# Benign familial neonatal seizures

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.

## Signs and symptoms

BFNS often presents in the first week of life with brief but frequent episodes of tonic-clonic seizures, outside of which a child is completely asymptomatic. During the tonic phase of these seizures, infants may stop breathing (apnea) and consequently appear blue (cyanosis) due to lack of oxygen. Accompanying this is focal or generalized muscle stiffening. The clonic phase usually follows, during which the infant may make noises, display focal or multi-focal rhythmic jerking of the body, and/or display abnormal eye and facial movement. Characteristically, testing for seizures between episodes with EEG is normal. However, the appearance of a “theta pointu alternant pattern” and/or non-specific abnormalities on EEG has been reported in several cases, although their relationship to BFNE has not been well delineated. These seizure episodes resolve entirely within days to weeks, and in most patients have no effects on neurodevelopment. With that said, several studies tracking the health of patients with BFNE into adulthood have reported consequent intellectual disability and seizure disorders.

## Pathophysiology
### BFNC1

The most prevalent known cause of BFNE is mutation of KCNQ2, a gene encoding a voltage-gated potassium channel (K$_V$7.2). There are at least 35 such mutations, see Table 1, primarily located in the voltage sensitive S4 segment through the C-terminus. Of these mutations, 5 are nonsense mutations, 13 are missense mutations and 11 cause a frameshift in the coding sequence. There are also 5 splice variants, one of which has been characterized at the protein level and leads to a nonsense mutation. Finally, there is one large deletion that removes much of the carboxy-terminus of the channel.
While most BFNC1 mutations have not been further characterized, 14 have and all seem to lead to functional defects. Two of the mutations in the voltage-sensitive S4 segment, R207W and R214W, do not lead to a decrease in the whole-cell current (M current) produced by KCNQ2 channels but to a change in channel kinetics. The R207W mutation takes fourfold longer and the R214W mutation takes twofold longer to reach maximal current compared to wild-type channels. Since the time-course of an action potential is shorter than the time required for mutant KCNQ2 channels to reach proper levels of inactivation these mutants are expected to lead to neuronal hyperexcitability.
Though many of the other characterized mutations lead to decreased whole-cell current that has not been further delineated, three mutations have. Y534fsX538, for example, leads to a truncation that removes much of the carboxy-terminus of the channel. This mutant has been studied and shown to not traffic properly to the membrane. Two other mutations, P709fs929X and W867fsX931, lead to altered carboxy-termini, though they actually lengthen rather than truncate the protein. These abnormal extended proteins have been shown to be more rapidly degraded within cells and, thus, produce little current.
Table 1. Mutations in KCNQ2 associated with BFNE :
| Mutation | Mutation | Region | Functional Consequence | References |
| Nucleotide | Amino acid | Region | Functional Consequence | References |
| c.232delC | Q78fsX132 | N-Terminus | | |
| c.314_316delCCT | S105CfsX872 | S1 | | |
| c.387+1G→T | Splicing | S2 | | |
| c.584_593del10insA | S195X | S4 | | |
| c.C587T+c.T590C | A196V+L197P | S4 | | |
| c.C619T | R207W | S4 | Slowed activation | |
| c.G622A | M208V | S4 | Current decreased by ~50% | |
| c.C641T | R214W | S4 | Slowed activation and increased deactivation | $^,$$^,$ |
| c.C674G | H228Q | S4-S5 | | |
| c.T727C | L243F | S5 | | |
| c.C740G | S247W | S5 | No current and dominant negative | |
| c.G807A | W269X | Pore | | |
| c.848_849insGT | K283fsX329 | Pore | | $^,$ |
| c.A851G | Y284C | Pore | Current decreased by ~50% | $^,$$^,$$^,$$^,$ |
| c.G916A | A306T | S6 | Current decreased by ~80% | $^,$$^,$$^,$ |
| c.C967T | Q323X | C-Terminus | Current reduction by ~50% | |
| c.G998A | R333Q | C-Terminus | Current reduction by ~40% | |
| c.T1016G | R339L | C-Terminus | | |
| c.1118+1G→A | Splicing | C-Terminus | | |
| c.Intron 8_3' UTR del | Deletion 382→3' UTR | C-Terminus | | $^,$ |
| c.1217+2T→G | Splicing | C-Terminus | | |
| c.C1342T | R448X | C-Terminus | Current reduction by ~40% | $^,$ |
| c.1369_1370delAA | K457EfsX458 | C-Terminus | | |
| c.1564_1576del | S522fsX524 | C-Terminus | | $^,$ |
| c.1600_1601insGCCCT | Y534fsX538 | C-Terminus | No current due to no trafficking | $^,$$^,$ |
| c.1630-1G→A | Splicing | C-Terminus | | $^,$ |
| c.G1658A | R553Q | C-Terminus | | |
| c.G1662T* | K554N | C-Terminus | Decreased voltage sensitivity of activation | |
| c.C1741T | R581X | C-Terminus | | |
| c.1764-6C→A | Splicing (V589X) | C-Terminus | | |
| c.1931delG | S644TfsX901(extX56) | C-Terminus | | |
| c.1959del? | T653fsX929(extX56) | C-Terminus | | |
| c.2127delT | P709fs929X(extX57) | C-Terminus | No current due to increased degradation | $^,$$^,$ |
| c.2597delG | G866AfsX929(extX56) | C-Terminus | Current decreased by ~95% due to increased degradation | $^,$$^,$ |
| c.2599_2600insGGGCC | W867fsX931(extX58) | C-Terminus | Current reduction by ~75% | |
| * Misreported (twice in the same article) as G1662A (G1620A in the original numbering), which would not cause an amino acid change. |||||
| N.B. Mutations nucleotide/amino acid positions in terms of transcript variant 1 (NM_172107) available from PubMed. Consequently, some mutation positions differ from those reported in the original literature. |||||

