Benign familial neonatal seizures ( BFNS ), also referred to as benign familial neonatal epilepsy ( BFNE ), is a rare autosomal dominant inherited form of seizures . This condition manifests in newborns as brief and frequent episodes of tonic-clonic seizures with asymptomatic periods in between. Characteristically, seizure activity spontaneously ends during infancy and does not affect childhood development. However, some studies have reported that a minority of children with BFNS consequently develop intellectual disability. Additionally, BFNS increases lifetime susceptibility to seizures as approximately 14% of those afflicted go on to develop epilepsy later in life. There are three known genetic causes of BFNE, two being the voltage-gated potassium channels KCNQ2 (BFNC1) and KCNQ3 (BFNC2) and the third being a chromosomal inversion (BFNC3). There is no obvious correlation between most of the known mutations and clinical variability seen in BFNE.
34-411: BFNS often presents in the first week of life with brief but frequent episodes of tonic-clonic seizures , outside of which a child is completely asymptomatic. During the tonic phase of these seizures, infants may stop breathing ( apnea ) and consequently appear blue ( cyanosis ) due to lack of oxygen. Accompanying this is focal or generalized muscle stiffening. The clonic phase usually follows, during which
68-553: A beta blocker , because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate. Class Ia agents include quinidine , procainamide and disopyramide . Class Ib antiarrhythmic agents are sodium channel blockers. They have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten
102-620: A complex partial seizure and now referred to as focal aware seizure and focal impaired awareness seizure, respectively ) can then spread to both hemispheres of the brain and cause a generalized tonic-clonic seizure. This type of seizure has a specific term called "focal to bilateral tonic clonic seizure." Other precipitating factors include chemical and neurotransmitter imbalances and a genetically or situationally determined seizure threshold , both of which have been implicated. The seizure threshold can be altered by fatigue , malnutrition, lack of sleep or rest, hypertension , stress , diabetes ,
136-402: A frameshift in the coding sequence. There are also 5 splice variants, one of which has been characterized at the protein level and leads to a nonsense mutation . Finally, there is one large deletion that removes much of the carboxy-terminus of the channel. While most BFNC1 mutations have not been further characterized, 14 have and all seem to lead to functional defects. Two of the mutations in
170-399: A grand mal seizure or GTCS , is a type of generalized seizure that produces bilateral, convulsive tonic and clonic muscle contractions. Tonic–clonic seizures are the seizure type most commonly associated with epilepsy and seizures in general and the most common seizure associated with metabolic imbalances . It is a misconception that they are the sole type of seizure, as they are
204-551: A membrane stabilizing effect . Class Ia agents block the fast sodium channel, which depresses the phase 0 depolarization (i.e. reduces V max ), which prolongs the action potential duration by slowing conduction. Agents in this class also cause decreased conductivity and increased refractoriness . Indications for Class Ia agents are supraventricular tachycardia , ventricular tachycardia , symptomatic ventricular premature beats, and prevention of ventricular fibrillation . Procainamide can be used to treat atrial fibrillation in
238-482: A focal onset (described above) that progresses into a generalized seizure or be a generalized seizure at onset. The term "Grand Mal" is nonspecific, referring to generalized tonic–clonic seizures with either a focal or generalized onset. Due to this lack of specificity in describing the onset of a seizure and being considered an archaic term, it is not typically used by medical professionals. Sodium channel blocker Sodium channel blockers are drugs which impair
272-749: A future date. This monitor is only kept as a safeguard as usually the medication wards off any seizures. Once the child is weaned off the phenobarbital, the monitor is no longer necessary. BFNE was first described in 1964 by Andreas Rett and named by Bjerre and Corelius four years later. Andreas Rett is better known for his later characterization of Rett syndrome . Both studies were published in German, but have yet to be translated in English. The mutations associated with BFNE were first mapped and descripted by Leppert and colleagues in 1989. Tonic-clonic seizures A generalized tonic–clonic seizure , commonly known as
306-399: A last line treatment for refractory life-threatening ventricular tachycardia or ventricular fibrillation. These agents are potentially pro-arrhythmic, especially in settings of structural heart disease (e.g. post- myocardial infarction ), and are contraindicated in such settings. Class Ic agents include encainide , flecainide , moricizine , and propafenone . Encainide is not available in
340-438: A prodrome. The prodrome of a generalized tonic–clonic seizure is a sort of premonitory feeling hours before a seizure. This type of prodrome is distinct from stereotypic aura of focal seizures that become generalized seizures. Phases A tonic–clonic seizure comprises three phases: the tonic phase, clonic phase and postictal phase. Diagnosis can be made definitively by Electroencephalography (EEG), which records
