Objective: We report a novel cause for SCA19. We obtained longitudinal exam data on the index case, and data on other family members. We conducted in silico analysis of potential functional consequences of the mutation and started experiments to test the resulting hypothesis.

Background: SCA19 is caused by missense mutations in KCND3, encoding a voltage-gated potassium channel Kv4.3. Kv4.3 associates with K channel interacting protein (KChIP) to reach the cell surface. High-resolution structures of Kv4.3 co-crystallized with KChIP show that the Kv4.3 hydrophobic N terminal 1-23 residues bind with KChIP. A 63 yo man presented with 3 years of slowly progressive ataxia and extensive negative workup.

Methods: Whole exome sequencing was used identify a potential disease cause. Exams including the Scale for the Assessment and Rating of Ataxia (SARA) and gait and balance measures were tracked over two years. A structured gait and balance home exercise program started after the initial exams was maintained to the present.

Results: A heterozygous c.5 C>A (A2E) genetic variant in KCND3 was identified. A2E introduces a negatively charged residue to the hydrophobic Kv4.3 segment: we speculate this destabilizes Kv4.3/KChIP interaction. Initial 2013 SARA total score was 9 (range across 2013 7-11). Highest scores were in gait and stance. By mid 2015 SARA total was stable at 7. Stance score improved. 2013 computerized dynamic posturography (CDP) showed mildly increased postural sway, marked inability to sustain standing with altered sensory input, and abnormal latencies to support surface perturbations; CDP measures mildly improved in 2015. From 2013 to 2015 mildly reduced gait speed (1.18 v 1.31m/sec) and wide base (19.3 v 19.7cm) worsened, and reduced step length (63 v 66.8cm) improved. Cardiac and neuropsychology workups were normal. Eye exam noted loss of smooth pursuit, ophthalmoplegia, ocular dysmetria, slow saccades. In 2015 a brother developed symptoms; genetic testing identified the A2E Kv4.3 variant. Adult offspring remain asymptomatic.

Conclusions: We report a KCND3 mutation in a protein region distinct from other SCA19 mutations. Clinical phenotype is relatively mild and slowly progressive. Gait and balance exercises may improve symptoms. Predicted reduction of KChIP association is expected to decrease cell surface Kv4.3 protein levels. Functional studies of the A2E Kv4.3 variant protein are underway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-causal-mutation-for-spinocerebellar-ataxia-1922-sca19/