The epilepsy phenotype of ST3GAL3-related developmental and epileptic encephalopathy

Abstract

Objective: ST3GAL3-related developmental and epileptic encephalopathy (DEE-15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioral difficulties, stereotypies, and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated.

Methods: A retrospective chart review of two siblings with ST3GAL3-related DEE was completed. In addition, we reviewed all published cases of ST3GAL3-related congenital disorder of glycosylation.

Results: Two brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood-onset seizures. Seizures started between 2.5 and 5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants in ST3GAL3, (a) c.302del, p.Phe102Serfs*34 and (b) c.781C>T, p.Arg261*, which were inherited in trans. Magnetic resonance imaging showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases of ST3GAL3-related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n = 6, 75%) had seizures despite anti-seizure medication treatment.

Significance: Seizures related to ST3GAL3-related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.

Keywords: ST3GAL3; congenital disorder of glycosylation; developmental and epileptic encephalopathy; genetics; genotype.

FIGURE 1

Ictal and interictal electroencephalogram findings. EEG epochs A to C: sensitivity 20 uV/mm, timebase 30 mm/s, high‐frequency filter = 70 Hz, low‐frequency filter = 1 Hz. Epochs A to C represent a focal asymmetric tonic seizure followed by right‐sided extremity clonic movements in the older sibling's case (case 1). Ictal onset was from the left temporal head region, which is then followed by diffuse attenuation of the EEG and then by focal spike and slow wave over the left temporal head regions and then the left parasagittal head regions with fields to the right. Epoch D, sensitivity 20 uV/mm, timebase 30 mm/s, high‐frequency filter = 70 Hz, low‐frequency filter = 1 Hz. Epoch D represents typical interictal activity seen throughout the EEG and shows focal spike and slow wave maximal over the left temporal head regions; here in NREM sleep.