Is it Dravet? SCN1A gene testing provides answers, guides treatment.
Mutations in other genes drive diseases with similar symptoms, study shows
Written by |
Diseases that mimic Dravet syndrome symptoms are usually caused by mutations in genes other than SCN1A — the gene most often mutated in Dravet — and identifying the exact genetic cause, through testing, is key to guiding appropriate treatment strategies, according to a new study from China.
While most patients in the study were found to carry mutations in the SCN1A gene, the researchers also identified alterations in nine other genes that cause Dravet-like symptoms, which include frequent seizures and mild developmental delays. Some of these mutations responded well to medications that should be avoided by those with Dravet, the scientists noted.
“These findings underscore the critical role of genetic testing in refining diagnosis [in Dravet] and enabling precision therapy,” the researchers wrote, adding that the study, overall, “expands the genetic spectrum of [Dravet syndrome-like diseases] and provides actionable insights for clinical management.”
Titled “Genotypic spectrum in 1215 patients with Dravet syndrome or Dravet syndrome-like phenotype,” the study was published in the journal Pediatric Research.
According to Anita N. Datta, MD, a clinical associate professor of pediatrics at the University of British Columbia in Canada, who wrote a comment on the study, “careful clinical assessment remains indispensable.”
Her comment, “Beyond SCN1A: genetic diversity in Dravet syndrome-like phenotype and the path to precision treatment,” was also published in Pediatric Research.
Advances in genetic testing have improved Dravet diagnosis
Dravet is a severe type of epilepsy that begins in early childhood and is most often caused by mutations in the SCN1A gene. These mutations are thought to disrupt normal communication between nerve cells in the brain, leading to the frequent seizures that are the disease’s hallmark. Other symptoms of Dravet include cognitive, behavioral, and motor problems.
Some patients have symptoms similar to those of Dravet but do not carry mutations in the SCN1A gene. Advances in genetic technology have led to the identification of other genes linked to Dravet-like symptoms, broadening the range of known genetic causes.
In this study, the researchers collected data from 1,215 patients diagnosed with Dravet syndrome or Dravet-like diseases. Most (87.3%) carried mutations in SCN1A.
Still, mutations in nine other genes — PCDH19, GABRA1, GABRB2, GABRG2, GABRB3, HCN1, SCN2A, TBC1D24, and ALDH7A1 — were identified in 31 patients with Dravet-like symptoms, the researchers noted.
Of the 1,061 patients with mutations in SCN1A, 57 (5.3%) were identified only by next-generation sequencing, an advanced genetic technology that can read many genes simultaneously and in great detail.
Such sequencing can detect genetic mutations that older technologies may miss.
“Unresolved cases should not be viewed as diagnostic endpoints,” Datta wrote, adding that “continued reanalysis … can reveal [disease-causing] variants that escape initial detection.”
Symptoms begin early for patients with SCN1A mutations
Among patients, Dravet syndrome linked to SCN1A usually began manifesting early. Most individuals developed seizures between 3 and 12 months of age. The most common types were generalized tonic-clonic seizures, in which stiffening and jerking affect the whole body, and hemi-clonic seizures, which affect one side of the body. All patients were highly sensitive to fever, which often triggers seizures.
Nearly all experienced status epilepticus, meaning seizures lasted more than five minutes or occurred repeatedly without recovery. Most seizures occurred in clusters, meaning they occurred close together, and many were triggered by light. Many patients also developed motor problems, such as poor balance or abnormal posture, or presented autistic features.
Some antiseizure medications, including oxcarbazepine, lamotrigine, and lacosamide, worsened seizures in many patients with mutations in SCN1A. These medications are sodium channel blockers, and they should be avoided in Dravet patients, research has shown. Because SCN1A mutations typically result in a loss of function in sodium channels within certain neurons, adding a sodium channel blocker further reduces the activity of these neurons, leading to more seizures.
A small proportion of patients — slightly more than 13% — remained free of seizures for one year or longer.
Some patients had Dravet-like symptoms caused by mutations in PCDH19 or genes encoding GABA receptors, which are proteins that inhibit brain activity. These patients sometimes responded better to treatment. Medications such as valproate and topiramate helped by stabilizing brain activity and enhancing inhibitory signals, reducing seizures, the researchers found.
One patient with a mutation in the SCN2A gene improved with oxcarbazepine because the mutation increased brain activity, so blocking sodium channels was effective. Two patients with mutations in the LDH7A1 gene responded well to pyridoxine (vitamin B6), data showed.
[Comprehensive genetic testing] should be considered standard of care.
An electroencephalogram (EEG), which records electrical activity, and MRI scans were used to support a diagnosis. EEG often showed abnormal brain activity, whereas MRI scans were usually normal. However, some patients showed changes after prolonged seizures, the researchers noted.
For Datta, “integrating detailed clinical characterization with genetic diagnosis will be central to advancing precision medicine, while preserving diagnostic frameworks that connect affected families to appropriate resources and support networks.”
Overall, comprehensive genetic testing “should be considered standard of care,” Datta said.
