Objective: To investigate a family affected by ataxia and paroxysmal motor exacerbations.

Background: Ataxia channelopathies share common traits such as slow progression and variable degree of cognitive impairment. Heterozygous mutations in KCND3, encoding K channel Kv4.3, are associated with the rare spinocerebellar ataxia 19 (SCA19) allelic with spinocerebellar ataxia 22 (SCA22). Some patients with mutations in KCND3 can present with cardiac arrhythmia. In the other hand, mutations in KCNC3, encoding Kv3.3, cause spinocerebellar ataxia 13 (SCA13).

Method: Comprehensive clinical and psychometric evaluation, neuroimaging and genotyping of a Swedish family (mother and son) affected by ataxia was carried out. Heterozygous and homozygous Kv3.3 A671V and Kv4.3 V374A variants were evaluated in Xenopus laevis oocytes using high-throughput, two-electrode voltage-clamp. Implications of modified Kv4 conductance on neuronal activity were investigated computationally using an established Purkinje neuron model.

Results: Adult-onset slowly progressive cerebellar ataxia with cognitive difficulties are the main findings in this family. Exacerbations occurred in the index case when he was exposed to sudden speed changes such as riding an elevator or trains. Treatment with acetazolamide (ACZ) attenuated these paroxysmal exacerbations. Both patients had attended special schools, their IQ ranged between 90-95. Despite these deficits, FDG-PET displayed hypometabolism only in the marked atrophic cerebellum in both cases. Genetic analyses revealed the new variant c.1121T>C (V374A) in KCND3 and c.2012T>C (A671V) in KCNC3. The latter has a MAF of 0.02%. A synergistic effect between both variants was suspected. However, reduced currents of Kv4.3 V374A, but not of Kv3.3 A671V, were observed, consistent with a dominant negative effect. Computational modeling suggested an increase in Purkinje neuron firing frequency based on the reduced Kv4.3 V374A current. Finally, we did not find evidence of cardiac arrhythmia.

Conclusion: Our findings demonstrate a pathogenic role for the novel variant Kv4.3 V374A. The index case displays paroxysmal ataxia exacerbation attenuated with ACZ which are new traits for SCA19/22. In addition, despite intellectual disability FDG-PET demonstrated hypometabolism limited to the atrophic cerebellum suggesting compensatory pathways.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-kcnd3-mutation-associated-with-paroxysmal-motor-exacerbations-in-spinocerebellar-ataxia-19/