Epilepsy and its treatment in Nicolaides-Baraitser syndrome

Abstract

Objective: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease manifesting in intellectual disability, congenital malformations (especially face/limbs) and often epileptic seizures. It is caused by SMARCA2-genemutations. This affects the regulation of the gene accessibility by influencing the chromatin's structure. The characteristics and therapy in particular of epilepsy have rarely been surveyed yet. Methods: Retrospective analysis of NCBRS patients within the “Network Therapy Rare Epilepsies” and an international parent support group regarding phenotype, MRI, EEG and therapy of epilepsy. Results: N = 25 (m = 17, f = 8); Age at first diagnosis: 1–35 years (mean 10) Proven SMARCA2 mutation: 25/25 Epileptic seizures occurred in 23/25 patients: generalized (n = 17), tonic-clonic (n = 12), atonic (n = 7), complex-focal (n = 7), tonic (n = 5), clonic (n = 5), absence (n = 4), myoclonic (n = 3), secondary generalized (n = 2). Onset of epilepsy was on average 21 months (range 7–41). MRI was normal in 23/25 patients. EEG: 12/25 patients with generalized epileptogenic activity. Therapy of epilepsy (applied/effective/worsening): VPA (12/9/1), LEV (12/9/1), PB (8/6/1), TPM (5/4/0), CBZ (5/2/0), OXC (4/3/0), STM (4/1/0), LTG (4/1/2), CLB (3/2/0), PHT (3/2/0), LCM (2/2/0), DZP (2/1/0), CZP (2/1/0) NZP (1/1/0), AZA (1/1/0), FBM (1/1/0), ZNS (1/1/0), RUF (1/0/1), VNS (2/1/0), KD (2/1/0). Withdrawal of an effective therapy with VPA because of hepatotoxicity in one patient: detection of a POLG1 mutation afterwards (c.3708G > T) Conclusion: Our results show, that epileptic seizures at NCBRS often appear with the following characteristics: 1. onset in early infancy 2. predominant generalized tonic-clonic seizures 3. cMRI predominant without pathological findings (despite multiple somatic malformations) 4. EEGs suggest a generalized epileptogenesis 5. effective reduction of seizures in our sample especially with VPA, LEV, PB, TPM and rather indicate a genetic than a structural etiology of NCBRS. As Coffin-Siris syndrome (CSS) has the same pathomechanism(both caused by gene mutations in “mammalian SWItch/Sucrose Non-Fermentable” complex) these results might also be valid for CSS.