dravet syndrome , or severe myoclonic epilepsy in infancy , is a rare form of epilepsy which is characterized by impaired psychomotor and neurologic development , occurring in the first year of life in an apparently normal infant .
the actual frequency is not known , but an incidence of < 1 per 40 000 live births and 1/20 000 or 30 000 was reported from the united states and france , respectively .
the disease starts with generalized , unilateral , or alternating unilateral febrile and afebrile clonic seizures in the first year of life . later on , multiple seizure types ,
electroencephalography is normal at onset , but generalized spikes , spike and waves , polyspikes and focal abnormalities appear on follow up .
a family history of febrile seizure and epilepsy is present in2054% of patients with dravet syndrome .
dravet syndrome has a genetic etiology and 7080% of patients carry sodium channel 1 subunit gene abnormalities .
most of the mutations are de novo and they are randomly distributed across the sodium channel 1 subunit protein . truncating mutations account for about 40% and are associated with an earlier age of seizure onset .
missense mutations also account for about 40% , and the remaining are the splice - site mutations .
the clinical and electroencephalography criteria for diagnosing dravet syndrome include ( 1 ) high frequency of familial seizures ; ( 2 ) normal developmental skills before onset ; ( 3 ) generalized , unilateral , or alternating unilateral febrile and afebrile clonic seizures beginning in the first year of life , with subsequent myoclonic and partial seizures ; ( 4 ) normal electroencephalography at onset , with later generalized spike - wave and polyspike wave discharges , focal abnormalities and photosensitivity ; ( 5 ) delayed developmental skills from the second year of life onward ; ( 6 ) refractoriness of seizures to antiepileptic drugs . some patients do not have myoclonic and atypical absences and they are accepted as borderline dravet patients . here , we report two patients with dravet syndrome in whom different mutations were identified in the sodium channel 1 subunit gene .
we also review the mutations of the sodium channel 1 subunit gene that were identified in the turkish population .
the first patient was a 7-year - old boy whose parents were healthy and non - consanguineous .
he was initially given phenobarbital at 6 months of age , but valproate was added at 12 months due to recurrent febrile seizures .
brain mri was normal , but electroencephalography revealed generalized spikes and polyspikes ( figure 1 ) .
the electroencephalographic and clinical findings suggested dravet syndrome and mutation analyses of the sodium channel 1 subunit gene revealed a heterozygous nucleotid substitution in exon 4 ( c.602 + 1g > a ; n.19003 ) .
interictal sleep electroencephalography of a 7-year - old boy with dravet syndrome ( case 1 ) showing frequent generalized spikes .
the second patient was a 6-year - old boy who was the first child of healthy and non - consanguineous parents .
generalized and focal febrile convulsions that were refractory to phenobarbital and valproate treatments continued until 2 years of age . after this age , generalized tonic , clonic , myoclonic and atypical absence seizures started .
electroencephalography of the patient revealed generalized spikes and polyspikes and waves with photosensitivity . despite appropriate combinations of antiepileptic drugs , atypical absences and myoclonic seizures continued with a frequency of 1015 times per day .
mutation analysis of the sodium channel 1 subunit gene revealed heterozygous deletion of five nucleotides in exon 24 ( e24 n.77532 - 535 , c.4486 - 4490delcaaga , p.gln1496argfsx14 ) .
the first patient was a 7-year - old boy whose parents were healthy and non - consanguineous .
he was initially given phenobarbital at 6 months of age , but valproate was added at 12 months due to recurrent febrile seizures .
brain mri was normal , but electroencephalography revealed generalized spikes and polyspikes ( figure 1 ) .
the electroencephalographic and clinical findings suggested dravet syndrome and mutation analyses of the sodium channel 1 subunit gene revealed a heterozygous nucleotid substitution in exon 4 ( c.602 + 1g > a ; n.19003 ) .
interictal sleep electroencephalography of a 7-year - old boy with dravet syndrome ( case 1 ) showing frequent generalized spikes .
the second patient was a 6-year - old boy who was the first child of healthy and non - consanguineous parents .
generalized and focal febrile convulsions that were refractory to phenobarbital and valproate treatments continued until 2 years of age . after this age , generalized tonic , clonic , myoclonic and atypical absence seizures started .
