KCNA2 ‐Associated Hereditary Spastic Paraplegia: Clinical Characteristics and Rationale for Targeted Treatment

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.