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Boßelmann, C.M.* ; Vyhnalek, M.* ; Blichova, Z.* ; Novotna, L.* ; Meszarosova, A.U.* ; Havránková, P.* ; Kuster, E.* ; Lauerer, R.J.* ; Hedrich, U.B.S.* ; Lyu, H.* ; Oosterloo, M.* ; Alber, M.* ; Schöls, L.* ; Müller-Schlüter, K.* ; Bischoff, A.T.* ; Klopstock, T.* ; Koutsis, G.* ; Karadima, G.* ; Efthymiou, S.* ; Houlden, H.* ; Salazar-Villacorta, A.* ; Ellis, C.A.* ; Scheper, A.* ; Gläser, D.* ; Haack, T.B.* ; Wagner, M. ; Zech, M. ; Platzer, K.* ; Striano, P.* ; Syrbe, S.* ; Schüle, R.* ; Lerche, H.*

KCNA2-associated hereditary spastic paraplegia: Clinical characteristics and rationale for targeted treatment.

Mov. Disord., DOI: 10.1002/mds.70555 (2026)
DOI PMC
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Epilepsy ; Eplerenone ; Genetics ; Hereditary Spastic Paraplegia ; Ion Channel Disorder
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Zeitschrift Movement Disorders
Verlag Wiley
Begutachtungsstatus Peer reviewed
Institut(e) Institiute of Neurogenomics (ING)