Severe epilepsy phenotypes in adults with succinic semialdehyde dehydrogenase deficiency: Novel clinical and therapeutic insights from an Italian multicenter retrospective cohort study

Purpose: To describe the epileptic phenotypes in a series of adults with succinic semialdehyde dehydrogenase deficiency (SSADHD) and to evaluate the efficacy of novel treatments.

Methods: We retrospectively reviewed the charts from seven adult patients followed at four Italian Epilepsy Centers. All cases had biallelic variants in the ALDH5A1 gene; three of these were novel: c.1205T>A (p.Val402Glu), c.1630delT (p.Cys544Valfs*15), and c.141C>G (p.Tyr47Ter).

Results: Patients (age at last follow-up: 33.8 ± 8.8 years) had moderate motor deficits and variable degrees of intellectual disability, often with psychiatric symptoms. Epilepsy had heterogeneous presentations, with a mean onset age of 13.1 ± 7.7 years. Drug-resistant seizures and convulsive status epilepticus (SE) occurred in five and three patients respectively; two had possible sudden unexpected death in epilepsy. Prolonged episodes of impaired awareness that preceded or followed convulsive SE were associated with epileptic discharges on EEG and were classified as non-convulsive seizures. In two patients, add-on cenobamate led to a reduction in tonic-clonic seizures and SE. In all cases, brain MRI showed T2 hyperintensity in pallidi and dentate nuclei.

Conclusions: Epilepsy in SSADHD is believed to result from compensatory mechanisms within the GABAergic system. Cenobamate could have a therapeutic effect on patients with SSADHD by modulating GABA_A receptors via a non-benzodiazepine site. However, this observation warrants further investigation, including potential benefits beyond seizure control. Epileptologists should consider SSADHD in patients with prolonged non-convulsive seizures or SE, especially when accompanied by developmental, movement, or psychiatric comorbidities and the characteristic neuroradiological features.