Two new cases of truncating (or nonsense) SCN1A mutations without the severe outcome of Dravet syndrome were described (Takaori, et. al. 2016). One, an 11-year old with approximately one seizure per year on two anti-epileptic medications, showed “moderate mental retardation.” The other, a 4-year old whose only seizures were febrile, showed a “borderline developmental quotient,” reinforcing the theory that not all truncating mutations cause the severe symptoms with which they are often associated.
Clinicians continue to note a variety of connections between SCN1A and the heart. In one case, a five month old girl with an SCN1A mutation and a clinical diagnosis of Dravet syndrome was found to have paroxysmal supraventricular tachycardia (PSVT) during one of her episodes of status epilepticus (Davario, M.D., et. al. 2016). PSVT is a rapid heart rate that starts above the ventricles and has several known causes.
As genetic testing becomes more prevalent and technology improves, researchers are finding that many patients originally thought to be SCN1A-negative do harbor mutations that were missed upon initial testing. Sanger sequencing has been the standard used by testing companies for many years, but is being replaced by next-generation sequencing. In Sanger sequencing, the sample DNA is placed into a machine that replicates segments of the DNA of varying lengths while adding chemically labeled components to the replicated segments. The segments are then separated by length using gel electrophoresis, and the labels on the segments allow a computer program to compare the nucleotide present at each location on the sample DNA with a control nucleotide, noting any differences. This method is difficult to use on larger sequencing projects and is time consuming.
Next-gen sequencing is a term used for many of the newer sequencing methods that produce thousands or millions of sequences from a sample, then use a computer system to theoretically reassemble them based on overlapping areas. These methods can sequence a much larger area of the genome, or even the entire exome, compared with Sanger sequencing.
One genetics lab asked several DNA testing facilities whether they had found samples to be SCN1A-negative using one method of sequencing, but later found a mutation using a different method (Djemie, T. et. al 2016). The lab identified 29 cases of missed mutations. Most of these were missed using Sanger sequencing and identified using next-gen approaches, though one case was identified using Sanger sequencing and missed with a next-gen technique (and the authors acknowledge there is far more Sanger-based data than next-gen data, creating a directional bias). Both techniques have advantages and limitations.
One novel method for compensating for the sodium ion channel deficits in SCN1A-mutated neurons includes upregulating (or increasing the reading of) the healthy copy of SCN1A (Hsiao, et. al. 2016). Remember, every cell has two copies of each gene. In Dravet syndrome, patients have one mutated copy of SCN1A and one healthy copy. This study sought to increase ion channel production from the healthy copy of SCN1A, both in vitro (in the lab) and in vivo (in mice and non-human primates), representing a possible approach to treating Dravet syndrome.
In an attempt to determine why some cases of epilepsy are resistant to pharmacological treatment, the authors studied 130 patients with epilepsy, 50 of whom were drug resistant (El Fotoh, et. al., 2016). They found that two specific SCN1A polymorphisms (or variants of the gene that a significant portion of the population carries, as opposed to the individual mutations patients with Dravet syndrome have) were found more often in patients with epilepsy than in the healthy controls. Interestingly, those SCN1A polymorphisms were also found more often in drug-resistant patients with epilepsy than in drug-responding patients with epilepsy, suggesting they may play a role in both epilepsy and pharmacoresistance.