Rationale:
To highlight focal EEG abnormalities in an ultra-rare spinocerebellar ataxia previously demonstrated to involve generalized seizures. Biallelic loss-of-function variants in RUBCN associated with endolysosomal autophagy defects cause an ultra-rare autosomal recessive spinocerebellar ataxia, SCAR15 (Salih ataxia), which has been reported in < 20 patients globally. Features include early-onset ataxia, cognitive impairment, dysarthria, and developmental delay. Some patients have been reported to have seizures, but given the rarity of this syndrome, the association with epilepsy is unclear.
Methods:
A 10-year-old boy with SCAR15 was evaluated in epilepsy clinic. Parental consent was obtained for a case report. EEG, neuroimaging, and genetic testing were reviewed retrospectively.
Results:
The proband had global developmental delay, mild ataxia, speech articulation issues, short stature on growth hormone therapy, sleep disturbance, ventricular septal defect, and presumed focal epilepsy. Trio exome sequencing showed a homozygous pathogenic variant in RUBCN, NM_001145642.5:c.1261C >T (p.R421*). The mechanism of homozygosity was maternal uniparental disomy.
No epileptogenic foci were identified on the MRI brain. PET revealed minimally decreased left cerebellar metabolism diffusely which could suggest a right cerebral pathology. The accompanying EEG revealed delta range slow activity in the posterior temporal-occipital region, at times with a notched quality, superimposed on a mildly slow background for age. Previously, he had medium-high amplitude polymorphic spike and wave discharges over the right occipital region. Patient developed seizures with onset at age 10 consisting of episodes of behavioral arrest and facial change lasting up to a minute, sometimes in clusters, initially occurring a few times per month. The seizures are currently well controlled on oxcarbazepine.
Conclusions:
This study contributes to the characterization of epilepsy and interictal EEG abnormalities in an emerging ultra-rare autophagy disorder, RUBCN-related SCAR15, and adds focal epilepsy to its possible presentations. Given the rarity of this syndrome, the type of associated epilepsy is not well characterized. Generalized seizure semiology and an association with myoclonic epilepsy have been reported in literature. For example, patients developed early-onset myoclonic seizures in infancy with no relapse reported after 3 years of age. A focal abnormality associated with epilepsy in SCAR15 patients has not yet been elucidated in the literature, and a possible association with underlying cortical malformations and focal structural lesions is yet to be explored and understood.
Most reported disease-causing RUBCN variants lead to loss of protein function. The RUBCN protein is a negative regulator of autophagy, suggesting that SCAR15 pathogenesis involves excessive autophagy. Further study of this novel mutation is needed to understand its role in epilepsy. A protective role of autophagy against epileptogenesis has been reported in the literature, which raises a pathophysiological dilemma in this genetic disorder associated with epileptogenesis in the setting of possible excessive autophagy.
Funding: No funding received.