/wnl.53.8.1749. PMID   10563623. S2CID   27745257.
  11. ↑ Leniger T, Kananura C, Hufnagel A, Bertrand S, Bertrand D, Steinlein O (2003). "A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy". Epilepsia. 44 (7): 981–5. doi: 10.1046/j.1528-1157.2003.61102.x . PMID   12823585.
  12. ↑ Phillips H, Scheffer I, Crossland K, Bhatia K, Fish D, Marsden C, Howell S, Stephenson J, Tolmie J, Plazzi G, Eeg-Olofsson O, Singh R, Lopes-Cendes I, Andermann E, Andermann F, Berkovic S, Mulley J (1998). "Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24". Am J Hum Genet. 63 (4): 1108–16. doi:10.1086/302047. PMC   1377480 . PMID   9758605.
  13. ↑ De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, Ballabio A, Wanke E, Casari G (2000). "The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy". Nat Genet. 26 (3): 275–6. doi:10.1038/81566. PMID   11062464. S2CID   21818633.
  14. ↑ Phillips H, Favre I, Kirkpatrick M, Zuberi S, Goudie D, Heron S, Scheffer I, Sutherland G, Berkovic S, Bertrand D, Mulley J (2001). "CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy". Am J Hum Genet. 68 (1): 225–31. doi:10.1086/316946. PMC   1234917 . PMID   11104662.
  15. ↑ Bertrand D, Elmslie F, Hughes E, Trounce J, Sander T, Bertrand S, Steinlein O (2005). "The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits". Neurobiol Dis. 20 (3): 799–804. doi:10.1016/j.nbd.2005.05.013. PMID   15964197. S2CID   29811931.
  16. ↑ Aridon P, Marini C, Di Resta C, Brilli E, De Fusco M, Politi F, Parrini E, Manfredi I, Pisano T, Pruna D, Curia G, Cianchetti C, Pasqualetti M, Becchetti A, Guerrini R, Casari G (2006). "Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear". Am J Hum Genet. 79 (2): 342–50. doi:10.1086/506459. PMC   1559502 . PMID   16826524.

Further reading

Related Research Articles

<span class="mw-page-title-main">Acetylcholine receptor</span> Integral membrane protein

An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

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.

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.

Juvenile myoclonic epilepsy (JME), also known as Janz syndrome or impulsive petit mal, is a form of hereditary, idiopathic generalized epilepsy, representing 5–10% of all epilepsy cases. Typically it first presents between the ages of 12 and 18 with myoclonic seizures. These events typically occur after awakening from sleep, during the evening or when sleep-deprived. JME is also characterized by generalized tonic–clonic seizures, and a minority of patients have absence seizures. It was first described by Théodore Herpin in 1857. Understanding of the genetics of JME has been rapidly evolving since the 1990s, and over 20 chromosomal loci and multiple genes have been identified. Given the genetic and clinical heterogeneity of JME some authors have suggested that it should be thought of as a spectrum disorder.

<span class="mw-page-title-main">Ring chromosome 20 syndrome</span> Medical condition

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.

<span class="mw-page-title-main">Gamma-aminobutyric acid receptor subunit gamma-2</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid receptor subunit gamma-2 is a protein that in humans is encoded by the GABRG2 gene.

<span class="mw-page-title-main">CHRNA7</span> Protein-coding gene in the species Homo sapiens

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).

SCN1A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

<span class="mw-page-title-main">CHRNA4</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CHRNB2</span> Protein-coding gene in the species Homo sapiens

Neuronal acetylcholine receptor subunit beta-2 is a protein that in humans is encoded by the CHRNB2 gene.

<span class="mw-page-title-main">CHRNA3</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CHRNE</span> Protein-coding gene

Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.

<span class="mw-page-title-main">CHRNA1</span> Protein-coding gene in the species Homo sapiens

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).

<span class="mw-page-title-main">CHRNB4</span> Protein-coding gene in the species Homo sapiens

Neuronal acetylcholine receptor subunit beta-4 is a protein that in humans is encoded by the CHRNB4 gene.

<span class="mw-page-title-main">LGI1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CHRNA2</span> Protein-coding gene in the species Homo sapiens

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).

<span class="mw-page-title-main">CHRND</span> Protein-coding gene in the species Homo sapiens

Acetylcholine receptor subunit delta is a protein that in humans is encoded by the CHRND 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.

People with epilepsy may be classified into different syndromes based on specific clinical features. These features include the age at which seizures begin, the seizure types, and EEG findings, among others. Identifying an epilepsy syndrome is useful as it helps determine the underlying causes as well as deciding what anti-seizure medication should be tried. Epilepsy syndromes are more commonly diagnosed in infants and children. Some examples of epilepsy syndromes include benign rolandic epilepsy, childhood absence epilepsy and juvenile myoclonic epilepsy. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance Lennox-Gastaut syndrome and West syndrome.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.