Kcnq2-Related Disorders

Clinical characteristics.

KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end.

• KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life.
• KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present.

Diagnosis/testing.

The diagnosis relies on the presence of characteristic clinical findings and heterozygous pathogenic variants in KCNQ2 (also known as Kv7.2), which codes for voltage-gated potassium channel subunits.

Management.

Treatment of manifestations:

• KCNQ2-BFNE. The majority of children can be kept seizure-free by using phenobarbital (20 mg/kg as loading dose and 5 mg/kg/day as maintenance dose). In some affected individuals, seizures require other antiepileptic drugs (AEDs).
• KCNQ2-NEE. Children have multiple daily seizures resistant at onset to phenobarbital and other common old- and new-generation AEDs, alone or in combination. Sodium channel blockers like phenytoin (PHT) or carbamazepine (CBZ) were shown to control seizures in several patients and should be considered first-line treatment.

Surveillance:

• KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. At 24 months EEG should be normal.
• KCNQ2-NEE. EEG monitoring is highly recommended, although specific guidelines are not available.

Genetic counseling.

KCNQ2-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with KCNQ2-BFNE have an affected parent; however, a proband may have KCNQ2-BFNE as the result of a de novo pathogenic variant. Almost all individuals with KCNQ2-NEE have a de novo pathogenic variant. Each child of an individual with a KCNQ2-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Testing

In KCNQ2-BFNE, all laboratory tests are normal, including brain CT and MRI.

In KCNQ2-NEE, brain MRI frequently shows bilateral or asymmetric hyperintensities in the basal ganglia, and sometimes in the thalamus; these may resolve over time. Other common findings are small frontal lobes with increased adjacent extra-axial spaces, thin corpus callosum, and decreased posterior white matter volume.

Establishing the Diagnosis

The diagnosis of a KCNQ2-related disorder is established in a proband with a characteristic history and examination when a heterozygous pathogenic variant is identified in KCNQ2 by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of KCNQ2 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes KCNQ2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes KCNQ2) fails to confirm a diagnosis in an individual with features of a KCNQ2-related disorder. Such testing may provide an unexpected or previously unconsidered diagnosis, such as mutation in another gene that causes a similar clinical presentation.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Suggestive Findings

KCNQ2-related disorders should be suspected in individuals with the following two presentations.

KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) [Berg et al 2010] is characterized by the following general features:

• Seizures starting between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life in an otherwise healthy infant
• Normal physical examination and laboratory tests prior to, between, and after seizures
• No specific EEG criteria

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

• A wide spectrum of seizure types is seen, encompassing tonic (often focal) or apneic episodes, focal clonic activity, or autonomic changes.
• Ictal motor activity may be confined to one limb, migrate to other body regions, or generalize.
• Seizures are generally brief, lasting one to two minutes. However, they may be very frequent and cause considerable concern, especially if the proband is the first family member being affected.
• Infants are well between seizures, feed normally, and show normal social and motor developmental progression.
• Rarely, seizures occur in a crescendo of activity, with a possible evolution into status epilepticus.
• Interictal EEG may be normal, rarely showing a pattern of "theta pointu alternant."
• Ictal EEG shows focal discharges with possible secondary generalization.

KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) is characterized by the following:

• Seizure onset occurs in the first week of life.
• Seizures are mostly tonic, with associated focal motor and autonomic features (similar to KCNQ2-BFNE).
• Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life.
• Cessation of seizures generally occurs between age nine months and four years.
• Encephalopathy is present from birth and persists during and after the period when seizures are uncontrolled. Subsequently, developmental impairment is moderate in about one third of individuals, and severe to profound in the remaining two thirds.
• EEGs in the first week of life show a burst suppression pattern or multifocal epileptiform activity.
• Over time, seizure frequency diminishes, and interictal epileptiform discharges become less frequent. EEGs after seizure freedom is achieved are normal or show mild slow background activity.

