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Epileptic Disorders

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Benign familial infantile epilepsy associated with KCNQ3 mutation: a rare occurrence or an underestimated event? Volume 22, issue 6, December 2020

Figures


  • Figure 1

Clinical studies, carried out in the last 20 years, have led to the identification of at least three distinct electroclinical patterns associated with infantile onset, characterized mainly by age at onset but all sharing a favourable outcome, and many individuals share the same phenotype within a family.

These specific clinical traits are highlighted in the respective definitions of benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE), and benign familial infantile epilepsy (BFIE) (Bureau et al., 2012).

The early gene sequencing studies showed a distinct phenotype-genotype correlation, in particular between BFNE and KCNQ2, BFNIE and SCN2A, and BFIE and PRRT2. In recent years, next-generation sequencing (NGS) panels have led to significant gene discovery related to many disorders including epilepsy. At present, the effort of researchers is aimed at establishing panels of genes as a gold standard to detect as many pathogenic variants as possible (Zara et al., 2013; Zeng et al., 2018). The expansion of NGS technology, mainly for familial infantile epilepsies, has confirmed the existence of three clusters related to the three phenotypes mentioned above. The three phenotypes share certain genetic mutations, albeit at a low incidence. Recent studies indicate that the phenotype associated with BFIE is the most genetically heterogeneous. In recent years, reports in the literature on the relevance of KCNQ3 gene mutation to the epilepsies have been marginal and a pathogenic role has been recognized in only a small number of patients with typical BFNE and rarely with BFIE (Miceli et al., 2019). Here, we describe a patient with a BFIE phenotype associated with a novel mutation in KCNQ3; c.1850G>C (p.Ser617Thr).

Case study

This study was approved by the Ethics Committee Palermo 1 of “Paolo Giaccone” University Hospital of Palermo, Italy. Written informed consent for publication was obtained from the patients’ parents. The proband, an Italian 20-month-old male, was born at term following an uneventful pregnancy and delivery. His family history was remarkable for epilepsy; he has a second-degree paternal cousin who has suffered from occasional seizures within his first year and is presently taking phenobarbital. Developmental milestones of our patient were normal: head control, sitting without support, and walking were achieved at three, six and 13 months, respectively. He spoke his first words at eight months. At five months and 15 days, he had a cluster of seizures, lasting for an hour, characterized by deviation of the head and eyes to the left, staring, stertorous breath, and clonic movements of the left upper limb that spread to the upper right limb, evolving into self-limited generalized tonic-clonic seizures lasting for 1.5 minutes. A similar focal seizure recurred at 20 months during a febrile illness. Neurological and EEG examination were normal, as well as brain MRI. He has never been on antiepileptic treatment.

At the last clinical evaluation, performed at 20 months of age, the child was alert, perceptive, and sensitive. He demonstrated a healthy interest in the testing materials with an appropriate level of activity, attention, adaptation to change, and task persistence. He was socially engaged with the examiner, showing good communicative intent and reciprocity. He vocalized in response to the examiner and expressed himself. During the clinical examination, the patient placed items (circle, square, triangle) in designated areas; pointed to objects, pictures, and actions; handled objects; and flicked through a book quickly. He achieved partial thumb opposition, built towers using four cubes, ran with coordination, swung his leg to a kick ball, went up/downstairs using both feet, followed directions, and said 10 different words and spoke a two-word utterance.

As the clinical data suggested BFIE diagnosis, we performed a molecular genetic analysis based on a NGS panel of 149 genes associated with epilepsy. The NGS showed a novel heterozygous missense KCNQ3 (NM_004519.3) c.1850G>C variant, not previously described in the literature (allele frequency: [ExAC] 0.00001). This nucleotide substitution, inherited by the asymptomatic father, leads to the missense mutation, p.Ser617Thr. The variant affects a residue conserved in the KCNQ2-5 channel subunit, located between helix-C and helix-D of the C-terminal region of the protein. The mutation Ser617Thr is predicted to be “probably damaging”, “deleterious”, and “disease causing” based on the three in silico models, PolyPhen2, SIFT, and Mutation Taster respectively (figure 1).

Discussion

The seizure semiology of our patient mirrors the clinical pattern of typical BFNE (Piro et al., 2019), including incomplete penetrance as the father is an asymptomatic carrier of the KCNQ3 variant. In addition, the clinical course of our patient demonstrated the occurrence of febrile seizures which have not previously been reported in patients with KCNQ3-BFIE. Indeed, BFIE is usually characterized by brief focal seizures, evolving to bilateral tonic-clonic seizures that occur in clusters at onset, at between three and 20 months of age, mostly between four and seven months, and remit within a year from onset, although some individuals may have seizures later (Vigevano, 2005). Unfortunately, we were not able to directly evaluate the detailed clinical history of our patient's relatives, and therefore we cannot establish whether the current epileptic seizures belong to long-lasting form of BFIE or a new epileptic syndrome. On the other hand, transition between different idiopathic age-related epileptic phenotypes has been reported in the literature, including some features in particular (Mangano et al., 2011, 2013), suggesting the existence of common genetically determined pathophysiological processes that confer susceptibility to seizures. BFIE is a genetically heterogeneous form of epilepsy with autosomal dominant inheritance and incomplete penetrance. Mutations in PRRT2, KCNQ2, SCN2A, and GABRA6 genes were mainly identified in patients with BFIE phenotype (Zara et al., 2013; Zeng et al., 2018). An additional missense KCNQ3 p.N468S variant was detected in all of the three siblings of a Chinese family affected with BFIE, but this was considered a polymorphic variant as the mutation did not demonstrate any statistically significant effect on current associated with the heteromeric channel (Singh, et al., 2003). As the data of our patient meet all the clinical criteria for diagnosis of BFIE, we may therefore compare his clinical history with those of the four BFIE cases with pathogenic variants in the KCNQ3 gene published so far (Zara et al., 2013; Fusco et al.,2015). Notably, the proband reported by Zara et al., at the age of three months and 25 days, had a single cluster of seizures characterized by staring, eye deviation, and hypertonus of brief duration. His sibling, at the age of four months, had an isolated secondary generalized focal seizure, and their father, at the age of five and seven months, had had two isolated convulsive seizures. None of the three subjects later had seizure relapse, or neurological or intellectual impairment. The fourth reported patient, a 30-month-old reported by Fusco et al., had benign epilepsy with centrotemporal spikes following benign infantile seizures. Notably, at the age of 10 months, she had several brief ictal events with psychomotor arrest and staring which was not characterized. At two years of age, she had a cluster of hemifacial motor seizures and clonic contractions of the limbs with hypertonia, evolving into generalized tonic-clonic seizures, lasting for one hour and self-limiting. Our patient showed a cluster of focal features evolving into self-limiting generalized tonic-clonic seizures. Taken together, a comparison of the clinical features of seizures and their course between our case and those reported in the literature appears premature given the small sample size reported in the literature and the differences in data collection. Thus, a detailed clinical history associated with accurate description of seizure semiology, possibly supported by video-EEG, and their clinical course would be useful in future studies. We therefore believe, based on our experience, that the KCNQ3 gene, which is increasingly reported in association with atypical BFNE (Miceli et al., 2015) and other infantile epilepsies, should be further investigated and included in the panel of genes for epilepsy.

Acknowledgements and disclosures

We thank the child and parents who participated in this study. We acknowledge Dr. Vincenzo Antona for his advice and support in genetic counselling.

None of the authors have any conflict of interest to declare.