Epilepsy, Nocturnal Frontal Lobe, 1

A number sign (#) is used with this entry because of evidence that nocturnal frontal lobe epilepsy-1 (ENFL1) is caused by heterozygous mutation in the gene encoding the neuronal nicotinic acetylcholine receptor (nAChR) alpha-4 subunit (CHRNA4; 118504) on chromosome 20q13.

Description

Autosomal dominant nocturnal frontal lobe epilepsy (ENFL, ADNFLE) is a partial epilepsy with frontal lobe seizure semiology. It is characterized by childhood onset of frequent violent and brief motor seizures occurring at night. The disorder may be misdiagnosed as night terrors, nightmares, hysteria, or paroxysmal nocturnal dystonia. The condition usually persists through adult life (Scheffer et al. (1994, 1995)). The disorder is clinically distinctive and relatively homogeneous, although seizure severity and specific frontal lobe seizure manifestations vary within families (Hayman et al., 1997).

Genetic Heterogeneity of Nocturnal Frontal Lobe Epilepsy

Nocturnal frontal lobe epilepsy is a genetically heterogeneous condition. See also ENFL2 (603204), which maps to chromosome 15q24; ENFL3 (605375), caused by mutation in the CHRNB2 gene (118507) on chromosome 1q21; ENFL4 (610353), caused by mutation in the CHRNA2 gene (118502) on chromosome 8p21; and ENFL5 (615005), caused by mutation in the KCNT1 gene (608167) on chromosome 9q34.

Nocturnal frontal lobe seizures are also observed in some patients with familial focal epilepsy with variable foci (FFEVF; 604364), caused by mutation in the DEPDC5 gene (614191) on chromosome 22q12.

Clinical Features

Scheffer et al. (1994) and Scheffer et al. (1995) reported 5 families from Australia, Britain, and Canada in which 47 members were affected with ADNFLE. The largest family contained 25 affected individuals spanning 6 generations. Onset was usually in childhood and the disorder persisted through adult life. The disorder was characterized by clusters of brief nocturnal motor seizures with hyperkinetic or tonic manifestations. Seizures occurred in clusters as patients dozed or shortly before awakening. Auras were often experienced, and patients were awake during the aura and seizures. Milder cases were often undiagnosed or misdiagnosed as nightmares or other sleep disorders, whereas more severely affected family members had frequent nocturnal seizures. All had normal psychomotor development and neurologic examination.

Thomas et al. (1998) described one of the first European families with nocturnal frontal lobe epilepsy, including 5 affected individuals spanning 4 generations. In the most severely affected subject, NFLE had onset during the second month of life and persisted through adult life. Seizures were very frequent during infancy, although long-term evolution was relatively benign. Ictal video-EEG studies showed that attacks occurred in clusters during sleep and were partial seizures that were consistent with a frontal origin. Neuroimaging was normal. Carbamazepine was dramatically effective. Thomas et al. (1998) suggested that underestimation of cases is likely; the disorder in their family was perceived as a 'hereditary curse,' and consequently was concealed, including concealment from medical attention.

Cho et al. (2003) reported a Korean family with ADNFLE in which 9 members from 3 generations were affected. The mean age at seizure onset was 11 years (range, 4 to 14 years). Seizure frequency ranged from 2 to 3 per year to 4 to 5 per night. All seizures arose from sleep, and no auras were reported. Episodes lasted about 20 to 40 seconds, and consisted of arm flexion, tonic head extension, mouth movements, and unintelligible speech. Ictal EEG and PET scans in some patients showed frontal lobe involvement. Unique features included mental retardation and poor response to carbamazepine.

Other Features

Using PET scans, Fedi et al. (2008) observed decreased striatal D1 receptor (DRD1; 126449) binding, particularly in the right putamen, in 12 ADNFLE individuals with the same mutation in the CHRNA4 gene (118504.0002) compared to controls. Decreased D1 receptor binding was postulated to represent receptor downregulation from increased extracellular levels of dopamine. Increased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release.

Inheritance

The transmission pattern of nocturnal frontal lobe epilepsy in the large Australian family reported by Scheffer et al. (1995) was consistent with autosomal dominant inheritance with incomplete penetrance.

Mapping

In a large affected French Canadian family and 2 affected Australian Anglo-Saxon families, Lopes-Cendes et al. (1995) excluded linkage to regions on chromosome 3, 6, and 15 that are homologous to the El1 gene on mouse chromosome 9. The El epileptic mouse is an animal model for partial epilepsy.

In a large ENFL Australian kindred with 27 affected individuals spanning 6 generations (Scheffer et al. (1994, 1995)), Phillips et al. (1995) mapped the disease locus to chromosome 20q13.2. The authors found maximum lod scores with no recombination with the same marker (D20S19) as in benign familial neonatal convulsions type 1 (121200) and a normal low-voltage variant of the EEG (130180).

Genetic Heterogeneity

Genetic heterogeneity has been demonstrated by Phillips et al. (1998) in a family in which linkage to 20q13.2 was excluded and linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster, was established. In yet other families, both 15q24 and 20q13.2 could be excluded.

Molecular Genetics

In affected members of a large Australian kindred with ADNFLE reported by Scheffer et al. (1995) and Phillips et al. (1995), Steinlein et al. (1995) identified a mutation in the CHRNA4 gene (118504.0002).

In a Japanese family with ADNFLE, Hirose et al. (1999) identified a ser252-to-leu mutation in the CHRNA4 gene (S252L; 118504.0004). Cho et al. (2003) identified the S252L mutation in a Korean family with ADNFLE. They noted that the clinical phenotype in the Korean family was similar to that reported in the Japanese family; shared features included mental retardation and drug resistance.

Associations Pending Confirmation

For discussion of a possible association between autosomal dominant nocturnal frontal lobe epilepsy and variation in the CRH gene, see 122560.0001.