374-449: Is also in the pore region of the channel. This mutation leads to an approximately 40% reduction in whole-cell current compared to wild-type expressing cells. The underlying mechanism for this current decrease has not been further delineated. The rarest cause of BFNE, occurring in only one known family, is a chromosomal inversion . This occurs on chromosome 5 and the inversion is of the p15 through q11 area. Affected individuals, thus, have
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#1732884900688408-461: Is an extended postictal state where the person is unresponsive and commonly sleeping with loud snoring. There is usually pronounced confusion upon awakening. The vast majority of generalized seizures are idiopathic . Some generalized seizures start as a smaller seizure that occurs solely on one side of the brain, however, and is referred to as a focal (or partial) seizure. These unilateral seizure types (formerly known as simple partial seizure or
442-440: Is because lidocaine selectively blocks Na channels in their open and inactive states and has little binding capability in the resting state. Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation. Class Ib agents include lidocaine , mexiletine , tocainide , and phenytoin . Class Ic antiarrhythmic agents markedly depress
476-426: Is having a seizure, as that can lead to injury. Nor should anything be put in a person's mouth, as these items can become choking hazards and, depending on what is put in, can potentially break the person's teeth. Long-term therapy may include the use of antiepileptic drugs, surgical therapy , diet therapy ( ketogenic diet ), vagus nerve stimulation , or radio surgery . Generalized tonic–clonic seizures can have
510-437: Is some degree of damage to a large number of neurons. The lesions (i.e., scar tissue) caused by the loss of these neurons can result in groups of neurons forming a seizure "focus" area with episodic abnormal firing that can cause seizures if the focus is not abolished or suppressed via anticonvulsant drugs. Prodrome Most generalized tonic–clonic seizures begin without warning and abruptly, but some epileptic patients describe
544-426: Is the first line therapy for BFNC. Recurrent seizures later in life are treated in the standard ways (covered in the main epilepsy article ). Depending on the severity, some infants are sent home with heart and oxygen monitors that are hooked to the child with stick on electrodes to signal any seizure activity. Once a month the monitor readings are downloaded into a central location for the doctor to be able to read at
578-423: Is typically interrupted by slow waves to create a spike-and-slow-wave pattern." Additionally, the postictal phase will show suppression of all brain activity, then slowing that gradually recovers as the patient awakens. For a person experiencing a tonic–clonic seizure, first-aid treatment includes rolling the person over into the recovery position , which can prevent asphyxiation by preventing fluid from entering
612-543: The Vaughan Williams classification . Class I antiarrhythmic agents interfere with the (Na ) channel . Class I agents are grouped by their effect on the Na channel, and by their effect on cardiac action potentials . Class I agents are called Membrane Stabilizing Agents. 'Stabilizing' refers to the decrease of excitogenicity of the plasma membrane affected by these agents. A few class II agents, propranolol for example, also have
646-503: The karyotype 46,XY,inv(5)(p15q11). Why this inversion leads to the BFNE phenotype is unknown. Generally speaking, Neonatal seizures are often controlled with phenobarbital administration. While phenobarbital can be used for symptomatic treatment of BFNC, several studies have shown favorable response to anti-seizure medications that specifically block sodium channels (see article on Sodium channel blocker ). However, at this time, phenobarital
680-640: The United States. Sodium channel blockers are also used as local anesthetics and anticonvulsants . Sodium channel blockers have been proposed for use in the treatment of cystic fibrosis , but current evidence is mixed. It has been suggested that the analgesic effects of some antidepressants may be mediated in part via sodium channel blockade. Voltage-dependent sodium channel blockers are used as insecticides , comprising Insecticide Resistance Action Committee (IRAC) mechanism of action group 22. As of March 2020 these are two, indoxacarb (22A,
714-471: The action potential duration and reduce refractoriness. These agents will decrease V max in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be more specific for voltage gated Na channels than Ia. Lidocaine in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This
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#1732884900688748-424: The conduction of sodium ions (Na ) through sodium channels . The following naturally-produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel: Drugs which block sodium channels by blocking from the intracellular side of the channel include: Sodium channel blockers are used in the treatment of cardiac arrhythmia . They are classified as "Type I" in
