LETTER TO THE EDITOR
|Ahead of print
Role of genotype–phenotype correlation in prognostication of a child with a novel potassium channelopathy
Bhanudeep Singanamalla, Ramesh Natarajan, Priyanka Madaan, Lokesh Saini
Pediatric Neurology Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
|Date of Submission||27-Nov-2020|
|Date of Decision||01-Feb-2021|
|Date of Acceptance||24-Mar-2021|
|Date of Web Publication||07-Jan-2022|
Pediatric Neurology Division, Department of Pediatrics, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh.
Source of Support: None, Conflict of Interest: None
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. 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. 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., 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. 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. 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. 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.
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.
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.
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