Authors :
Presenting Author: Alex Dudley, MB BCh BAO – Beaumont Hospital, Ireland
Javier Pena-Ceballos, ANP – Beaumont Hospital, Ireland
Hany El-Naggar, Consultant Neurologist – Beaumont Hospital, Ireland
Patrick Moloney, Consultant Neurologist – Mater Hospital, Ireland
Norman Delanty, Consultant Neurologist – Beaumont Hospital, Ireland
Rationale:
Dravet syndrome (DS) is a rare and severe developmental and epileptic encephalopathy (DEE). Although seizure onset is in infancy, some adults with DS remain undiagnosed and therefore inappropriately treated. In adults, one challenge is distinguishing DS caused by loss-of-function (LOF) SCN1A variants from early infantile developmental and epileptic encephalopathy (EIDEE) caused by a gain-of-function (GOF) SCN1A variants . This distinction is critical as the use of sodium channel blockers (SCB’s) may contribute not only to worse seizure control in DS but is associated with poorer cognitive skills, adaptive skills, mobility, and parkinsonian features. 1 In contrast, SCB’s are effective in over 70% of SCN1A GOF DEE’s.2
Methods:
We reviewed our electronic patient record identifying adults with drug resistant epilepsy (DRE) and intellectual disability (ID) who had SCN1A variants identified in the last 4 years.
Results:
We identified four adults with DEE’s and SCN1A variants. It is remarkable that although the age at first seizure ranged from day one of life to 11 months, the age at molecular diagnosis was 39-48 years. All patients have ongoing DRE and moderate-severe ID. All patients were treated with SCB’s prior to molecular diagnosis.
While structural brain imaging was normal, EEG was abnormal, including video-EEG monitoring in three patients. Genetic testing identified pathogenic or likely pathogenic SCN1A variants in three patients, including two missense (c.3620T >C,c.748G >A), and one intronic variant (c.2589+3A >T). Genetic testing in the fourth patient led to a detailed review of childhood records and a clinical diagnosis of DS, but the variant is of uncertain significance (c.1191A >C). Interpreting variants in adults can be more challenging without segregation data.
DS was diagnosed in three patients, one of whom is three years seizure free after withdrawal of lamotrigine. Importantly however the fourth patient with a c.748G >A variant had a GOF effect predicted based on the Heyne model and SCB response. His seizures began on day one of life, and he had perioral hyperkinetic movements. Genetic testing resulted in a diagnosis of SCN1A EIDEE. Due to recurrent and prolonged myoclonic-tonic-clonic seizures, his rescue medication was changed from benzodiazepines to buccal fosphenytoin which has effectively reduced the frequency of status epilepticus.
Conclusions:
Genetic testing should be considered in all adults with unexplained DRE and ID. When an SCN1A variant is identified, it is important to consider the phenotype, the variants pathogenicity and its function. These cases highlight the significant impact on seizure control and quality of life that a change in SCB’s can have, even in adults. Making an accurate diagnosis is increasingly important as more therapies become available and we take a step closer to precision medicine.
Funding:
This research received no specific grant from any funding agency in the public, private, or not-for-profit sectors.