Contiguous Gene Rearrangements

In two individuals with BFNE in whom exon deletions in KCNQ2 were identified, concomitant deletions of the adjacent gene CHRNA4, encoding the cholinergic receptor, nicotinic alpha 4 subunit, have been described [Kurahashi et al 2009]. The clinical course in these individuals was that of typical BFNE, and neither had the phenotype of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), another focal epilepsy caused by pathogenic missense (but not deletion) variants in CHRNA4.

Individuals with chromosomal microdeletions at 20q13.33 were shown to have epileptic seizures mostly beginning within the neonatal period and disappearing by age four months, similar to epilepsy phenotypes of BFNE; developmental outcome was good in patients with deletion restricted to CHRNA4, KCNQ2, and COL20A1, whereas delay in developmental milestones and behavioral problems such as autistic spectrum disorder was observed in patients with a wider range of deletion [Traylor et al 2010, Pascual et al 2013, Okumura et al 2015].

Clinical Description

KCNQ2-related disorders include a continuum of overlapping neonatal-onset epileptic phenotypes ranging from benign familial neonatal epilepsy at the mild end to epileptic encephalopathy at the severe end.

Genotype-Phenotype Correlations

Given the rarity of KCNQ2-related disorders and the inter- and intrafamilial phenotypic variability, genotype-phenotype correlations are difficult to establish. Nonetheless, attempts are under way to correlate the KCNQ2 variant type with the clinical course and severity of the disease.

In general, haploinsufficiency caused by the loss of function of a single KCNQ2 allele (nonsense, splice, or frameshift variant) is the most common cause of familial KCNQ2-BFNE. Pathogenic variants so far identified in KCNQ2-NEE are all de novo missense variants, and are thought to exert more severe functional defects on potassium current function [Miceli et al 2013, Orhan et al 2014].

Individuals harboring identical recurring pathogenic variants so far appear to have broadly similar seizure and developmental outcomes, although some cases in which clinical heterogeneity appears to be associated with the same variant are also present in the literature. For example, the p.Arg213Trp KCNQ2 pathogenic variant has been reported in a severely affected individual and in a family with BFNS [Sadewa et al 2008, Milh et al 2015]. Moreover, although neurodevelopmental outcome was overall poor among individuals with KCNQ2-NEE caused by the recurrent p.Ala294Val variant, and all infants had burst-suppression on EEG, one child appeared less impaired (i.e., sat up and spoke 3 words at age 2 years). Genetic background and environmental factors such as treatment and seizure duration may further influence the phenotypic expression of the variants.

A few children with KCNQ2-NEE were born from mosaic parents (the pathogenic allele detected in blood, skin, and hair root samples ranging from 5% to 30% of cells). The neurologic development of the mosaic parents was normal, although several had neonatal seizures [Weckhuysen et al 2012, Milh et al 2015]; these findings suggest that in order to cause a persistent neurologic disease, KCNQ2 pathogenic variants with a more severe functional effect must be present in a sufficient proportion of cells.

Penetrance

For KCNQ2-BFNE, penetrance is incomplete, with about 77%-85% of individuals heterozygous for a pathogenic variant in KCNQ2 showing neonatal or early-infantile seizures [Plouin & Neubauer 2012, Grinton et al 2015].

Penetrance is complete for germline variants leading to KCNQ2-NEE.

No age- or sex-related differences have been reported.

Nomenclature

The familial occurrence of neonatal seizures was first reported by Rett & Teubel [1964], 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 & 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.

Subsequently it was noted that in rare instances, KCNQ2 pathogenic variants can be observed in children who develop a therapy-resistant epileptic encephalopathy shortly after birth and a variable degree of intellectual disability by age four to five years [Alfonso et al 1997, Dedek et al 2003, Borgatti et al 2004, Schmitt et al 2005]. Thus, the favorable outcome of this disorder implied by the name "benign" was questioned [Steinlein et al 2007]. More recent reports of certain KCNQ2 pathogenic variants leading to a neonatal epileptic encephalopathy with early-onset refractory seizures and intellectual disability of unknown origin have led to proposal of the name "KCNQ2 encephalopathy" [Weckhuysen et al 2012].

