Epilepsy, Nocturnal Frontal Lobe, 4

A number sign (#) is used with this entry because nocturnal frontal lobe epilepsy-4 (ENFL4) is caused by heterozygous mutation in the gene encoding the neuronal nicotinic cholinergic receptor alpha-2 subunit (CHRNA2; 118502) on chromosome 8p21.

Description

Nocturnal frontal lobe epilepsy is a childhood-onset focal epilepsy that displays clusters of sleep-related hypermotor seizures (summary by Aridon et al., 2006). Some patients with CHRNA2 mutations may have a slightly different phenotype that is more consistent with a clinical diagnosis of benign familial infantile seizures (BFIS6) (Trivisano et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of nocturnal frontal lobe epilepsy, see ENFL1 (600513).

For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (601764).

Clinical Features

Aridon et al. (2006) reported a Sardinian family in which 10 members had a sleep-related epilepsy inherited in an autosomal dominant pattern. Mean age at onset was 10 years (range 4 to 29). The phenotype was characterized by episodes of sudden awakening, vocalization or grunting, fearful expression, fear sensation, tongue movements, and nocturnal wandering, suggesting frontolimbic involvement. Complex motor behaviors and nocturnal wanderings were more frequent in childhood, and both frequency and severity of the episodes tended to decrease with age. EEG of 4 affected family members showed frontal lobe involvement. The attacks had been interpreted in some as nightmares and sleep walking.

Conti et al. (2015) reported a family in which 7 individuals had nocturnal frontal lobe epilepsy. Six of the patients had onset of seizures between 3 and 10 years, whereas 1 patient had onset of seizures at age 16. The features were homogeneous, characterized by paroxysmal arousal during sleep, often accompanied by gestural automatisms or posturing dystonia, vocalizations, and postictal confusion. EEG studies showed sleep-related paroxysmal epileptic arousals, and interictal EEG showed frontal spikes and slow waves. All patients responded to treatment with oxcarbazepine.

Benign Familial Infantile Seizures 6

Trivisano et al. (2015) reported a family in which a father and his 2 daughters had a relatively benign seizure disorder with onset in the first years of life. The 35-year-old father, who had normal neurologic development and function, had onset of febrile and afebrile seizures at 8 months of age. He was treated with medication until age 10 years, at which time treatment was withdrawn with no further seizures. His 2 daughters developed seizure clusters at ages 2 years and 6 months, respectively. The seizures were characterized by psychomotor arrest, hyper- or hypotonia, deviation of the eyes, and cyanosis. The seizures or EEG abnormalities tended to be worse at night. Both daughters were successfully treated with medication and both had normal psychomotor development. A third daughter, who did not carry the mutation, had a phenocopy manifest as benign myoclonus in infancy that remitted spontaneously.

Inheritance

The transmission pattern of ENFL4 in the family reported by Aridon et al. (2006) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In all 10 affected members of a Sardinian family with nocturnal frontal lobe epilepsy, Aridon et al. (2006) identified a heterozygous missense mutation in the CHRNA2 gene (I279N; 118502.0001). One unaffected family member carried the mutation, indicating incomplete penetrance.

In 7 affected members of a large family with ENFL4, Conti et al. (2015) identified a heterozygous missense mutation in the CHRNA2 gene (I297F; 118502.0002). The mutation, which was found by targeted sequencing of 150 probands with a similar disorder, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the heterozygous mutation resulted in a reduction in current density to about 40% of wildtype values. Homozygosity for the mutation resulted in no measurable currents. These findings were consistent with a loss of receptor function.

In affected members of a family with BFIS6, Trivisano et al. (2015) identified a heterozygous missense mutation in the CHRNA2 gene (R376W; 118502.0003). The mutation, which was found by targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.