Mutations of SCN1A were evident in 16 of 69 children. No individual criterion of the International League Against Epilepsy was 100% accurate in predicting the presence of a mutation in SCN1A, which supports the idea that a syndrome is involved that requires the presence of multiple factors to establish a diagnosis. The three criteria that best distinguished mutation-positive from mutation-negative children comprised exacerbation with hyperthermia, normal development before the onset of seizures, and the appearance of ataxia, pyramidal signs, or interictal myoclonus. These criteria remained significant after correction for multiple comparisons ( and ). Using either exacerbation with hyperthermia or normal development before the onset of seizures as the sole factor in the decision to perform mutation testing in children with features broadly consistent with Dravet syndrome (i.e., a sample similar to the one in this study) would yield a sensi- tivity of 94% and a specificity of about 60%. This strategy would reduce the number of children tested by approximately 50%, but would result in missing approximately 5% of diagnoses. Using the criterion regarding the appearance of ataxia, pyramidal signs, or interictal myoclonus yields a sensitivity of 63% and specificity of 72%, and would not in itself provide effective guidance in testing.
Figure 1 Frequency of ILAE criteria in mutation-positive vs mutation-negative patients. Mutation-positive frequencies are indicated in dark gray, and mutation-negative frequencies are indicated in light gray. AEDs, antiepileptic drugs; Dev’t, development; (more ...)
Because this study is retrospective, we do not know exactly why each clinician ordered SCN1A mutational analysis. However, a care-ful review of clinical data suggests that the main reasons for ordering the test included intractability (i.e., resistance to multiple antiepileptic drugs), multiple seizure types, specific electroencephalogram features, and psychomotor retardation, which were present in ≥80% of all 69 patients tested. Each of the neurologists who treated patients with intractable epilepsy sent at least one test. indicates that intractability was present in 100% of mutation-positive patients. This intractability may explain why patients as young as 2 months of age were tested. Our findings, therefore, are relevant for clinicians who emphasize a high-sensitivity approach to genotype testing, but who wish to narrow their test population according to the most predictive clinical features.
A molecular diagnosis provides a foundation for expert-consensus medical treatment and discussions about prognosis, and therefore demonstrates high clinical value. In our study sample, the presence of at least four of nine criteria from the International League Against Epilepsy was 100% sensitive (negative predictive value,100%) for a positive SCN1A mutation, with a positive predictive value of 26%. Using this result as a decision point for mutational testing does not greatly reduce the number of children tested. However, it offers a reasonable high-sensitivity strategy for testing.
At the time of our chart review, four of our 16 mutation-positive patients met all nine criteria for Dravet syndrome. The question of whether the remaining 12 mutation-positive patients manifest a variant of Dravet syndrome (e.g., severe myoclonic epilepsy in infancy or borderline Dravet syndrome) is not as easily answered. The syndrome of severe myoclonic epilepsy in infancy was defined as “children who lack several of the key features” of severe myoclonic epilepsy in infancy by Harkin et al. [3
], who further subdivided these children according to the missed feature of severe myoclonic epilepsy in infancy. They included the category of severe myoclonic epilepsy in infancy-O, which they defined as “patients who had more than one feature that was not in keeping with” severe myoclonic epilepsy in infancy [3
]. In a study by Fukuma et al. [16
], patients with borderline myoclonic epilepsy in infancy were defined as lacking myoclonic seizures. However, patients with atypical absence seizures were placed in a group with severe myoclonic epilepsy in infancy, regardless of the presence or absence of myoclonic seizures [16
Mutations in SCN1A
of clinical significance were evident in 23% of our tested patients. This frequency is lower than that previously reported by Nabbout et al., who reported a frequency of 35% in a group of 93 patients who fulfilled all nine criteria for Dravet syndrome [9
]. This finding suggests that a relatively broad testing strategy was used in our clinic, based on an expectation of variable phenotypes within the SCN1A
Several other clinical features in our sample bear emphasis. The incidence of status epilepticus in Dravet syndrome was reporte at 67-77%, which is consistent with our findings of status epilepticus in 14 of 16 patients (88%) either before or after age 1 year [19
]. A family history of febrile seizures or epilepsy was reported in 44% of mutation-positive patients vs 32% of mutation-negative patients, which is consistent with the incidence of 25-64% reported by Dravet et al. [6
In our study, the mutation-positive patients who met at least eight of the International League Against Epilepsy criteria for Dravet syndrome were more likely to manifest a truncation mutation (six of nine patients). Location also affects severity insofar as mutations in severe myoclonic epilepsy in infancy occurred more frequently in the pore-forming region of the gene [8
]. The mutations in our 16 mutation-positive patients most frequently located in the pore-forming region of the gene.
The limitations of this study include those inherent to retro-spective studies, primarily involving biases related to clinicians’ decisions about testing. In addition, the majority of patients underwent SCN1A DNA sequence analysis only. These patients were examined before the commercial availability of multiplex ligation-dependent probe amplification testing. As a result, some duplications or deletions of the SCN1A gene may have been missed in our mutation-negative patients.
As we were performing our chart reviews, we had to make a few assumptions based on the limited amount of clinical data available at the time of the study. For the electroencephalographic criteria, if a patient demonstrated any one of the three electroencephalogram features defined by the International League Against Epilepsy, we considered that a positive finding. For pleomorphic epilepsy, if a patient manifested more than one type of seizure listed in the International League Against Epilepsy criteria, we considered that a positive finding. If ataxia, pyramidal signs, or interictal myoclonus were not documented in the chart, we assumed that to be a negative finding. We included febrile seizures in determining the presence of exacerbation by hyperthermia. If a chart did not mention exacerbation with hyperthermia, we assumed that the patient did not meet that criterion.
Dravet syndrome is an epileptic encephalopathy that can present with prolonged febrile seizures in previously healthy children before age 1 year. This clinical picture shares similarities with several other disorders in their early stages. Patients with SCN1A mutations may be diagnosed with complex febrile seizures upon initial evaluation. The full phenotype often does not become apparent until after age 2 years, delaying genetic testing for clinicians who do not consider Dravet syndrome in their differential diagnosis because of a lack of familiarity with the disorder.