despite appropriate combinations of antiepileptic drugs , atypical absences and myoclonic seizures continued with a frequency of 1015 times per day .
mutation analysis of the sodium channel 1 subunit gene revealed heterozygous deletion of five nucleotides in exon 24 ( e24 n.77532 - 535 , c.4486 - 4490delcaaga , p.gln1496argfsx14 ) .
dravet syndrome is a distinct epileptic syndrome characterized by frequent seizures and impaired neurologic and psychomotor development beginning in the first year of life .
our cases had all the diagnostic criteria of the disease except history of familial seizures . to the best of our knowledge ,
all of these patients had classical findings of the disease and none of them was reported as borderline dravet syndrome .
mutations of the sodium channel 1 subunit gene are responsible for 7080% cases of dravet syndrome . in children with suspected dravet syndrome , the three criteria that best predicted a mutation in sodium channel 1 subunit were reported as seizure exacerbation with hyperthermia , normal development before seizure onset , and the appearance of ataxia , pyramidal signs or interictal myoclonus .
mutations in the sodium channel 1 subunit gene result in either the reduction or complete loss of sodium current or in noninactivating sodium channels with abnormal kinetics .
sodium channel 1 subunit mutations have also been found in generalized epilepsy with febrile seizures plus , infantile spasms and severe epilepsy of infancy .
more than 500 mutations have been reported in dravet syndrome and most of them are de novo .
sequencing mutations are found in about 70% of cases and comprise truncating ( 40% ) and missense mutations ( 40% ) with the remaining being splice - site changes .
phenotype - genotype correlation studies have failed to show a clear relationship between the type of mutation and phenotypic expression . in the study of arlier et al ,
a total of 13 patients from istanbul university cerrahpaa school of medicine with the diagnosis of dravet syndrome were studied and authors reported heterozygous point mutations in six patients ( 46% ) .
two missense mutations ( g2585a , g2860a ) ; one frameshift mutation ( t1033del ) ; two nonsense mutations ( c1738 t , c3733 t ) ; and one splice site mutation ( int14 [ + ] g1a ) were identified .
of the six patients , four of the mutations were novel ( 66% ) , while the other two ( c1738 t , c3733 t ) had been previously reported .
five of the six identified mutations corresponded to coding segments of the sodium channel 1 subunit gene , while one was at a splice site .
two novel missense mutations resulted in theoretical intolerable amino acid changes . a novel deletion in exon 8 , t1033 , is also expected to cause a premature stop codon secondary to frameshift .
a splice site mutation is thought to theoretically compromise the mrna sequence and result in an aberrant protein product . in the case of gkben
et al , mutation analysis in the proband revealed a heterozygous silent nucleotide substitution in exon 9 ( c.1245a > g ; p.v415v ; rs7580482 ) and a nonsense amino acid mutation in exon 26 ( c.4933 c > t ; p.r1645x ) .
the r1645x mutation is located in the d4 / s4 domain that is implicated in voltage sensing of fast inactivation .
the same nucleotide substitutions in exon 9 and exon 26 were also found in the father .
although the patient and father shared the same nonsense mutation , their clinical phenotypes were completely different .
the father had only a few febrile seizures during childhood , but his daughter had dravet syndrome .
the mutation in our first patient was a splice donor mutation which impaired the splicing of mrna .
the mutation identified in the second patient was a novel frame shift mutation that resulted from the deletion of five nucleotides in exon 24 .
taken together , the diagnosis of dravet syndrome is easier in patients presenting with typical clinical findings , but the diagnosis is difficult in patients whose seizures are atypical and/or the psychomotor development is normal .
sodium channel 1 subunit gene mutations are not found in all patients and genotype - phenotype correlations are not elucidated .
defining the clinical and genetic features of more cases with dravet syndrome should provide new insights for the disease .
 dravet syndrome is a rare epileptic encephalopathy characterized by frequent seizures beginning in the first year of life and behavioral disorders . 
 mutations in the sodium channel 1 subunit gene are the main cause of this disease . 
 we report two patients with refractory seizures and psychomotor retardation in whom the final diagnosis was dravet syndrome with confirmed mutations in the sodium channel 1 subunit gene . 
 the mutation identified in the second patient was a novel frame shift mutation , which resulted from the deletion of five nucleotides in exon 24 . 