among the neonatal seizure syndromes , benign familial neonatal convulsions ( bfnc ) , a rare autosomal dominant epilepsy characterized by unprovoked , generalized convulsions occurring in the first days of life , must be differentiated from non - epileptic paroxysmal events of the newborn and from other etiologies of neonatal seizures .
the seizures are characterized by generalized hypertonia with apnea and cyanosis , followed by head movement and/or clonic or tonicclonic limb jerks ( 1 ) .
most patients are seizure - free by 6 months of age , and psychomotor development in affected children is usually normal ( 2 ) .
although bfnc represent a benign epilepsy syndrome , between 10% and 16% of patients experience seizure recurrence at a later time ( 1 ) .
the idiopathic epilepsies , among which bfnc was listed , have been regarded as genetic in origin .
this presumption was confirmed by the identification of mutations in kcnq2 and kcnq3 in families with bfnc .
five individuals in 3 generations were affected , and molecular analysis disclosed a kcnq2 mutation .
a female infant weighing 2.8 kg was born at 39 weeks , 2 days gestation to a 28-yr - old mother after an uncomplicated pregnancy . on the 3rd day of life , she presented with three brief generalized tonic seizures with upward deviation of the eyes and cyanosis of the lips which lasted approximately one minute .
electrolytes , calcium , glucose , cerebrospinal fluid examination , brain magnetic resonance imaging and electroencephalography ( eeg ) were all normal .
she was discharged after 3 days without further seizures on phenobarbital . in follow - up , her phenobarbital was weaned at 3 months of age , but her seizures recurred 1 month later .
her eeg showed several spike discharges originating from the left and right central - temporal areas at that time .
phenobarbital was restarted and tapered off successfully without any seizure recurrence at 7 months of age .
detailed review of her family history revealed five affected family members , in three separate generations , who experienced similar neonatal convulsions , including the patient 's grandfather , father , paternal uncle , and cousin ( fig .
ia ( grandfather ) : patient ia had 3 convulsions within the 1st month of life , but no further seizures after those initial episodes .
iic ( paternal uncle ) : this patient experienced 5 convulsions within the first 3 months of his life .
iie ( father ) : he experienced a single convulsion on the 2nd day of life .
iiic ( a cousin ) : eight months - old at the time of this writing .
although he experienced 6 convulsions within the 6 months of life , he has shown normal development . in sum , despite multiple infantile seizures , no epilepsy or psychomotor dysfunction occurred in any affected family members even without the use of antiepileptic drugs . to search for mutations in kcnq2 in the pedigree , 16 exons and adjacent short intronic sequences of the gene were amplified by polymerase chain reaction ( pcr ) with dna obtained from the affected individuals .
sixteen exons of the kcnq2 gene and their intronic flanking sequences were amplified by pcr using a total of 19 sets of primers with exon 1 split into two and exon 6 into three primer pairs .
genetic study revealed an r448x mutation located in the c - terminal segment of kcnq2 in the family members with neonatal seizures ( ia , iie , iiid , fig .
a female infant weighing 2.8 kg was born at 39 weeks , 2 days gestation to a 28-yr - old mother after an uncomplicated pregnancy . on the 3rd day of life , she presented with three brief generalized tonic seizures with upward deviation of the eyes and cyanosis of the lips which lasted approximately one minute .
electrolytes , calcium , glucose , cerebrospinal fluid examination , brain magnetic resonance imaging and electroencephalography ( eeg ) were all normal .
she was discharged after 3 days without further seizures on phenobarbital . in follow - up , her phenobarbital was weaned at 3 months of age , but her seizures recurred 1 month later .
her eeg showed several spike discharges originating from the left and right central - temporal areas at that time .
phenobarbital was restarted and tapered off successfully without any seizure recurrence at 7 months of age .
detailed review of her family history revealed five affected family members , in three separate generations , who experienced similar neonatal convulsions , including the patient 's grandfather , father , paternal uncle , and cousin ( fig .
ia ( grandfather ) : patient ia had 3 convulsions within the 1st month of life , but no further seizures after those initial episodes .
iic ( paternal uncle ) : this patient experienced 5 convulsions within the first 3 months of his life .
