Clinical Guidance

Pathogenic variants in KCNQ3 reported in typical familial forms of self-limited epilepsies (SLFNE and SLFIE) are commonly missense alterations located within the pore region (S5, S6, and intervening loop) and resulting in loss of function (LOF) of channel activity. Similar but more dramatic functional LOF effects have also been found in KCNQ3 channels carrying autosomal dominantly transmitted pathogenic variants responsible for more severe phenotypes, leading to the hypothesis that the degree of KCNQ3 functional impairment may contribute to clinical disease severity . Given the low number of pathogenic KCNQ3 variants described to date, definitive genotype-phenotype correlations are not very clear.

Source: GeneReviews — "KCNQ3-Related Disorders"

Penetrance

In KCNQ3-SLFNE, penetrance is reduced (0.8-0.85): SLFNE is found in 72/80 (90%) of individuals with a KCNQ3 pathogenic variant [, , , , , , , , , , , , , , , , , ]. Reduced penetrance in KCNQ3-SLFNE and KCNQ3-SLFIE may be due to failure to recognize the seizures (which can be brief and disappear spontaneously very soon after onset) in some individuals. Penetrance in KCNQ3-NDD is little studied given the small number of reported individuals, but pathogenic variants with a proven functional effect are fully penetrant.

Source: GeneReviews — "KCNQ3-Related Disorders"

Diagnostic Criteria

KCNQ3-related disorders include self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE), which are epilepsy syndromes associated with a structurally normal brain and mostly normal neurologic findings and psychomotor development. Pathogenic variants in KCNQ3 have also been described in individuals with neurodevelopmental features including developmental delay or intellectual disability with or without seizures.

Suggestive Findings

KCNQ3-related disorders should be suspected in individuals with the following clinical and laboratory findings (by phenotype), imaging findings, and family history.

KCNQ3-related self-limited familial neonatal epilepsy (KCNQ3-SLFNE)

• Clinical findings

Source: GeneReviews — "KCNQ3-Related Disorders"

Differential Diagnosis

The genetic differential diagnosis of KCNQ3-related epilepsy includes the differential diagnoses for:

• Self-limited familial neonatal epilepsy (SLFNE);

• Self-limited familial infantile epilepsy (SLFIE); and

• Self-limited familial neonatal-infantile epilepsy (SLFNIE).

Source: GeneReviews — "KCNQ3-Related Disorders"

Management Guidelines

No clinical practice guidelines for KCNQ3-related disorders have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a KCNQ3-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. KCNQ3-Related Disorders: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "KCNQ3-Related Disorders"

Clinical Guidance

In individuals with known gain-of-function pathogenic variants in KCNQ3, the use of the potassium channel opener retigabine/ezogabine may be contraindicated.

Source: GeneReviews — "KCNQ3-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "KCNQ3-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 6.

KCNQ3-Related Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| Monitor w/EEG | KCNQ3-SLFNE:

• EEG at onset age 3, 12, 24 mos is recommended.

• EEG at 24 mos should be normal.

KCNQ3-SLFIE:

• EEG at onset age 12, 24, 36 mos is recommended.

• The EEG at 36 mos should be normal.

KCNQ3-NDD: sleep EEG at diagnosis is recommended to evaluate presence of sleep-activated epileptic activity.

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

Neurobehavioral/

Psychiatric

| Assessment for anxiety, ADHD, ASD, aggression, self-injury

Family/Community

| Assess family need for social work support care coordination.

Source: GeneReviews — "KCNQ3-Related Disorders"