Because of the variable clinical phenotypes associated to pathogenic variants in KCNQ2, the authors refer to a spectrum of KCNQ2-related diseases ranging from self-limiting KCNQ2-BFNE to severe KCNQ2-NEE.

Prevalence

KCNQ2-related disorders comprise a large spectrum of phenotypes. Both KCNQ2-related classic BFNE and the recently described KCNQ2-NEE are rare. To date, about 100 families with KCNQ2-BFNE and about 100 individuals with KCNQ2-NEE from many different nationalities have been described in the literature. It is likely that many cases of KCNQ2-BFNE go untested and/or are not reported owing to the brief duration of symptoms and good outcome. KCNQ2-NEE is a very recently described syndrome. Therefore, at present, it is difficult to determine overall prevalence or ethnicity-dependent variability.

Other Causes of Benign Familial Neonatal Epilepsy (BFNE)

KCNQ3, a close homolog of KCNQ2, encodes a voltage-gated potassium channel subunit that co-assembles with the KCNQ2 protein product [Wang et al 1998, Cooper et al 2000]. KCNQ3 is a minor locus for BFNE [Charlier et al 1998]. The clinical characteristics of BFNE caused by pathogenic variants in KCNQ2 or in KCNQ3 appear indistinguishable; thus, molecular genetic testing of both genes is commonly performed when BFNE is suspected. See KCNQ3-Related Disorders.

Other genetic loci. The existence of other loci associated with BFNE cannot be excluded. Concolino et al [2002] reported a family in whom a pericentric inversion of chromosome 5 segregates with BFNE; no linkage to KCNQ2 or KCNQ3 was found in this family. Among 36 families with familial neonatal-onset seizures, three did not have pathogenic variants identified in KCNQ2 or KCNQ3, as well as in other genes associated with early-onset epilepsies (SCN2A or PRRT2); in these families, no linkage was found to any other chromosomal region [Grinton et al 2015].

Other Causes of Neonatal Epilepsy

The diagnosis of BFNE is based on the absence of any other explanation for the seizures. The reason for ordering laboratory tests is, therefore, to exclude other possible causes of the seizures.

Late hypocalcemia, vitamin B₆ deficiency, hyperthyroidism, and benign sleep myoclonus should be excluded. It is also important not to miss a diagnosis of a treatable meningoencephalitis in the early stage or an intracranial hemorrhage. Both of these conditions in neonates lack the typical findings observed in older infants and children, and seizures may be the only early symptom.

The following laboratory, imaging, and instrumental studies may be helpful for the differential diagnosis:

• Chemistries
  • Basic metabolic panel plus serum concentration of calcium, magnesium, phosphorus
  • Evaluation of alpha-AASA levels in serum and urine as a biomarker of pyridoxine (vitamin B₆)-dependent seizures, a rare genetic disorder of vitamin B₆ metabolism caused by pathogenic variants in ALDH7A1 and characterized by neonatal-onset seizures that are resistant to common anticonvulsants, but controlled by daily treatment with vitamin B₆
    In this context it should be noted that in a recent study, a de novo KCNQ2 pathogenic variant (c.629G>A; p.Arg210His) was identified in a patient age seven years whose neonatal seizures showed a response to pyridoxine and who had a high plasma-to-CSF pyridoxal 5'-phosphate ratio but no further proof of an inborn error of vitamin B₆ metabolism [Reid et al 2016].
  • Thyroid function tests, as neonatal hyperthyroid state and thyrotoxicosis may be associated with excessive tremor and jitteriness, clinical conditions that should be differentiated from seizures
• Basic hematologic labs. CBC, prothrombin time, activated partial thromboplastin time
• Lumbar puncture. Cerebrospinal fluid examination to exclude neonatal meningoencephalitis or occult blood
• MRI and/or CT scan of the brain. Indicated for any individual with neonatal seizures to exclude structural lesions and intracranial hemorrhage
• Electroencephalography. No specific EEG trait characterizes BFNE during neonatal seizures; the interictal EEG is most commonly normal (50%-70% of infants).