A de novo KCNQ2 Gene Mutation Associated With Non-familial Early Onset Seizures: Case Report and Revision of Literature Data

Abstract

Among neonatal epileptic syndromes, benign familial neonatal seizures (BFNS) are often due to autosomal-dominant mutations of the KCNQ2 gene. Seizures are usually characterized by asymmetric tonic posturing with apnea with onset in the first 7 days of life; they may even occur more than 10 times per day or evolve into status epilepticus. The delivery course of our patient was uneventful and family history was negative; on the second day of life the baby became pale, rigid, and apnoic during breastfeeding and appeared jittery and irritable when stimulated or examined. At age 3 days, she experienced clusters of generalized tonic seizures with pallor, desaturation, bradycardia, and partial response to intravenous phenobarbital; during her 4th and 5th days of life, three episodes of tonic seizures were noticed. At age 6 days, the patient experienced about 10 episodes of tonic seizures involving both sides of the body, which gradually responded to intravenous phenytoin. Electroencephalograms revealed abnormalities but brain MRI was normal. The patient is seizure-free since postnatal day 21; she is now 12 months old with cognitive development within normal limits at Bayley III Scale and mild motor delay. The patient is on maintenance therapy with phenobarbital since she was 7 months old. A de novo heterozygous mutation (c.853C>T/p.P285S) in the KCNQ2 gene was identified. We therefore describe a case of de novo KCNQ2-related neonatal convulsions with necessity of multiple anticonvulsants for the control of seizures, mutation occurring in the pore channel of the voltage-gated potassium channel subfamily Q member 2 associated with a likely benign course; furthermore, the same mutation of the KCNQ2 gene and a similar one (c.854C>A/p.P285H) have already been described in association with Ohtahara syndrome. Probably acquired environmental, perinatal and genetic risk factors are very important in determining the different phenotype; we hope that the rapid progress of analysis tools in molecular diagnosis can also be used in the search of an individualized therapeutic approach for these patients.

Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants

“…While benign/self-limited neonatal seizures-associated variants are distributed throughout the Kv7.2 protein, mutations associated with KCNQ2-related DEE usually located in the voltage sensor domain, the pore, the C-terminus proximal region, and the calmodulin-binding B helix region 4 , 19 , 27 , 28 . However, there are previous case reports mutations in the pore domain that display variable phenotypes including benign/self-limited neonatal seizures and DEE 29 .…”

“Fifth‐day fits” revisited: A literature review of benign idiopathic neonatal seizures and comparison with KCNQ2‐ and KCNQ3‐associated benign familial epilepsy syndromes

“…22 While the majority of KCNQ2-and KCNQ3-associated neonatal seizure cases reported are familial and autosomal dominantly inherited, de novo variants in neonates with initial presentation consistent with BINS have been reported. 23,24 The significant phenotypic overall between confirmed de novo "BFNS" and cases of BINS with negative genetic testing for known Mendelian epilepsy disorders (including potassium channelopathies) raises the question of whether there is some common pathogenic genetic disruption in channel expression or function that we cannot detect with current molecular genetic diagnostic techniques. There is increasing recognition that deep intronic variants and tissue-specific mosaic variants can cause epilepsy and evade detection via targeted and broad-spectrum sequencing.…”

KCNQ2-Related Benign Infantile Epilepsy in Preterm Dizygotic Twins

“…A family history of neonatal seizure is crucial for the diagnosis [1]. KCNQ2-related non-familial benign neonatal epilepsy has been previously reported [2]. However, KCNQ2-related benign infantile epilepsy in dizygotic twins with no family history of seizures has not been reported to date.…”

“…Mutations in KCNQ2 and KCNQ3, which encode two different KCNQ channel subunits, have been identified as causes of BFNE [1,2]. However, the exact pathogenic mechanisms underlying the age-dependent development and spontaneous remission of BFNE have not been elucidated.…”