ORPHA: 98784; DO: 0060686;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.3 | Epilepsy nocturnal frontal lobe, 5 | 615005 | Autosomal dominant | 3 | KCNT1 | 608167 |
A number sign (#) is used with this entry because nocturnal frontal lobe epilepsy-5 (ENFL5) is caused by heterozygous mutation in the KCNT1 gene (608167) on chromosome 9q34.
Nocturnal frontal lobe epilepsy-5 (ENFL5) is an autosomal dominant focal epilepsy syndrome characterized by childhood onset of clusters of motor seizures during sleep. Some patients may develop behavioral or psychiatric manifestations and/or intellectual disability. The phenotype is more severe than observed in other genetic forms of ENFL (summary by Heron et al., 2012).
For a general description and a discussion of genetic heterogeneity of ENFL, see ENFL1 (600513).
Derry et al. (2008) reported a family (family B) in which 6 individuals had childhood onset of partial nocturnal seizures associated with psychiatric disorders and cognitive impairment. Age at seizure onset ranged between 1 and 15 years, and all had partial nocturnal seizures. Seizures were typical of frontal lobe epilepsy, with dystonic posturing, prominent vocalization, and hypermotor automatisms. Two also had partial diurnal seizures, and 1 also had rare generalized tonic-clonic seizures. Four patients had refractory seizures and 2 had a history of status epilepticus. Five had a personality/behavioral disorder or depression, and 3 had intellectual disability. One patient, aged 21 years, showed developmental regression; seizure frequency in this patient was between 40 and 60 per night. Derry et al. (2008) excluded linkage to or mutations in several candidate genes, including CHRNA4 (118504), CHRNB2 (118507), and CHRNA2 (118502), all of which encode proteins involved in nicotinic acetylcholine receptors (nAChR).
Heron et al. (2012) reported 4 unrelated families with ENFL5, including the family reported by Derry et al. (2008). Affected individuals had a more severe phenotype compared to patients with other genetic forms of ENFL. Those with ENFL5 had an earlier mean age of onset at 6 years of age (compared to 10 years of age in other forms), as well as a significantly higher frequency of psychiatric or behavioral problems, including psychosis, catatonia, and aggression. In addition, 6 individuals from 2 families had varying degrees of intellectual disability.
The transmission pattern of nocturnal frontal lobe epilepsy-5 in the families reported by Heron et al. (2012) was consistent with autosomal dominant inheritance showing complete penetrance.
By genomewide linkage analysis of the family reported by Derry et al. (2008) (family B), Heron et al. (2012) found linkage to a 2.36-Mb region on chromosome 9q34.3 (maximum parametric lod score of 2.71).
By whole-exome capture and sequencing of patients from the family with ENFL reported by Derry et al. (2008), Heron et al. (2012) identified a heterozygous mutation in the KCNT1 gene (R928C; 608167.0005). The mutation, which was confirmed by Sanger sequencing and not identified in multiple control samples, segregated with the disorder. Subsequent analysis of this gene in 108 additional unrelated cases with a similar disorder identified 3 more pathogenic mutations in 3 families (608167.0006-608167.0008).
Derry, C. P., Heron, S. E., Phillips, F., Howell, S., MacMahon, J., Phillips, H. A., Duncan, J. S., Mulley, J. C., Berkovic, S. F., Scheffer, I. E. Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability. Epilepsia 49: 2125-2129, 2008. [PubMed: 18479385] [Full Text: https://doi.org/10.1111/j.1528-1167.2008.01652.x]
Heron, S. E., Smith, K. R., Bahlo, M., Nobili, L., Kahana, E., Licchetta, L., Oliver, K. L., Mazarib, A., Afawi, Z., Korczyn, A., Plazzi, G., Petrou, S., Berkovic, S. F., Scheffer, I. E., Dibbens, L. M. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet. 44: 1188-1190, 2012. [PubMed: 23086396] [Full Text: https://doi.org/10.1038/ng.2440]