iie ( father ) : he experienced a single convulsion on the 2nd day of life .
iiic ( a cousin ) : eight months - old at the time of this writing .
although he experienced 6 convulsions within the 6 months of life , he has shown normal development . in sum , despite multiple infantile seizures , no epilepsy or psychomotor dysfunction occurred in any affected family members even without the use of antiepileptic drugs . to search for mutations in kcnq2 in the pedigree , 16 exons and adjacent short intronic sequences of the gene were amplified by polymerase chain reaction ( pcr ) with dna obtained from the affected individuals .
sixteen exons of the kcnq2 gene and their intronic flanking sequences were amplified by pcr using a total of 19 sets of primers with exon 1 split into two and exon 6 into three primer pairs .
genetic study revealed an r448x mutation located in the c - terminal segment of kcnq2 in the family members with neonatal seizures ( ia , iie , iiid , fig .
bfnc remains a diagnosis of exclusion , since many neonates present with cryptogenic convulsions associated with uncertain outcomes .
symptomatic neonatal seizures , secondary to hypoxic - ischemic - encephalopathy , metabolic disturbances or to an infectious process should be ruled out .
subsequently , the finding of self - limited neonatal seizures in multiple affected family members can clinch the diagnosis .
the kcnq2 and kcnq3 genes encode the heteromeric assembly of subunits through which muscarinic - regulated potassium current ( m - current ) , a primary regulator of neuronal excitability , is established ( 3 ) .
the functional analysis of mutations thus far has indicated that a partial loss of activity of the k+ current is sufficient to produce epilepsy , and dominant negative mutations in kcnq2 or kcnq3 can result in a more severe phenotype ( 4 ) . in our case , the family history given by the grandmother of the proband was key to the diagnosis , and further genetic study identified a putative causative mutation in kcnq2 , the r448x ( 5 , 6 ) . consistent with prior cases of r448x ( 5 ) , none of our patients have experienced seizures outside of infancy .
interestingly , the kcnq2 c - terminal truncation mutant r448x has been shown to reduce the potassium current by < 50% and to cause no changes in the ion channel 's biophysical properties ( 6 ) . given recent findings that ion channels may regulate diverse cellular functions in addition to their current conduction properties , this finding may suggest that another property of the kcnq2 may be involved in its epileptogenic properties .
( 7 ) have demonstrated simultaneous high expression of kcnq2 and kcnq3 in human brain from late fetal life through infancy , coinciding with the time that bfnc occurs .
such developmental changes in potassium channel activity in the developing brain may explain the age - dependent expression of bfnc . however , inter - familial differences in susceptibility to subsequent febrile or afebrile seizures ( 1 , 8) have been observed , and further genotype - phenotype correlations may facilitate our understanding of this condition . due to the immaturity of neonatal brain structures ,
analyzing the ictal phenomenology and eeg and definitive classification of bfnc is still difficult . on the other hand ,
bfnc shares features with benign rolandic epilepsy , the most common idiopathic localization - related epilepsy , including its age - dependency and presence of centrotemporal spikes ( 9 , 10 ) . in our study , the index case showed intermittent right or left centrotemporal sharp wave discharges , and the seizures observed were generalized tonic seizures .
it is thought that as data accumulates , the electroclinical features of the ictal , interictal and follow - up eeg may yield insight into the mechanism of seizure generation . in conclusion ,
 neonatal seizures represent a heterogeneous group of disorders with vastly different etiologies and outcomes . 
 benign familial neonatal convulsions ( bfnc ) are a distinctive epileptic syndrome of autosomal dominant inheritance with a favorable prognosis , characterized by the occurrence of unprovoked partial or generalized clonic seizures in the neonatal period or early infancy . 
 recently , mutations in two potassium channel genes , kcnq2 and kcnq3 , have been described in this disorder . in this report 
 , we describe a family with bfnc due to a kcnq2 mutation , the first such family to be described in the korean population . the diagnosis of bfnc can be made based on clinical suspicion and careful history taking with special emphasis on the familial nature of the disorder . 
 kcnq2 mutations may be associated with bfnc in a number of different races , as has been reported in other ethnic groups . 
INTRODUCTION
CASE REPORT
Index case (IIId)
Patients
DISCUSSION