### BFNC2

Shortly after the discovery of mutations in KCNQ2 related to BFNE, a novel voltage-gated potassium channel was found that is highly homologous to KCNQ2 and contains mutations also associated with BFNE. This gene, KCNQ3, contains 3 known mutations associated with BFNE, all within the pore region of the channel. The first of these mutations, G310V, leads to a 50% reduction in whole-cell current compared to cells expressing wild-type channels. The reason for this change is unknown as the mutation does not lead to altered protein trafficking.
A second mutation, W309G, has also been found to be associated with BFNE. This mutation was only found in one family and has not been further characterized.
The final known BFNC2 mutation, D305G is also in the pore region of the channel. This mutation leads to an approximately 40% reduction in whole-cell current compared to wild-type expressing cells. The underlying mechanism for this current decrease has not been further delineated.

### BFNC3

The rarest cause of BFNE, occurring in only one known family, is a chromosomal inversion. This occurs on chromosome 5 and the inversion is of the p15 through q11 area. Affected individuals, thus, have the karyotype 46,XY,inv(5)(p15q11). Why this inversion leads to the BFNE phenotype is unknown.

## Management

Generally speaking, Neonatal seizures are often controlled with phenobarbital administration. While phenobarbital can be used for symptomatic treatment of BFNC, several studies have shown favorable response to anti-seizure medications that specifically block sodium channels (see article on Sodium channel blocker). However, at this time, phenobarital is the first line therapy for BFNC. Recurrent seizures later in life are treated in the standard ways (covered in the main epilepsy article). Depending on the severity, some infants are sent home with heart and oxygen monitors that are hooked to the child with stick on electrodes to signal any seizure activity. Once a month the monitor readings are downloaded into a central location for the doctor to be able to read at a future date. This monitor is only kept as a safeguard as usually the medication wards off any seizures. Once the child is weaned off the phenobarbital, the monitor is no longer necessary.

## History

BFNE was first described in 1964 by Andreas Rett and named by Bjerre and Corelius four years later. Andreas Rett is better known for his later characterization of Rett syndrome. Both studies were published in German, but have yet to be translated in English. The mutations associated with BFNE were first mapped and descripted by Leppert and colleagues in 1989.