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Historical Note and Nomenclature
Antoni described a hereditary form of neonatal seizures with good outcome for neurologic development (Antoni 1941). Rett and Teubel reported the second case of benign neonatal familial seizures (Rett and Teubel 1964). The first case reported in the English literature appeared in 1968 (Bjerre and Corelius 1968). Since 1989 benign-familial neonatal seizures have appeared in the classification of epilepsy and epilepsy syndromes. They are classified in the chapter of Idiopathic Generalized Epilepsies.

Clinical Manifestations
In the majority (54%) of reported neonates with this disorder, seizures begin by 2 to 8 days of life and remit by 16 months (Zonana et al 1984; Miles and Holmes 1990). In several cases (31%), seizures initially appeared after the first week of life but during the neonatal period. The remaining patients had onset of seizures before 3.5 months (Miles and Holmes 1990). Infants born prematurely will have seizure onset at an older chronological age than infants born at term.

Seizures occur in full-term neonates without any known precipitating factors after a normal pregnancy and delivery (Plouin 1990). Both the physical examination and laboratory tests are normal prior to, between, and after the seizures. Psychomotor development is normal in most children, but risk of seizure disorders in later life is increased (Zonana et al 1984). A family history of similar seizures can be traced in all children affected with benign-familial neonatal seizures. The seizures may be either focal clonic or with a generalized tonic-clonic component and are often accompanied by episodes of apnea (Commission on Classification and Terminology of the International League Against Epilepsy 1989). Only 1 case is reported of a patient who experienced tonic seizures (Petit and Fenichel 1980). The seizures are brief, usually 1 to 2 minutes (Miles and Holmes 1990). The frequency of seizures may be as high as 20 to 30 episodes per day (Zonana et al 1984).

Video tape recordings with EEG have been reported in at least 6 babies (Hirsch et al 1993; Bye 1994; Plouin 1997). In most cases the seizures start with a tonic component, followed by various autonomic and motor changes, which can be unilateral or bilateral and symmetric or asymmetric. Generalized seizures have not been reported.

Clinical Vignette
An infant presented with a flurry of seizures on the third day of life. The seizures were characterized by bilateral tonic posturing followed by asynchronous, clonic movements of the face and all 4 extremities. In between the ictal events, the baby continued to behave normally and ate at regular intervals. Video EEG showed partial seizures affecting either side of the body during different bouts. The EEG tracing showed diffuse attenuation of background frequencies followed by rhythmic centrotemporal discharges; there was no consistent lateralization as the seizure discharges were at times more prevalent on the right side and on other occasions more prevalent on the left side. The interictal tracing was normal. The seizures persisted for 48 hours. The infant was treated with phenobarbital; the seizures stopped within 48 hours and did not recur. Phenobarbital was discontinued at 3 months.

The baby was The product of full-term pregnancy and uncomplicated delivery, with a birth weight of 3.5 kg.

The family history was significant for neonatal seizures on the paternal side including the father, 1 aunt, the grandmother, and a second cousin. The family always considered these events as benign.

At 8 years of age, the child has normal development and has not had any additional epileptic or provoked seizures.

Etiology
Benign-familial neonatal seizures is a rare, dominantly inherited epileptic syndrome with a penetrance as high as 85%. The disease was first mapped to chromosome 20q (Leppert et al 1989). Today it is known that the syndrome exhibits genetic heterogeneity and is caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2 located at 20q13.3 (Biervert et al 1998; Singh et al 1998; Lerche et al 1999; Miraglia del Giudice et al 2000) and KCNQ3 mutations on chromosome 8q24 (Charlier et al 1998; Hirose et al 2000). Recently, three de novo mutations in KCNQ2 were found in four patients with benign neonatal seizures (Claes et al 2004) without a family history.

Currently, there are more than 10 mutations identified in KCNQ2, but only 2 in KCNQ3. Mutations in either KCNQ2 or KCNQ3 can produce the same phenotype. Interestingly, mutations in KCNQ2 can arise de novo in patients with benign idiopathic neonatal seizures suggestive of an overlap.

Pathogenesis and Pathophysiology
Both KCNQ2 and KCNQ3 can form homomeric potassium channels when expressed alone but also can combine to form heteromeric channels (KCNQ2/KCNQ3), leading to the expression of larger currents. It is theorized that the association of both channels is the molecular equivalent of the so-called “M current,” a neuronal potassium current highly expressed in the cortex and hippocampus (Brown and Adams 1980). This current is slowly activated by depolarization, and its slow activation is important in regulating neuron stability, functioning as a brake for repetitive action potential firing. Reduction by approximately 25% in KCNQ2/KCNQ3 caused by loss of function mutations is enough to increase neuronal excitability. Recently, it has been postulated that reduction of KCNQ channels alone cannot produce seizures, but can facilitate their development under conditions of unbalanced neurotransmission, either by increase in excitation or decrease in inhibition (Okada et al 2002). Thus, this unbalance could be 1 possible explanation as to why the neonatal period is a vulnerable time for the seizures to occur (Swann and Moshe 1997). After the first week of life in the rat, there is a decrease of KCNQ2 channel activity. Furthermore, GABA-mediated responses switch from depolarizing to hyperpolarizing; the latter responses are the hallmark of GABA A-mediated inhibition in the mature brain (Okada et al 2003). The switch in GABA function appears to be related to a change in the expression of a potassium-chloride co transporter KCC2. During the early period, KCC2 expression is low and intracellular chloride is much higher than extracellular chloride. When GABA A receptors open chloride channels, there is chloride efflux, leading to depolarization (Ben-Ari 2002; Galanopoulou et al 2003). With maturation, as the expression of KCC2 increases, GABA A-mediated responses cause influx of chloride and hyperpolarization. Other possibilities for the decreased incidence of seizures after the neonatal period is the differential expression of potassium channels during different stages of maturation and the development of compensatory mechanisms to suppress the aberrant M current.

