KCNA2. We have previously discussed KCNA2 and that pathogenic variants in this gene can lead to a spectrum of neurological phenotypes. Pathogenic KCNA2 variants were first recognized in individuals with early-onset developmental and epileptic encephalopathies and have subsequently been found also in individuals and families with hereditary spastic paraplegia, episodic ataxia, and milder epilepsies. KCNA2 encodes the Kv1.2 potassium channel, a delayed rectifier class of potassium channel that enables neuronal repolarization after an action potential. A new study by Masnada and colleagues provides clinical and functional data from 23 patients, representing the largest KCNA2 cohort reported to date. Within the KCNA2-related encephalopathy spectrum, it now seems that there may be three distinct phenotypes.
Three functional classes. When we first wrote about KCNA2, we discussed the activating and abolishing categories of variants. The recent work by Masnada and colleagues expands and complicates this functional picture. The abolishing (loss-of-function) and activating (gain-of-function) classes of variants remain, but a third functional class emerges that shows a combination of activating and abolishing properties (gain- and loss-of-function). The loss-of-function variants lead to a loss of channel activity with a dominant-negative effect on wildtype subunits. The gain-of-function variants lead to permanently open channels. However in the third functional class, the observed gain-of-function effect is reduced by an additional loss-of-function, through a variety of mechanisms including shifts in steady state activation and decreased current amplitude.
The three phenotypes. Masnada and colleagues propose that KCNA2-encephalopathy is a spectrum that consists of three clinical phenotypes, which correspond to the effect of the underlying KCNA2 variant on Kv1.2 channel function: (1) loss-of-function, (2) gain-of-function, and (3) gain- and loss-of-function. All three phenotypic groups have overlapping features, including seizure onset within the first year of life, fever-sensitive seizures, developmental and cognitive impairment, behavioral issues, and signs of cerebellar involvement such as ataxia, coordination difficulties, and dysarthria. However each of the three groups has distinctive features. The loss-of-function group showed predominant focal seizures compared to predominant generalized seizure in the gain-of-function group. EEG findings in the loss-of-function group showed activation of epileptiform activity during non-REM sleep, which raised the concern for ESES in some patients. Although ataxia was observed in all three groups, it was most severe in the two gain-of-function groups. MRI was normal in the loss-of-function group, but both gain-of-function groups showed progressive cerebellar atrophy, beginning in childhood in the gain- and loss-of-function group. Developmental outcomes appear to be more severe in the two gain-of-function groups compared to the loss-of-function group. The most severe phenotypes were observed among patients with gain- and loss-of-function variants, who often had neonatal-onset epilepsy with severe to profound intellectual disability.
Variant specific effects. It is worth noting that three recurrent variants accounted for two-thirds of the patients in the study. The P405L loss-of-function variant was found in 5 individuals and accounts for 5/8 (63%) patients in the loss-of-function group. The R297Q gain-of-function variant was found in 7 individuals and accounts for 7/9 (78%) patients in the gain-of-function group. The T374A gain- and loss-of-function variant was found in 3 individuals and accounts for 3/6 (50%) patients in the gain- and loss-of-function group. Taking into account the high proportion of each of these three variants in the three respective functional/phenotypic classes, it is reasonable to wonder whether we are observing variant-specific effects rather than functional class-specific effects. For example, patients with the P405L variant present with a relatively homogeneous clinical picture, including febrile, focal dyscognitive, and hemiclonic seizures, with remission in late childhood or early adolescence, and an EEG picture reminiscent of ESES. Is the emerging clinical picture of the loss-of-function class of variants due to loss of Kv1.2 function in general, or is there something specific about the P405L variant itself that is leading to this clinical picture? Additionally, the severe phenotype associated with gain- and loss-of-function variants may be highly influenced by the T374A variant, which seems to be associated with a particularly severe outcome including neonatal-onset seizures, spastic quadriplegia, cerebellar atrophy, and profound ID. The remaining three patients in the gain- and loss-of-function group do not appear to be as severely affected as the three who carry the T374A variant. Further studies of larger patient cohorts are required before we can confidently assess whether KCNA2-related phenotypes are determined based on functional class or are variant-specific.