Clinical Guidance

Pathogenic changes associated with KCNQ2-SLFNE are truncating variants (splice, nonsense, and frameshift), whole-gene deletions, or heterozygous missense variants resulting in haploinsufficiency with a 20%-30% reduction of the M-current density when mutated subunits are expressed together with wild type subunits in heterologous cell systems . Pathogenic changes identified in KCNQ2-NEO-DEE are all de novo heterozygous missense variants or in-frame indels shown to exert more severe functional defects on potassium current function. Most cause a dominant-negative reduction of more than 50% of the M-current function .

Source: GeneReviews — "KCNQ2-Related Disorders"

Penetrance

Penetrance is incomplete in KCNQ2-SLFNE, with about 77%-85% of individuals heterozygous for a pathogenic variant in KCNQ2 showing neonatal or early-infantile seizures . Penetrance is complete for germline variants leading to KCNQ2-related NEO-DEE or to rarer phenotypes such as neonatal encephalopathy with non-epileptic myoclonus, non-neonatal-onset DEE, or isolated ID. No age- or sex-related differences have been reported.

Source: GeneReviews — "KCNQ2-Related Disorders"

Diagnostic Criteria

KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from self-limited familial neonatal epilepsy (SLFNE) at the mild end to neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) at the severe end. Individuals with pathogenic variants in KCNQ2 with other phenotypes including neonatal encephalopathy with non-epileptic myoclonus, epilepsy developing in infancy or childhood, and isolated intellectual disability (ID) without epilepsy have also been described.

Suggestive Findings

A KCNQ2-related disorder should be considered in individuals with the following presentations.

Self-limited familial neonatal epilepsy (SLFNE)

Source: GeneReviews — "KCNQ2-Related Disorders"

Differential Diagnosis

Genetic disorders in the differential diagnosis of KCNQ2-related epilepsy. No specific EEG trait characterizes a KCNQ2-related disorder. The genetic differential diagnosis of KCNQ2-related epilepsy includes the differential diagnoses for: • Self-limited familial neonatal epilepsy (SLFNE); • Self-limited familial infantile epilepsy (SLFIE); • Self-limited familial neonatal-infantile epilepsy (SLFNIE); and • Developmental and epileptic encephalopathy (DEE). Table 2. Selected Genes To Consider in the Differential Diagnosis of KCNQ2-Related Epilepsy

Management Guidelines

No clinical practice guidelines for KCNQ2-related disorders have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a KCNQ2-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with a KCNQ2-Related Disorder

Source: GeneReviews — "KCNQ2-Related Disorders"

Clinical Guidance

In individuals with known gain-of-function pathogenic variants in KCNQ2, the use of the potassium channel opener retigabine/ezogabine may be contraindicated.

Source: GeneReviews — "KCNQ2-Related Disorders"

Therapies Under Investigation

Ezogabine (US approved name; also known as retigabine [trade name Trobalt in Europe or Potiga in US]) is a KCNQ activator that was approved in 2011 for clinical use as an adjunctive treatment of focal-onset seizures in individuals who respond inadequately to alternative treatments. Commercialization of retigabine was discontinued after June 2017, mainly due to its tendency to cause retinal and muco-cutaneous blue-gray discoloration after prolonged (5 years) treatment.

Source: GeneReviews — "KCNQ2-Related Disorders"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with a KCNQ2-Related Disorder

System/Concern | Evaluation | Frequency

Neurologic

| Monitor w/EEG. | KCNQ2-SLFNE:

• At age 3, 12, 24 mos

• EEG at 24 mos should be normal.

KCNQ2-NEO-DEE less common phenotypes: as clinically indicated

Assess for new manifestations such as changes in seizure types, changes in tone, movement disorders. | At each visit

Video EEG monitoring | When new or different seizure types are suspected

Development

| Monitor developmental progress, communication skills, educational needs. | At each visit

Psychiatric/

Behavioral

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

Gastrointestinal

| Monitor for reflux constipation.

Family/

Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) care coordination.

NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; OT = occupational therapy; PT = physical therapy; SLFNE = self-limited familial neonatal epilepsy

Source: GeneReviews — "KCNQ2-Related Disorders"