Clinical Diagnosis

Individuals with benign familial neonatal seizures (BFNS) show the following general features:

• Seizures starting around postnatal day three and spontaneously disappearing within the first month of life in otherwise healthy infants

• Seizure-free interval between birth and the onset of seizures

• Normal physical examination and laboratory tests prior to, between, and after seizures

• No specific EEG criteria

Seizure features include [International League Against Epilepsy 1989, Ronen et al 1993, Engel 2001]:

• Generalized or focal

• Usually partial clonic; may be confined to one body part or migrate from one region to another

• Generally brief, lasting one to two minutes

• Often occur in a crescendo of activity until the child goes into status epilepticus

• Mean duration of status epilepticus approximately 20 hours (range 2 hours – 3 days)

• In some affected individuals, brief seizures not followed by the typical tonic and/or tonic-clonic cluster

• Apnea with the clonic activity or as the sole manifestation of the seizure

• Normal or abnormal interictal EEG; when abnormal, findings are frequently transient

• Rarely, tonic seizures

Testing

In general, all laboratory tests are normal, including brain CT and MRI.

Molecular Genetic Testing

Genes. The following genes are known to be associated with BFNS:

• KCNQ2 (also known as Kv7.2, KQT-like subfamily, member 2), encoding for voltage-gated potassium channel subunits, represents the major locus for BFNS [Biervert et al 1998, Singh et al 1998].

• KCNQ3 (also known as Kv7.3, KQT-like subfamily, member 3), encoding for voltage-gated potassium channel subunits, represents the minor locus for BFNS [Charlier et al 1998].

Other loci. The existence of loci additional to KCNQ2 or KCNQ3 cannot be excluded. Concolino et al [2002] reported a family in whom a pericentric inversion of chromosome 5 segregates with benign familial neonatal convulsions (BFNC); no linkage to KCNQ2 or KCNQ3 mutations was found in this family.

Clinical testing

• Sequence analysis. Mutations in KCNQ2 or KCNQ3 are found in 60%-70% of the families evaluated by conventional sequence analysis of the coding region and associated intron boundaries. KCNQ2 mutations include missense, nonsense, splicing, and frameshift mutations from small intragenic insertions and deletions (see Table 2). Missense mutations have been reported in KCNQ3 (see Table 2).

• Deletion/duplication analysis. One large duplication and several large deletions involving KCNQ2, some also involving contiguous genes, have been reported [Singh et al 1998, Heron et al 2007, Kurahashi et al 2009] (see Molecular Genetics). Deletion analysis can be performed by a variety of methods (Table 1, footnote 2) and is an efficient second-tier testing strategy.
  
  Deletions involving KCNQ3 have not been described; it is not known if such deletions would result in the BFNS phenotype.

Table 1. Summary of Molecular Genetic Testing Used in Benign Familial Neonatal Seizures

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Gene Symbol/ Locus Name	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
KCNQ2 / EBN1	Sequence analysis	Sequence variants 2	>60%	Clinical
	Deletion/ duplication analysis 3, 4	Exonic, whole-gene, and contiguous-gene deletions	4/21 (~20%) 5
KCNQ3 / EBN2	Sequence analysis	Sequence variants 2	5% (8 families)	Clinical
	Deletion/ duplication analysis 3, 4	Exonic and whole-gene deletions	Unknown 6

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array genomic hybridization (array GH) (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

4. Extent of deletion detected may vary by method and by laboratory.

5. Submicroscopic deletions or duplications were found in four of 21 (~20%) individuals with BFNS, benign familial neonatal-infantile seizures (BFNIS), or simplex neonatal seizures (i.e., a single occurrence in a family) who had no identifiable KCNQ2 or KCNQ3 mutation by conventional PCR-based techniques.

6. To date, no BFNS-causing deletions or duplications in KCNQ3 have been reported; therefore, the mutation detection rate for this method is unknown.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Clinical evaluation

  • Generalized or focal clonic convulsions starting around day three of life and spontaneously disappearing within the first month of life

  • Normal physical examination and laboratory tests prior to, between, and after the seizures

  • No specific EEG criteria

• Molecular genetic testing

  • The clinical diagnosis of BFNS can be confirmed by identification of a BFNS-causing mutation in KCNQ2 or KCNQ3 by conventional sequence analysis.

  • If no mutation is identified by this method, deletion/duplication testing may be indicated.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

KCNQ2. Myokymia in the absence of neonatal seizures was described in one simplex case (i.e., single occurrence in a family) who had a KCNQ2 mutation [Wuttke et al 2007]. Thus, it seems that KCNQ2 mutations can be responsible for both BFNS with peripheral nerve hyperexcitability and peripheral nerve hyperexcitability alone.

Linkage analysis studies revealed that a condition with later seizure onset (age ~6 months) and termed benign familial infantile seizures (BFIS) is not an allelic form of BFNS [Malafosse et al 1994]. In BFIS, linkage to loci on chromosome 16p12-q12 [Caraballo et al 2001] or 19q12-q13.1 [Guipponi et al 1997] has been found. In addition, one causative mutation in SCNA2 that encodes a brain sodium channel on chromosome 2q24 has been described in BFIS [Striano et al 2006]. However, a KCNQ2 mutation has been detected in a Chinese family with BFIS [Zhou et al 2006].

KCNQ3. No other phenotypes are known to be associated with mutations in KCNQ3.

Natural History

Seizures in neonates with BFNS are generalized or focal tonic-clonic, with typical age of onset around day three of life and spontaneous remission within the first month (remission after the first month is also reported).

The neurologic examination is normal.

