Explaining variants of uncertain significance – a guide for clinicians

VUSThe dreaded variant of uncertain significance. With the advent of next generation sequencing panels and exome sequencing, what used to be an occasional laboratory finding in epilepsy has now become a daily occurrence. Lab reports detailing multiple VUS findings for an individual patient have become a routine part of clinical practice. How do you, as a healthcare provider, explain the meaning and implications of VUS findings to patients and families in a way that is understandable to them?  Continue reading

TBC1D24 – what’s new in 2016?

The story of TBC1D24. As with many epilepsy genes, the TBC1D24 story increases in complexity over time. Initially described to be associated with autosomal recessive familial infantile myoclonic epilepsy by Falace and colleagues and with autosomal recessive focal epilepsy by Corbett and colleagues in 2010, pathogenic variants in TBC1D24 have since been identified as a major cause of DOORS syndrome and have also been identified in individuals with familial malignant migrating partial seizures of infancy, progressive myoclonus epilepsy, early-onset epileptic encephalopathy, and autosomal dominant and autosomal recessive non-syndromic hearing loss. However, little is known about a potential genotype-phenotype correlation of TBC1D24-related disorders, as well as the underlying mechanism. Keep reading to learn more about recent discoveries related to TBC1D24. Continue reading

The genetic sibling of NMDA receptor encephalitis

GRIN1 encephalopathy. In the early 2000s Dalmau and collaborators observed a condition in women with ovarian teratoma who presented with psychosis or memory problems and rapidly progressing neurological deficits that required prolonged intensive care support. Auto-antibodies against the NR1 subunit of the NMDA receptor were found to be the causative agent. The clinical spectrum of anti-NMDA-receptor encephalitis has since expanded significantly and this initial discovery fueled the discovery of an entirely disease mechanism, the concept of the autoimmune encephalitis. In a recent publication in Neurology, we describe a novel neurodevelopmental syndrome affecting the gene for the NR1 receptor, the genetic sibling of NMDAR encephalitis. This blog post is about the unexpected overlap of autoimmune disorders with the genetic epilepsies and the spectrum of GRIN1-related genetic encephalopathies. Continue reading

Closing the knowledge gap – this is SYNGAP1

Mind the Gap. Ever since its discovery in 2009, SYNGAP1 has been a prominent gene connected to autism and intellectual disability. However, even though probably more than half of all patients with pathogenic SYNGAP1 variants have seizures, it was never a gene that was particularly prominent in the epilepsy field. In a recent publication, we were able to delineate the epilepsy phenotype of patients with pathogenic SYNGAP1 variants, identifying a peculiar combination of generalized seizures types. Here is a blog post about a gene that I admittedly knew very little about before we started working on it. Continue reading