To highlight the increasing complexity of phenotype-genotype correlations in the channelopathies implicated in the epilepsies, a mutation in the alpha-2 subunit of the sodium channel SCN2A has been reported, with seizure onset in the first months of age–an intermediate phenotype between benign familial neonatal and infantile seizures (Heron et al 2002).

Epidemiology
Since benign-familial neonatal seizures is a rare disorder, its actual incidence is difficult to calculate, but a recent population-based study concerning the population of Newfoundland in Canada found 5 cases of benign-familial neonatal seizures among the 34,615 live births in the center involved (between the period of January 1, 1990 and December 31, 1994); thus, the calculated incidence of benign-familial neonatal seizures was estimated to be 14.4 per 1000,000 live births (Ronen et al 1999).

It has been suggested that the disorder may be under-recognized (Zonana et al 1984).

Prevention
No information is available.

Differential Diagnosis
The diagnosis can be made only after other causes of neonatal seizures have been excluded. Syndromes of neonatal seizures with favorable outcome include late hypocalcemia, subarachnoid hemorrhage, benign neonatal seizures (nonfamilial), and certain meningitides (Plouin 1990). A family history is necessary (Miles and Holmes 1990). The seizures in benign neonatal seizures (nonfamilial) occur as a cluster during a narrow age window (4 to 6 days postnatal), and they are never tonic. Benign sleep myoclonus should also be considered in the differential diagnosis.

Diagnostic Workup
The diagnosis of benign-familial neonatal seizures is based on a family history, negative laboratory findings, and neuroimaging examinations.

Laboratory evaluations such as serum electrolytes, glucose, calcium, and magnesium are within normal range. The EEG may be of limited value; it can be normal or abnormal (Miles and Holmes 1990). If abnormal, the findings are not diagnostic and include ictal epileptic patterns (Dobrescu and Labrisseau 1982; Camfield et al 1991) or interictal sharp transients (Petit and Fenichel 1980; Cronin and Cosgrove 1986). In particular, patients with benign-familial neonatal seizures may develop centrotemporal spikes and sharp waves or benign epilepsy with centrotemporal spikes (Maihara et al 1999). The theta pointu alternant pattern has also been reported (Alvarez et al 1986; Plouin 1990). No case with either severe EEG pattern or generalized abnormalities has been reported.

Prognosis and Complications
The seizures of affected infants usually remits spontaneously by 16 months of age (Zonana et al 1984). Only exceptionally will the seizures continue into childhood or adulthood (Bjerre and Corelius 1968). About 11% of patients develop other types of seizures in later life, 5% with febrile seizures (Commission on Classification and Terminology of the International League Against Epilepsy 1989). This rate is about 1% higher than that observed in the general population; however, the increased risk appears to be associated with some and not all pedigrees. These data lend further support to the notion that the syndrome may be heterogeneous (Kaplan and Lacey 1983; Ryan et al 1991). The prevalence of mental retardation and learning disability is reported to be approximately 2.5%, which is not significantly different from the expected rate for the general population (Zonana et al 1984). Finally, unexpected deaths have also been reported (Bjerre and Corelius 1968).

Management
The efficacy of antiepileptic drugs is not clear because many seizures remit spontaneously (Miles and Holmes 1990). Conventional anticonvulsants such as phenobarbital, phenytoin, and valproate have been tried (Miles and Holmes 1990; Plouin 1990), especially in some refractory cases (Plouin 1990). Treatment is usually for a short period of time (weeks to months). The experimental drug retigabine activates KCNQ2/KCNQ3 channels by shifting their voltage dependence to more negative voltages, increasing the channel-opening activity, and making these channels suitable targets for the development of new therapy (Main et al 2000; Rundfeldt and Netzer 2000; Wickenden et al 2000). This drug is currently in trials in Europe.

Pregnancy
Not applicable.

Anesthesia
There are no special considerations.

References Cited
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Abbreviations
EEG:electroencephalogram

ICD Code
345.9

McKusick MIM number
121200

Synonyms
Benign familial neonatal seizures
Benign-familial neonatal convulsions
Benign neonatal familial convulsions

Associated Disorders
Benign neonatal seizures (nonfamilial)
Channelopathies
Hypocalcemia
Meningitis
Neonatal seizures
Subarachnoid hemorrhage

Major Keyword Descriptors
apnea
chromosome 20q13.3
chromosome 8q24
clonic seizures
epilepsy
neonate
seizures
status epilepticus
theta pointu alternant

Minor Keyword Descriptors
convulsions
KCNQ2
KCNQ3
neonatal
infant

Age of Presentation
0-01 month
01-23 months

Age of Typical Presentation
0-01 month

Population Groups Preferentially Affected
none selectively affected

Occupation Groups Preferentially Affected
none selectively affected

Sex
male=female

Family History
family history may be obtained
family history typical

Heredity
heredity may be a factor
heredity typical
autosomal dominant

Permuted Topic, Synonyms, Subtopics
Benign-familial neonatal seizures
familial neonatal seizures, Benign
neonatal seizures, Benign-familial
seizures, Benign-familial neonatal
neonatal familial convulsions, Benign
familial convulsions, Benign neonatal
convulsions, Benign neonatal familial

Related Summaries
Benign familial and nonfamilial infantile seizures
Benign neonatal seizures (nonfamilial)
Epilepsy
Neonatal seizures
Benign nonepileptic infantile spasms

Differential Diagnosis
late hypocalcemia
subarachnoid hemorrhage
benign neonatal convulsions (nonfamilial)
meningitides
benign sleep myoclonus

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