Autosomal dominant nocturnal frontal lobe epilepsy
| Autosomal dominant nocturnal frontal lobe epilepsy | |
| OMIM | 600513 603204 605375 610353 |
|---|---|
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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 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 encode various nicotinic acetylcholine receptor α and β subunits CHRNA4, CHRNB2, and CHRNA2.
Pathophysiology
CHRNA4
The first mutation associated with ADNFLE is a serine to phenylalanine transition at position 248 (S248F) according to the jellyfish torpedo protein numbering, located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor α subunit.[1] 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.[2] Interestingly, these mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine.[3][4][5] Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to calcium.[6]
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.[7] Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.[4][5]
Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE.[8] This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.[5][9]
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.[10]
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. [11]
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.[12] The V287M mutant displays a higher affinity for acetylcholine when compared to wild-type receptors.[5][13] As with the mutations in CHRNA4, these mutants lead to receptors less sensitive to calcium.[6]
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.[14]
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.[15]
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 twofold. 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.
History 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.
Diagnosis
Diagnosis is typically made upon patient history, although EEG recordings can be confirmatory if they occur during attacks.
Medical Therapy
Anti-epileptic drugs are normally used to combat ADNFLE. These drugs are discussed in the main epilepsy article.
References
- ↑ 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. PMID 7550350.
- ↑ 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. PMID 8946959.
- ↑ 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. PMID 9364050.
- ↑ 4.0 4.1 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. PMID 9831911.
- ↑ 5.0 5.1 5.2 5.3 Bertrand D, Picard F, Le Hellard S, Weiland S, Favre I, Phillips H, Bertrand S, Berkovic S, Malafosse A, Mulley J. "How mutations in the nAChRs can cause ADNFLE epilepsy". Epilepsia. 43 Suppl 5: 112–22. PMID 12121305.
- ↑ 6.0 6.1 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. PMID 12754307.
- ↑ 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. PMID 9175743.
- ↑ 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. PMID 10563623.
- ↑ 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. PMID 11904236.
- ↑ 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. PMID 12823585.
- ↑ 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. PMID 9758605.
- ↑ 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. PMID 11062464.
- ↑ 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. PMID 11104662.
- ↑ 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. PMID 15964197.
- ↑ 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. PMID 16826524.