In this report, we reported a 6-month-old boy who presented with epileptic spasms from the age of 4 months, hypsarrhythmia on interictal EEG, and psychomotor delay in development. Common blood counts, biochemical tests, and urine and blood metabolic investigations were all normal. Brain MRI showed no obvious abnormality. WES revealed presence of the c.244C > T/p.Arg82Cys variant of the KCNA2 gene (NM_004974.3), which is inherited in an autosomal dominant manner and is likely pathogenic. Finally, we successfully controlled the seizures by TPM therapy alone, and the results of EEG and clinical follow-up showed a good prognosis.
The KCNA2 gene is located on chromosome 1p13.3, a member of the voltage-gated potassium channel Kv1 family, encodes the voltage-gated delayed rectifier potassium channel α-subunit Kv1.2 , which is abundantly expressed in the large axon terminals of basket cells of the central nervous system (CNS) that make powerful axosomatic synapses on Purkinje cells. Kv1.2 plays a key role in the efficient detoxification and synaptic plasticity of neurons, and neuronal membrane repolarization after an action potential, thereby regulating a neuron’s electrical excitability [6, 7]. Kv1.2 belongs to the voltage-gated delayed rectifier class of potassium channels, which is composed of four subunits. Different combinations of these subunits lead to various nerve cell types, which can play different roles in different neurons [8,9,10], and effectively maintain repolarization of the neuronal membrane following an action potential [7, 11]. Knockout of Kv1.2 gene in mice leads to the development of severe brain stem epilepsy, respiratory failure, excitatory disorder of the CNS, and even premature death at 15 days after birth [12, 13]. Heterozygous deletion of Kv1.2 results in increased seizure susceptibility, and mutations in KCNA2 are also confirmed to be associated with more severe phenotypes. This indicates that the KCNA2 gene mutation interferes with the normal function of Kv1.2 and damages repolarization, leading to hyperexcitability and repetitive discharge tendency in neurons [7, 11, 13, 14].
Several gene functional studies have confirmed that the KCNA2 pathogenic mutations include the loss-of-function (LOF) effect, gain-of-function (GOF) effect, and gain- and loss-of-function effect. These three phenotypes actually overlap with each other to various degrees, but the latter two are more severe [6, 7, 10, 14,15,16,17]. Mutations causing the LOF effect, the most common phenotype, are almost completely loss-of-function with a dominant-negative effect. This type of patient has seizure onset in infancy or early childhood, and most of them have focal seizures, and there is a trend of multifocal epileptiform discharge in the non-rapid eye movement sleep period, particularly at the back of the head, and the phenomenon of electrical status epilepticus during sleep discharge may appear [6, 10, 17]. Development is normal before disease onset. Intellectual and motor retrogression often appear after onset with mild-to-moderate intellectual disability and ataxia . Mutations causing the GOF effect account for approximately 50% of KCNA2 encephalopathy, which leads to permanent channel opening, particularly severe epileptic seizures, ataxia and mental retardation, which may be accompanied by hypotonia and myoclonus. Children with GOF mutations and gain- and loss-of-function effect mutations have relatively serious phenotypes and early onset. Epileptic seizures usually occur in the neonatal period, most of which are generalized epilepsy. EEG recording often shows multifocal epileptiform discharges, and the epileptic seizures are severe, usually having no response to many AED therapies. Cerebellar involvement is more common, leading to ataxia in most patients, with shrinking of the cerebellum or even the whole brain. In severe cases, children cannot walk independently, and the prognosis is poor. Most children have severe mental retardation [6, 18, 19].
Concerning drug treatment, at present, acetazolamide, a carbonic anhydrase, proves to be effective in the treatment of paroxysmal ataxia. In animal experiments, acetazolamide can partially improve motor incoordination in mice with KCNA2 gene mutations. Acetazolamide can rapidly and remarkably improve the epileptic seizures and ataxia of patients with R297Q gene mutation. In addition, a patient with a c.1120A > G gene mutation shows an apparent quick improvement in the frequency and severity of epileptic seizures after taking acetazolamide [5, 12, 15, 19].
In this report, the case was characterized by generalized seizures that manifest as epileptic spasms and frequent seizures, and diagnosed as early-onset West syndrome. The condition was hard to be controlled with sodium valproate, large doses of vitamin B6 and adrenocorticotropic hormone. EEG recording showed multifocal epileptiform discharges, especially in the bilateral posterior regions, and burst suppression, and interictal EEG showed hypsarrhythmia, similar to the reported GOF effect on EEG discharges. In addition, these abnormal EEG recordings were accompanied by psychomotor retardation and cerebellar involvement without obvious ataxia. This case was therefore considered to be the KCNA2 GOF mutation-related encephalopathy, which usually has a severe phenotype.
TPM is a sulfamate-substituted derivative of the monosaccharide D-fructose [20, 21], which may exert its antiseizure effect through five different ways: (1) selectively blocking voltage-gated sodium channels to limit the continuously repeated discharges of neurons; (2) slightly modulating the voltage-gated and receptor-gated calcium ion channels ; (3) acting on the γ-aminobutyric acid A (GABA-A) receptor and the GABA transporter 1 to increase the inward chloride ion current caused by GABA, in order to enhance the GABA-mediated inhibitory neurotransmission [5, 23]; (4) inhibiting the release of the excitatory neurotransmitter glutamate and antagonizing ionotropic glutamate receptors, such as a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors to block excitatory neurotransmission mediated by glutamate [23, 24]; and (5) slightly inhibiting the carbonic anhydrase activity [22, 25]. It has been reported that both sodium valproate and TPM have GABA inhibitory effects, but in this case sodium valproate failed to control epilepsy after 2 months of administration at the beginning of illness, while TPM completely controlled the epileptic seizures after administration for a short time. Therefore, whether the effect of TPM was due to the GABA inhibitory mechanism needs to be further investigated. We believe that TPM as a carbonic anhydrase, can provide slight inhibition of carbonic anhydrase activity, and is effective in treating epileptic seizures in children with KCNA2 mutations [5, 12, 15].