Episodic Ataxia Associated With Synaptosomal-Associated Protein 25 (SNAP25) Variant: Beyond Epilepsy and...

Developmental and epileptic encephalopathies (DEEs) of infancy and childhood are characterized by early-onset seizures and developmental impairment. Heterozygous missense or loss-of-function variants in synaptosomal-associated protein 25 (SNAP25), a core component of the presynaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, have been implicated in a spectrum of DEEs with variable neurological features. We report a male child carrying a novel de novo splice-site variant in SNAP25, expanding the known mutational and phenotypic spectrum of this condition. The patient presented at 32 months with afebrile seizures since seven months of age, with frequent seizure clusters and status epilepticus. He exhibited a moderate global developmental delay and recurrent, transient episodes of gait ataxia triggered by febrile illnesses, lasting up to one week and resolving without residual deficits. Neurological examination revealed mild microcephaly and a clumsy gait without persistent ataxia or weakness between febrile episodes. Brain magnetic resonance imaging (MRI) was normal, and the electroencephalogram (EEG) showed bilateral frontal paroxysmal activity. Genetic testing identified a heterozygous SNAP25 variant (NM_003081.5:c.114+2dup), predicted to abolish the donor splice site and confirmed as de novo, classified as likely pathogenic. The patient achieved complete seizure control under levetiracetam monotherapy and continues to show moderate global developmental delay. This case broadens the genotypic and phenotypic spectrum of SNAP25-related DEE, highlighting febrile illness-triggered episodic ataxia as a previously unreported manifestation. It underscores the relevance of recognizing transient neurological decompensations in the context of SNARE complex dysfunction and highlights the potential for meaningful neurodevelopmental progress despite early epileptic encephalopathy.