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Updated: Oct 9, 2026
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Published on: August 9, 2024
KCNA2-Associated Hereditary Spastic Paraplegia: Clinical Characteristics and Rationale for Targeted Treatment
Christian M Boßelmann1, Martin Vyhnalek2, Zuzana Blichova2
1Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research and Hertie Center of Neurology, University of Tübingen, Tübingen, Germany.
Background:
A single recurrent variant, NM_004974.4(KCNA2):c.881G>A:p.(Arg294His), causes hereditary spastic paraplegia (HSP) through a unique variant-specific mechanism. Data from paralogous variants suggest that this may be a druggable mechanism.
Objective:
The objective of this work is to give an overview of the clinical spectrum and course of KCNA2-p.(Arg294His)-associated HSP (HSP-KCNA2) and report treatment with eplerenone, a potassium-sparing diuretic.
Methods:
In this retrospective study, we recruited individuals with the variant of interest through international rare disease networks. Treatment with eplerenone was done as off-label use, and outcome measures were recorded during routine clinical care.
Results:
We report the clinical characteristics of 23 individuals from 17 families with HSP-KCNA2. We observed a consistent core phenotype of abnormal evoked potentials (100%), cerebellar ataxia (83%), and lower limb spasticity (70%). Childhood-onset was more commonly associated with epilepsy (odds ratio, 4.16; P = 0.042), and 52% had developmental delay. Progression of motor disability was slow even in childhood onset. We observed full (100%) penetrance and estimated the prevalence to be 0.18 to 0.69 case per million. Treatment with eplerenone was associated with a decrease on the Scale for the Assessment and Rating of Ataxia (Cohen's d = -1.8; -7.9% change from baseline, P = 0.015), but not on the Spastic Paraplegia Rating Scale, whereas stopping treatment was associated with worsening symptoms. At 2-year follow-up, four of five (80%) individuals chose to remain on treatment.
Conclusions:
HSP-KCNA2 is a syndrome with a recognizable variant-specific core phenotype. Our exploratory analyses on eplerenone may serve as rationale for future investigations on targeted treatments. © 2026 International Parkinson and Movement Disorder Society.
