Developmental and Epileptic Encephalopathy as a Novel Clinical Hallmark of SCA21

Abstract

Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurodegenerative disorder due to pathogenic variants of the TMEM240 gene. Its clinical presentation usually includes slowly progressive cerebellar ataxia, myoclonus-dystonia syndrome, cognitive impairment, and behavioral problems. Here, we reported the first patient with SCA21 presenting with a developmental and epileptic encephalopathy with seizure onset during late childhood, a seizure semeiology including atonic, clonic, myoclonic seizures, and absences with eyelid myoclonia and an EEG pattern characterized by diffuse spike and wave discharges. Epilepsy was associated with a progressive motor deterioration (the International Cooperative Ataxia Rating Scale-ICARS Total Ataxia score switched from 23/100 to 35/100 over a period of 2 years), a worsening of a preexisting tremor, and a disabling drowsiness. Nonverbal measure of intellectual functioning revealed a moderate intellectual disability (Leiter-R: brief IQ 40; fluid reasoning 52). The epileptogenic mechanisms involving TMEM240 might be correlated with disinhibition of excitotoxic networks due to the loss of Purkinje cells in the cerebellum, but also damage in neuronal bioenergetic pathways and synaptic vesicular trafficking within cortico-cerebellar and thalamo-cerebellar circuits.

Keywords

epilepsy - neurodegenerative disorders - seizures - cerebellar disorders - children

Publication History

Received: 04 February 2025

Accepted: 25 June 2025

Accepted Manuscript online:
02 July 2025

Article published online:
14 July 2025

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