A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism.

Scientists found a genetic change in a brain chemical channel in a person with both autism and epilepsy. They grew the person's skin cells in the lab and tested different medications. One medication called acetazolamide helped both the lab-grown cells and improved the person's epilepsy and thinking skills. When they stopped the medication, the symptoms got worse again.

This case study reports a novel loss-of-function mutation in the Kv10.2 potassium channel gene in a patient with both epilepsy and autism. Researchers cultured skin cells from the patient and demonstrated that the mutation caused cellular growth defects and altered differentiation. Treatment with carbonic anhydrase inhibitors (brinzolamide, acetazolamide, retigabine) restored the mutant channel's function in laboratory tests and improved the patient's skin cell growth. Clinical treatment with acetazolamide improved the patient's epilepsy and cognitive skills, with symptoms worsening when treatment was temporarily stopped.

This study suggests potassium channel dysfunction as a potential mechanism underlying some cases of autism with epilepsy and demonstrates the utility of patient-derived cell cultures for personalized treatment testing.

This case suggests potassium channel mutations may contribute to autism-epilepsy comorbidity. Patient-derived cell cultures may enable personalized treatment testing. Acetazolamide shows promise but requires controlled trials before clinical recommendations. Genetic testing for Kv10.2 mutations may be considered in similar presentations.

Single case study limits generalizability. No control group or standardized outcome measures reported. Sample size and detailed clinical assessments not specified. Long-term safety and efficacy data lacking.

Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments. We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome.

A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel.

Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again. By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial.

The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.