KCNA2-Associated Hereditary Spastic Paraplegia: Clinical Characteristics and Rationale for Targeted Treatment.
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Boßelmann Christian M, Vyhnalek Martin, Blichova Zuzana, Novotna Ludmila, Meszarosova Anna Uhrova, Havránková Petra, Kuster Elena, Lauerer Robert J, Hedrich Ulrike B S, Lyu Hang, Oosterloo Mayke, Alber Michael, Schöls Ludger, Müller-Schlüter Karen, Bischoff Almut Turid, Klopstock Thomas, Koutsis Georgios, Karadima Georgia, Efthymiou Stephanie, Houlden Henry, Salazar-Villacorta Ainara, Ellis Colin A, Scheper Anna, Gläser Dieter, Haack Tobias B, Wagner Matias, Zech Michael, Platzer Konrad, Striano Pasquale, Syrbe Steffen, Schüle Rebecca, Lerche Holger
Аннотация
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.