Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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Benign familial neonatal seizures is a syndrome characterized by focal clonic seizures, occasionally with a generalized tonic-clonic component, that occurs in full-term neonates. The seizures usually begin within 2 to 8 days of birth and remit by 16 months. As the name implies, this syndrome is usually familial and self-limited, but a work-up is necessary to rule out other causes of seizures. This syndrome is caused by a mutation in the gene that encodes voltage-gated K+ channel subunits (KCNQ2, KCNQ3). These subunits are responsible for the M-current, which is important in neuronal stability. There is no specific treatment at this time; however, there are several drugs for which the mechanism of action looks promising.
• Seizures occur in full-term neonates, usually beginning within 2 to 8 days from birth.
• The disorder is familial and benign.
• There is no specific treatment. Antiseizure medications are sometimes used.
• This syndrome is caused by mutations in the gene encoding voltage-gated K+ channels.
Antoni described a hereditary form of neonatal seizures with good outcomes for neurologic development (03). Rett and Teubel were the first to describe the syndrome in a family (50). The term “benign” was not in the original description by Rett but was added 4 years later. Interestingly, a reanalysis of Rett’s original kindred 40 years later revealed that they met current clinical and genetic criteria for benign familial neonatal seizures (68). The first case reported in the English literature appeared in 1968 (06). Since 1989, benign familial neonatal seizures have been included in the classification of epilepsy and epilepsy syndromes.
In the majority (54%) of reported neonates with this disorder, seizures begin by 2 to 8 days of life and remit by 16 months (69; 37). 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 (37). 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 (46). Both the physical examination and laboratory tests are normal before, between, and after the seizures. Psychomotor development is normal in most children, but the risk of seizure disorders in later life is increased (69). 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 (14). Only one case is reported of a patient who experienced tonic seizures (44). The seizures are brief, usually 1 to 2 minutes (37). The frequency of seizures may be as high as 20 to 30 episodes per day (69).
Videotape recordings with EEG have been reported in at least six babies (28; 09; 47). 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.
Although seizures usually remit in these patients, long-term subclinical changes may occur. For example, some patients show subclinical dysfunction of K(v)7.2 subunit of the slow potassium channel in peripheral nerves into adulthood, which is encoded by KCNQ2 (64). A case report described a family with an inherited missense mutation in KCNQ2. The affected individuals in this family had fewer benign courses and required multiple anticonvulsants for seizure control (01).
The seizures of affected infants usually remit spontaneously by 16 months of age (69). Only exceptionally will the seizures continue into childhood or adulthood (06). About 11% of patients develop other types of seizures in later life, 5% being febrile seizures (14). 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 further support the notion that the syndrome may be heterogeneous (29; 53). The prevalence of mental retardation and learning disability has been reported to be approximately 2.5%, which is not significantly different from the expected rate for the general population (69). However, a study found that four of 10 families had at least one member with developmental delay or profound mental retardation (61). In addition, there is phenotypic variability of the neurologic symptoms in individuals with mutations in KCNQ2 and KCNQ3 (07). Although some patients have benign seizures, others present with severe epileptic encephalopathy, focal seizures, mental retardation, generalized epilepsy with febrile seizures, severe myoclonic epilepsy of infancy, and myotonia (19). KCNQ2 has also been associated with psychiatric illness, such as bipolar disorder (11). In another study, a large multigenerational family had good outcomes in 11 of 13 affected members. One member had generalized epilepsy beginning at puberty and the other had a mild learning disability (17). Unexpected deaths have also been reported (06). Studies are finding that in addition to the known mutations, other mutations may be involved, such as a duplication of a region near SCN1A, which can affect sodium channels. At times, these other mutations may also be associated with some psychomotor disability (26). In 2015, Grinton and colleagues suggested that seizures in later life are more common than expected and reported a greater number of neonatal seizures than prior studies had shown (22).
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 four 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; 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, one aunt, the grandmother, and a second cousin. The family always considered these events benign.
At 8 years of age, the child has normal development and has not had any additional epileptic or provoked seizures.
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 (31). Today, it is known that the syndrome exhibits genetic heterogeneity and is associated with mutations in the voltage-gated potassium channel subunit gene KCNQ2 located at 20q13.3 (05; 57; 32; 38) and KCNQ3 mutations on chromosome 8q24 (12; 27). Three de novo mutations in KCNQ2 were found in four patients with benign neonatal seizures (13) without a family history.
BFNS1 is associated with KCNQ2 mutations, and BFNS2 with KCNQ3 mutations. Seventy-three mutations have been identified in KCNQ2, but only four in KCNQ3. Three of theKCNQ3 mutations were found in exon 5, and one in exon 6 of a Chinese family (20). 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, suggesting an overlap.
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 (08). This current is slowly activated by depolarization. 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. Specific mutations can cause gating changes that may decrease M-current function, resulting in neuronal hyperexcitability (60). For example, at the RNA level, the mutation in KCNQ2 results in aberrant slicing, adding four nucleotides to the transcript. This leads to a stop codon downstream of the insertion and the creation of a truncated protein (45), the most common result of described mutations. In approximately one sixth of families, submicroscopic deletions and duplications in KCNQ2 are seen (24). Multiplex ligation-dependent probe amplification can be used as an efficient second-tier testing strategy for KCNQ2. With this method, one can identify pathogenic intragenic mutations not detectable by conventional DNA sequencing methods (24). A study in W309R mutant KCNQ3 and KCNQ2 channels revealed a lack of potassium current, which can explain the neuronal hyperexcitability and development of seizures (62). A novel mutation was found in a large family with benign familial neonatal seizures. The mutation was in exon 9 of the KCNQ2 gene encoding for the K(v)7.2 potassium channel (54). Functional studies revealed that mutations in the S domain of K7.2 subunits destabilized the open state, causing a dramatic decrease in channel voltage sensitivity (36). Modeling experiments in CA1 hippocampal pyramidal cells revealed that these mutations increased cell firing frequency. Mutations in R213Q prompted more dramatic changes than those in R213W mutations. This may partially explain the differences in disease severity. It has been shown that mutations in KCNQ2 and KCNQ3 genes can alter the binding of calmodulin, thereby decreasing heteromeric channel assembly, which is essential at the axonal initial segment (33). Adding exogenous calmodulin reversed this by enhancing heteromeric subunit association.
