THE FIRST CASE OF BENIGN FAMILIAL NEONATAL EPILEPSY DIAGNOSED IN SERBIA

Introduction. The exact prevalence of Benign Familial Neonatal Epilepsy (BFNE) is unknown due to the likelyhood of overlooking the disease and not diagnosing affected patients correctly. The rare autosomal dominant inherited disorder occurs usually within a few days after birth to an otherwise healthy newborn, and disappears after one to four months. Most patients develop no psychomotor deficiencies, nor any other forms of seizures. The disorder is most commonly linked to the KCNQ2 gene, with mutations located on chromosome 20q13.33; which cause voltage gated potassium channel changes. This clinically rare condition presents as repeated tonic-clonic episodes of focal and generalized convulsions; which is effectively treated with anti- epileptic therapy. Case report. We describe a five-day old affected male infant, with genetically proven KCNQ2 gene mutation, in addition to a positive familial history of epilepsy, with verified KCNQ2 gene mutations. Seizures did not reoccur after several episodes in the fifth day of life and further psychomotor development of the child was proved normal. Conclusion. Neonatal seizures have extensive differential diagnosis. However, BFNE should be suspected when the most common neonatal seizure causes have been excluded, and factors such as the hereditary factor in addition to the typical clinical course resembling BFNE, can be observed. Genetic identification of BFNE has resulted in easier and more specific diagnosis of this rare neonatal seizure disorder and is therewith the GOLD standard diagnostic measurement for this disorder.

3 Abstract Introduction. The exact prevalence of Benign Familial Neonatal Epilepsy (BFNE) is unknown due to the likelyhood of overlooking the disease and not diagnosing affected patients correctly. The rare autosomal dominant inherited disorder occurs usually within a few days after birth to an otherwise healthy newborn, and disappears after one to four months. Most patients develop no psychomotor deficiencies, nor any other forms of seizures. The disorder is most commonly linked to the KCNQ2 gene, with mutations located on chromosome 20q13.33; which cause voltage gated potassium channel changes. This clinically rare condition presents as repeated tonic-clonic episodes of focal and generalized convulsions; which is effectively treated with anti-epileptic therapy.
Case report. We describe a five-day old affected male infant, with genetically proven KCNQ2 gene mutation, in addition to a positive familial history of epilepsy, with verified KCNQ2 gene mutations. Seizures did not reoccur after several episodes in the fifth day of life and further psychomotor development of the child was proved normal.
Conclusion. Neonatal seizures have extensive differential diagnosis. However, BFNE should be suspected when the most common neonatal seizure causes have been excluded, and factors such as the hereditary factor in addition to the typical clinical course resembling BFNE, can be observed.
Genetic identification of BFNE has resulted in easier and more specific diagnosis of this rare neonatal seizure disorder and is therewith the GOLD standard diagnostic measurement for this disorder. should be treated. However, to prevent damage due to seizure attacks, anti-epileptic therapies are advised to be administered for no longer than six months 4 .
Most cases have shown no psychomotor development impairment after the seizures, however some studies may suggest otherwise. In one hand, the risk for subsequent occurrence of febrile seizures is stated to be 5%, which corresponds to the average frequency in the general population; on the other hand, a significantly higher risk with 11 % of subsequent epilepsy could be observed, which differs to the general population 5  Hence the well-established connection of potassium gated channel dysfunctionality, the neurological hyperexcitability is likely to be due impaired repolarization of action potentials.
Besides potassium, calcium channel and nicotinic acetylcholine receptor subunit defects, some biochemical markers are known as specific diagnostic measurements of neonatal epilepsy conditions 12 . Besides routine testing for sepsis, serum electrolyte markers; such as hyponatremia, hypocalcemia and hypoglycemia, have been found to be another possible metabolic cause of these conditions 13,14 . However in BFNE it is important to note that neither infectious, nor metabolic disturbances are the cause of disease but rather the M-type potassium channel protein disinhibition due to genetic mutation 15 .
In this report we present the first recorded patient in Serbia with suspicious clinical and genetically proven diagnosis of Benign Familial Neonatal Epilepsy.

Case Report
A five-day old male infant was referred to our Neonatal Unit in Belgrade, Serbia; due to recurrent episodes of afebrile seizures.
The patient was born to a 32-year-old mother by caesarian section due to placenta previa at 37, 2 gestational weeks. At birth, his Apgar scores were 9 and 9, at 1 and 5 min, respectively. After the delivery, the fetus received Vitamin K and Hepatitis B vaccine. He was the second child of healthy parents without any complications during pregnancy up to the delivery. Historically, the 32-yearold healthy father, confirmed a positive history of neonatal seizures for himself. He reported to have 6 taken Phenobarbital therapy up to 3 years of age. Also, the patient's elder female sibling, was reported to have had seizures starting at three days of age, reoccurring at six weeks and three months of life. She was given an oral sodium-valproate therapy up to four years of age, with no reoccurring seizures after (Figure1).
The male neonate presented at our clinic with 3200 g, a length of 57 cm and head circumference of 36 cm (97 percentile). The infant presented in a conscious and overall healthy appearance, with normal tolerance of oral feedings and no other pathological signs.
The seizures appeared as tonic-clonic with the limb's involvement, which were reported by the mother to have first occurred on the left leg of the infant, expanding after the first episode with seizing to the right arm. The seizures lasted 5-10 seconds, and would reoccur at 5-10 minutes. The  4 . However many more severe and more prevalent differential diagnosis, such as; hypoxicischaemic encephalopathy (40-60%), intra cranial hemorrhages (7-18%), cerebral infarctions or malformations (6-17%, and 3-17 % respectively), meningitis/septicaemia (2-14%), electrolyte disturbances (1-4%), inborn errors of metabolism (1-4%), maternal drug withdrawal, but also Benign Non-Familial Neonatal Epilepsy have to be excluded before making a definite diagnosis of BFNE 16 . Similar to other etiologies benign neonatal seizures need to be excluded. Genetic testing may be done to confirm the diagnosis. Table 1 As Q. Zeng et. al. have summarized KCNQ2 to be the most causative gene for BFNE 17 , we would like to highlight the importance of early genetic screening to exclude more harmful disease aetiologies, such as the pathologies mentioned before. However, due to the heterozygous state of the genetic substitution, a frameshift or other forms of mutations of KCNQ2 could be expected, leading to possible pathologic states, such as neonatal seizure encephalopathy 17 . In our case, the gene sequence analysis showed a stop codon (p.Glu130*) which leads to potassium channel inhibitions. Therefore, it is according to our knowledge, also necessary to work on further investigations of potassium-channel-opening drugs, in addition to more antenatal routine genetic analysis in positive family history of BFNE individuals.

Conclusion
BFNE is an autosomal dominant inherited disorder, affecting neonates up to six months of age. Due to the genetic heterozygous mutations of the KCNQ2 gene, M-ligated potassium channel disruption cause hypopolarization of action potentials leading to tonic-clonic seizures. The disorder is treated effectively with anti-epileptic agents, with Phenobarbital as first choice. In our opinion more research about potassium-channel-opening drugs should be performed, with emphasis of how antenatal genotyping could benefit individuals affected by BFNE with preventive treatment during the postnatal period. According to our knowledge, a low rate of BFNE patients may suffer from psychomotor development delay, reoccurring epilepsy or even progress to neonatal seizure encephalopathy 18 . In summary, genetic identification of BFNE has resulted in easier and more specific diagnosis of this rare neonatal seizure disorder and is there with the GOLD standard diagnostic measurement for this disorder.

Conflicts of Interest Statement
The authors have no conflict of interest to declare.