Inherited SCN1A missense mutation in a Dravet Syndrome family: Neuropathological correlation, family screening and implications for adult carriers

Introduction: Neuropathological findings in Dravet Syndrome (DS) are scarce, especially in adult patients, and often do not have a genetic confirmation. Additionally, the missense SCN1A pathogenic variant found has only been described as de novo mutation in previous literature.

Methods: We describe the clinical and genetic findings of a family (including three sisters and his father), using Sanger sequencing in the three sisters and in postmortem brain tissue in the father. The present study also shows the neuropathological findings of the father.

Results: Despite the presence of long term drug resistant epilepsy, starting with febrile seizures between 6 and 12 months of age, and intellectual disability (ID), the three sisters were diagnosed with DS in adulthood, identifying a missense SCN1A pathogenic variant in exon 20, previously described as de novo -p.Gly1332Glu (c .3995 G>A). The oldest sister had the most severe phenotype, with severe ID and wheel chair dependency, passing away at 52. The other two sisters had a moderate phenotype, being at the present seizure free, but with significant comorbidities, such as crouch gait and parkinsonism. Several relatives from the paternal path (including the father) presented epilepsy, but without ID. The father was diagnosed with Alzheimer´s Disease (AD) at 60, and because he donated his brain, the same variant was confirmed in postmortem study. Neither the MRI nor the histopathology showed specific morphological changes for DS, consistent with previous studies.

Conclusions: This work supports the need to review the clinical and genetic spectra of DS in adults with epilepsy and unknown ID. The clinical consequences of this syndrome seem to have a functional rather than a structural basis, supported by the absence of specific neuropathological findings.