The seizures are not associated with specific EEG traits. In BFNS, the interictal EEG is normal in 50%-70% of infants. The theta pointu alternant pattern also is observed but only in approximately 25% of children. In a small percentage of children, focal, often rolandic, discharges or spikes may be present [Plouin 1997]. The EEG should be normal by age 24 months.

About 10%-15% of individuals with BFNS develop epileptic seizures again later in life with a variable age of onset and duration; these are mostly generalized tonic or tonic-clonic seizures. In particular, during early childhood children with BFNS may develop an EEG trait characterized by centrotemporal spikes (CTS) and sharp waves or benign epilepsy with centrotemporal spikes (BECT) [Coppola et al 2003]. Although the age-dependent CTS trait seems to segregate independently from KCNQ2 [Neubauer et al 1997], it seems that the presence of a KCNQ2 mutation may anticipate its appearance [Coppola et al 2003].

Children with BFNS have mostly normal psychomotor development.

Genotype-Phenotype Correlations

No major phenotypic differences are observed between persons with BFNS caused by a KCNQ2 mutation and those with BFNS caused by a KCNQ3 mutation.

Because of the small number of families with BFNS (~80 described to date), each corresponding to a specific variant, genotype-phenotype correlations are speculative [Soldovieri et al 2007].

Penetrance

Penetrance is incomplete (0.8-0.85).

Anticipation

Anticipation has not been observed.

Nomenclature

The familial occurrence of neonatal seizures was first reported by Rett & Teubel [1974], who described an epileptic syndrome in which children in three generations had neonatal seizures that mostly disappeared in girls after six to eight weeks but persisted in boys throughout adolescence. The neonatal seizures were not associated with perinatal complications, such as intracranial bleeding. The term ‘‘benign’’ was added to the designation ‘‘familial neonatal convulsions’’ by Bjerre and Corelius [1968], who described a five-generation family with neonatal convulsions but normal motor and mental development, highlighting the mostly favorable outcome of the syndrome.

Prevalence

BFNS is rare. About 80 pedigrees from many different nationalities have been identified so far; thus, it is difficult to determine prevalence or possible ethnicity-dependent variability.

Evaluations Following Initial Diagnosis

In an individual diagnosed with benign familial neonatal seizures (BFNS), an in-depth neurologic examination is recommended.

Treatment of Manifestations

The majority of individuals with BFNS can be kept seizure free by using phenobarbital (20 mg/kg-1 as loading dose and 5 mg/kg-1/day as maintenance dose).

In some affected individuals, seizures require other antiepileptic drugs (AEDs) such as carbamazepine, phenytoin, valproic acid, clonazepam, midazolam, or vigabatrin. In two individuals with BFNS and seizures resistant to most common AEDs, therapy with ACTH was attempted [Dedek et al 2003, Borgatti et al 2004]

Surveillance

EEG at age three, 12, and 24 months is appropriate. The EEG at 24 months should be normal.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Seizures in BFNS are generally controlled with conventional antiepileptic treatment.

Retigabine is a novel anticonvulsant which selectively enhances the function of potassium channels formed by neuronal Kv7 subunits, and is currently being tested as an adjunctive therapy in individuals with partial-onset seizures [Porter et al 2007].

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Benign familial neonatal seizures (BFNS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with BFNS have an affected parent.

• A proband with BFNS may have the disorder as the result of a new gene mutation; three cases caused by de novo mutations have been described [Ishii et al 2008, Sadewa et al 2008, Miceli et al 2009].

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation. To date one case of germline mosaicism has been reported [Sadewa et al 2008].

• Recommendations for the evaluation of parents of a proband with a BFNS-causing mutation include molecular genetic testing. Detection of the same mutation as found in the proband identifies an affected parent who was previously undiagnosed (by failure of health care professionals to recognize the syndrome and/or because of a milder phenotypic presentation). Therefore, an apparently negative family history cannot be confirmed until appropriate genetic evaluations have been performed.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected and has a disease-causing mutation, the risk to the sibs of inheriting the mutation and being affected is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband may be low, although still significant because of the possibility of reduced penetrance in a parent or of a germline mutation occurring in a parent.

Offspring of a proband. Each child of an individual with BFNS has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed. For laboratories offering custom prenatal testing, see .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions that (like BFNS) have only transient symptoms, usually do not interfere with neurocognitive development, and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The Kv7.2 and Kv7.3 channels, encoded by the KCNQ2 and KCNQ3 genes, respectively, are mainly expressed in the nervous system, where they form heteromultimeric channels that mediate the so-called M-current (I_KM), a slowly activating, non-inactivating potassium conductance that inhibits neuronal excitability. Suppression of I_KM upon activation of G-protein-coupled receptors (including muscarinic receptors, hence the term M-current) increases neuronal excitability.

Studies on the functional consequences of BFNS-causing mutations in heterologous expression systems suggest that, in most cases, a decrease of I_KM carried by Kv7.2/Kv7.3 heteromeric channels of only 25% is sufficient to cause BFNS, arguing in favor of haploinsufficiency as the primary pathogenic mechanism for BFNS. Various molecular mechanisms appear responsible for the mutation-induced current decrease, including a reduced number of functional channels in the plasma membrane, changes in the subcellular targeting of the channels, an altered regulation of their function by associated proteins (e.g.,calmodulin, Ankirin-G), and a reduced sensitivity to changes in membrane potential by correctly assembled channels.

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Acknowledgments

The Authors acknowledge funding agencies for supporting their studies; in particular: Telethon GP07125, E-Rare JTC 2007 (EUROBFNS), and PRIN 2007. Collaborations from patients and their families is also highly appreciated.

Revision History

• 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for KCNQ2 and KCNQ3

• 27 April 2010 (me) Review posted live

• 4 December 2009 (mt) Initial submission