782-480: The electrical activity of the brain. This is typically done after a seizure episode in a clinical setting with an attempt to "capture" a seizure while it happens. According to "Harrisons Manual of Medicine," the EEG during the tonic phase will show a "progressive increase in low-voltage fast wave activity, followed by generalized high-amplitude, poly spike discharges." The clonic phase EEG will show "high amplitude activity that
816-518: The health of patients with BFNE into adulthood have reported consequent intellectual disability and seizure disorders. The most prevalent known cause of BFNE is mutation of KCNQ2, a gene encoding a voltage-gated potassium channel (K V 7.2). There are at least 35 such mutations, see Table 1, primarily located in the voltage sensitive S4 segment through the C-terminus. Of these mutations, 5 are nonsense mutations , 13 are missense mutations and 11 cause
850-581: The infant may make noises, display focal or multi-focal rhythmic jerking of the body, and/or display abnormal eye and facial movement. Characteristically, testing for seizures between episodes with EEG is normal. However, the appearance of a “theta pointu alternant pattern” and/or non-specific abnormalities on EEG has been reported in several cases, although their relationship to BFNE has not been well delineated. These seizure episodes resolve entirely within days to weeks, and in most patients have no effects on neurodevelopment. With that said, several studies tracking
884-471: The lungs. Other general actions to take as recommended by the Epilepsy Foundation include staying with a person until a seizure is over, paying attention to length of seizure as a possible indication for status epilepticus and/or indication to give rescue medication and call for emergency help, moving close objects out of the way to prevent injury. It is also not recommended to hold a person down that
918-424: The main seizure type in approximately 10% of those with epilepsy. These seizures typically initiate abruptly with either a focal or generalized onset. A prodrome (a vague sense of impending seizure) may also be present before the seizure begins. The seizure itself includes both tonic and clonic contractions, with tonic contractions usually preceding clonic contractions. After these series of contractions, there
952-447: The other characterized mutations lead to decreased whole-cell current that has not been further delineated, three mutations have. Y534fsX538, for example, leads to a truncation that removes much of the carboxy-terminus of the channel. This mutant has been studied and shown to not traffic properly to the membrane. Two other mutations, P709fs929X and W867fsX931, lead to altered carboxy-termini, though they actually lengthen rather than truncate
986-403: The phase 0 depolarization (decreasing V max ). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have the most potent sodium channel blocking effects. Class Ic agents are indicated for supraventricular arrhythmias (i.e. atrial fibrillation ) and as
1020-463: The pore region of the channel. The first of these mutations, G310V, leads to a 50% reduction in whole-cell current compared to cells expressing wild-type channels. The reason for this change is unknown as the mutation does not lead to altered protein trafficking. A second mutation, W309G, has also been found to be associated with BFNE. This mutation was only found in one family and has not been further characterized. The final known BFNC2 mutation, D305G
1054-449: The presence of strobe -flashes or simple light/dark patterns, raised estrogen levels at ovulation , fluorescent lighting , rapid motion or flight, blood sugar imbalances, anxiety, antihistamines and other factors. Tonic–clonic seizures can also be induced deliberately with electroconvulsive therapy . In the case of symptomatic epilepsy , the cause is often determined by MRI or other neuroimaging techniques showing that there
Benign familial neonatal seizures - Misplaced Pages Continue
1088-467: The protein. These abnormal extended proteins have been shown to be more rapidly degraded within cells and, thus, produce little current. Shortly after the discovery of mutations in KCNQ2 related to BFNE, a novel voltage-gated potassium channel was found that is highly homologous to KCNQ2 and contains mutations also associated with BFNE. This gene, KCNQ3, contains 3 known mutations associated with BFNE, all within
1122-494: The setting of Wolff–Parkinson–White syndrome , and to treat wide complex hemodynamically stable tachycardias . Oral procainamide is no longer being manufactured in the US, but intravenous formulations are still available. While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent such as digoxin or verapamil , or
1156-599: The voltage-sensitive S4 segment, R207W and R214W, do not lead to a decrease in the whole-cell current ( M current ) produced by KCNQ2 channels but to a change in channel kinetics. The R207W mutation takes fourfold longer and the R214W mutation takes twofold longer to reach maximal current compared to wild-type channels. Since the time-course of an action potential is shorter than the time required for mutant KCNQ2 channels to reach proper levels of inactivation these mutants are expected to lead to neuronal hyperexcitability. Though many of
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