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Role of genotype–phenotype correlation in prognostication of a child with a novel potassium channelopathy

 Pediatric Neurology Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Date of Submission27-Nov-2020
Date of Decision01-Feb-2021
Date of Acceptance24-Mar-2021
Date of Web Publication07-Jan-2022

Correspondence Address:
Lokesh Saini,
Pediatric Neurology Division, Department of Pediatrics, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_294_20


How to cite this URL:
Singanamalla B, Natarajan R, Madaan P, Saini L. Role of genotype–phenotype correlation in prognostication of a child with a novel potassium channelopathy. J Pediatr Neurosci [Epub ahead of print] [cited 2023 May 27]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=335200

A 2-year-old girl born to non-consanguinously married couple presented with sleep myoclonus since 1 month of age, which subsided gradually. Electroencephalography (EEG) was normal. At 8 months of age, she developed seizures in the form of uprolling of eyeballs along with turning of head toward right side, 3–4 episodes/day, each lasting for 1–2 min. The frequency reduced to 1–2 episodes/day after addition of levetiracetam and valproate. Her antenatal and perinatal history was normal and had normal gross motor milestones with delay in social and language domains. Neurological examination was normal. Initial clinical diagnosis considered was early infantile epileptic encephalopathy with probable genetic/structural cause. EEG showed generalized spike/polyspike along with high amplitude delta-theta slowing of background. Magnetic resonance imaging brain was normal. Clinical exome sequencing revealed a known pathogenic autosomal dominant heterozygous missense variant in exon 3 of the KCNA2 gene [c.1214C>T p.Pro405Leu]. Targeted parental carrier testing was negative. The child continued to have infrequent brief focal seizures (one seizure/3–4 months) on valproate and lacosamide and have language predominant global developmental delay, however consistently gaining new milestones at 3 years of age.

Epileptic encephalopathies are commonly caused due to the mutations affecting ion channels in the brain. Recently, KCNA2 joins a growing list of voltage-gated potassium channel-related epileptic encephalopathies such as KCNQ2, KCNQ3, KCNT1, and KCNB1.[1] KCNA2 encodes KV1.2, a delayed rectifier class of potassium channel subunit, and plays a key role in the repolarization of cell membrane following an action potential.[2] The KCNA2 gene mutations lead to a spectrum of neurological phenotypes corresponding to its effect on KV1.2 channel functions like loss-of-function, gain-of-function, or both. All these groups have certain common features like fever-sensitive seizures, language impairment, behavioral issues, and ataxia.[1],[2] Early onset generalized seizures are predominant in the gain-of-function group, whereas later-onset focal seizures are predominant in the loss-of-function group. Children in the loss-of-function group are prone to develop electrical status epilepticus in sleep (ESES) in EEG but with normal neuroimaging. Those with gain-of-function have severe ataxia, progressive cerebellar atrophy in neuroimaging, and severe developmental delay. Children with both gain-of-function and loss-of-function variants have neonatal-onset epilepsy with severe intellectual disability.[3] Other important genetic causes of ESES include GRIN2A, KCNQ2, SCN2A, SRPX2, SLC6A1, KCNB1, CNKSR2, and OPA3 mutations. Other newly recognized clinical phenotypes include hereditary spastic paraplegia, episodic ataxia type 1, and dystonia.[3] It is well known that precision medicine has revolutionized the treatment of single gene epileptic encephalopathies. Recently, a repurposed drug, 4-aminopyridine, has been approved to treat the gain-of-function mutations of KCNA2.[4] In the index patient, clinical exome sequencing was considered as a relevant genetic testing because the child had no facial dysmorphism and single gene epileptic encephalopathies were relatively common in early infancy. Our patient had P405L mutation which has been reported to be associated with less severe phenotype and caused due to loss-of-function variant.[5]

Hence, genotype–phenotype correlation is crucial in prognosticating the parents, and careful follow-up is needed as the children with loss-of-function variants are prone to develop ESES.



Author contributions

B. S., P. M., and R. N.: involved in patient care, did the literature review, and prepared the initial draft of the manuscript.

L. S.: involved in patient care, critically reviewed the manuscript, and provided intellectual input.

Financial support and sponsorship


Conflicts of interest

The authors have no conflict of interest to disclose with regard to this article.

   References Top

Hundallah K, Alenizi A, AlHashem A, Tabarki B Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: expansion of the genotypic and phenotypic spectrum. Eur J Paediatr Neurol 2016;20: 657-60.  Back to cited text no. 1
Corbett MA, Bellows ST, Li M, Carroll R, Micallef S, Carvill GL, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology 2016;87:1975-84.  Back to cited text no. 2
Masnada S, Hedrich UBS, Gardella E, Schubert J, Kaiwar C, Klee EW, et al. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain 2017;140:2337-54.  Back to cited text no. 3
Sisodiya SM Precision medicine and therapies of the future. Epilepsia 2021;62(Suppl 2):S90-105.  Back to cited text no. 4
Sachdev M, Gaínza-Lein M, Tchapyjnikov D, Jiang YH, Loddenkemper T, Mikati MA Novel clinical manifestations in patients with KCNA2 mutations. Seizure 2017;51:74-6.  Back to cited text no. 5


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