Potassium. The channelopathies are the largest group of genetic epilepsies, and disease-causing variants in genes for neuronal sodium channels, calcium channels, and potassium channels are among the most common causes of genetic epilepsies. However, amongst the various ion channel families, potassium channels stand out due to sheer number. There are more than 70 potassium channel genes encoded in the human genome, and the combination of various subtypes and auxiliary units generates an enormous combinatorial potential. In a recent publication, de novo variants in KCNA6, the gene for the voltage-gated potassium channel Kv1.6, were identified in childhood-onset neurodevelopmental disorders. Here is the somewhat unusual story of the most recent potassium channel gene implicated in human epilepsy.
Figure 1. De novo variants in KCNA6 were identified in four individuals with neurodevelopmental disorders and epilepsy. The KCNA6 gene encodes the voltage-gated potassium channel Kv1.6, which is one of the delayed rectifier potassium channels involved in in facilitating the repolarization of neurons after the depolarization in the setting of neuronal firing. In contrast to other epilepsy-related channelopathies, the clinical features include infantile-onset epilepsy with variable neurodevelopmental differences without either the clear neonatal features of the KCNQ2/3-related epilepsies or the ataxia observed in KCNA1/2-related disorders.
Kv1.6. Each time I revisit the large family of potassium channels, I need to remind myself on how I can keep them apart. This is especially true as the various potassium channelopathies related to human disease have little in common apart from being potassium channels. In Jasper’s Basic Mechanisms of the Epilepsies, Cooper described this large heterogeneity as a diverse superfamily derived from an extraordinarily useful template. For example, KCNT1, the causative gene for migrating focal seizures in infancy, belongs to a completely different class of potassium channels than KCNQ2 or KCNA2. The former is a calcium-activated potassium channel, whereas the latter represent voltage-gated potassium channels. The two other major classes of potassium channels include the inwardly rectifying potassium channels that include genes such as KCNJ10, the gene for SESA syndrome, which is characterized by seizures, sensorineural deafness, ataxia, and intellectual disability. Another group is the family of two-pore domain potassium channels (K2P), which include genes such as KCNK9, which is associated with KCNK9 Imprinting Syndrome, a neurodevelopmental disorder with hypotonia and facial differences.
Delayed rectifiers. Delayed rectifier potassium channels are named based on their ability to produce a delayed outward potassium current in response to membrane depolarization – they allow the membrane depolarization to go back to the initial state after the depolarization through voltage-gated sodium channels, encoded by genes such as SCN1A or SCN2A. This delayed rectifier current is responsible for the repolarization phase of the action potential, which is the phase where the membrane potential of the neuron returns to its resting state. Several of the delayed rectifier potassium channels differ in their “speed” or response. The Kv1 potassium channels, including the potassium channels encoded by KCNA1, KCNA2, and KCNA6 activate relatively quickly after the action potential. This family of channels is referred to as the Shaker-related family of potassium channels. Other delayed rectifier potassium channels spring into action later during the action potential, such as the Kv2 proteins encoded by KCNB1 and KCNB2 (Shab-related family) or the Kv3 family, encoded by KCNC1 or KCNC2 (Shaw-related family).
De novo variants. In their recent publication in Epilepsia, Salpietro and collaborators identify four individuals with infantile-onset epilepsies and mild to moderate neurodevelopmental differences. All individuals carry de novo variants in KCNA6, which were shown in functional studies to delay deactivation, leading to delays in channel closure. This represents a gain-of-function effect, which appears to be the predominant disease mechanism in this newly described genetic etiology. One single individual did not have seizures, but mild to moderate neurodevelopmental differences, while a single individual with treatable infantile seizures had typical development. This emphasizes a wide range of clinical features with a predominance of seizures in infancy. This clinical presentation suggests an entirely novel disease spectrum; KCNA6-related syndrome is much broader than the neonatal spectrum of KCNQ2, though it demonstrates an absence of neurological features such as ataxia, which would be expected in KCNA2, for example. This is particularly relevant, as there is only a limited differential diagnosis of genetic causes for self-resolving infantile seizures.
What you need to know. Salpietro and collaborators report on four individuals with de novo variants in KCNA6, encoding one of the major voltage-gated potassium channel in humans. Gain of function was identified as a plausible disease mechanism in this condition, which may pave the way to precision medicine approaches in the near future for these conditions, with the ultimate goal to improve both seizures and development in individuals with KCNA6-related disorders.
Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.