It has been postulated that a reduction of KCNQ channels alone cannot produce seizures but can facilitate their development under conditions of unbalanced neurotransmission, either by an increase in excitation or decrease in inhibition during a particularly vulnerable period of brain development (40). The unbalance of neurotransmission during this vulnerable period could be one of the possible explanations for why the seizures occur during this period (63). After the first week of life in the rat, KCNQ2 channel activity is decreased. Furthermore, GABA-mediated responses switch from depolarizing to hyperpolarizing; the latter responses are the hallmark of GABA A-mediated inhibition in the mature brain (41). The switch in GABA function appears to be related to a change in the expression of a potassium-chloride cotransporter 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, chloride efflux leads to depolarization (04; 21). With maturation, as the expression of KCC2 increases, GABA A-mediated responses cause an 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. It has been shown that voltage-dependent M-channels are activated during interictal bursts and may contribute to burst termination. When these channels are compromised, the bursts may not end, transforming the interictal periods to ictal events through sustained depolarizations. This sequence of events is more likely to happen in the immature hippocampus (49). These observations may provide another explanation to account for the transient nature of the seizures.
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; this is an intermediate phenotype between benign familial neonatal and infantile seizures (25).
An animal model has been developed by introducing a mutant KCNQ2 and KCNQ3 gene in a mouse (58). Heterozygous knock-in mice exhibited reduced thresholds for electrically induced seizures. Homozygous knock-in mice exhibited early onset spontaneous generalized tonic-clonic seizures with recurrent seizures into adulthood. This model also displayed a lack of seizure-induced pathology paralleling the benign neurodevelopmental cognitive profile exhibited by the majority of patients with benign familial neonatal convulsions. In a heterozygous mouse model, the mice had increased seizure susceptibility, although spontaneous seizures did not occur (42). Differences in seizure threshold were found to be dependent on the mutation expressed, the seizure testing paradigm, and the genetic background strain. In addition, the seizure susceptibility was dependent on gender, possibly due to the reasons described above. Another animal model being developed is the adult zebrafish. The overall expression of KCNQ channel transcripts in zebrafish is similar to the expression in mammals (66). Finding appropriate animal models for the different forms of epilepsy is crucial to gaining a better understanding of the pathophysiology and treatment of seizures (15).
Because benign familial neonatal seizures is a rare disorder, its actual incidence is difficult to calculate, but a population-based study concerning the population of Newfoundland in Canada found five 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 incidence of benign familial neonatal seizures was estimated to be 14.4 per 1,000,000 live births (51).
It has been suggested that the disorder may be under-recognized (69). As more testing is done, more families will likely be identified with the mutation. For example, the first case of a KCNQ2 mutation in the Korean population has been identified in a family with benign familial neonatal seizures (67).
The diagnosis can be made only after other causes of neonatal seizures have been excluded. Syndromes of neonatal seizures with favorable outcomes include late hypocalcemia, subarachnoid hemorrhage, benign neonatal seizures (nonfamilial), and certain meningitides (46). A family history is necessary (37). 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.
Some neonates with seizures similar to benign familial neonatal seizures are eventually diagnosed with a more severe epileptic encephalopathy. KCNQ2 and KCNQ3 mutations are found in several more severe epilepsies, including KCNQ2 encephalopathy. These are usually de novo mutations, but some cases have been identified in families with more than one member. The EEG in patients with KCNQ2 encephalopathy shows lack of organization interictally with ictal low voltage fast activity and theta rhythms. These features may help differentiate KCNQ2 encephalopathy from benign familial neonatal seizures (39). One study showed that syntaxin-1A is involved in channel regulation in some KCNQ2-related epilepsies (59).
The diagnosis of benign familial neonatal seizures is based on 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 (37). If abnormal, the findings are not diagnostic and include ictal epileptic patterns (18; 10) or interictal sharp transients (44; 16). In particular, patients with benign familial neonatal seizures may develop centrotemporal spikes and sharp waves or benign epilepsy with centrotemporal spikes (34). The theta pointu alternant pattern has also been reported (02; 46). No case with either severe EEG pattern or generalized abnormalities has been reported.
The efficacy of antiepileptic drugs is not clear because many seizures remit spontaneously (37). Conventional anticonvulsants such as phenobarbital, phenytoin, and valproate have been tried (37; 46), especially in some refractory cases (46). Treatment is usually for a short period (weeks to months). A phase III trial of the drug retigabine was completed, and retigabine was approved by the FDA in March 2011 to treat focal seizures, making it the first neuronal potassium channel opener for treating epilepsy. The specific mechanism of action has been described as a positive allosteric modulator of KCNQ2-5 ion channels (23). 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 a therapy (35; 52; 65). Retigabine specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels that contain a tryptophan residue (56). Retigabine has since been discontinued mainly because of drug-induced phototoxicity and pharmacokinetic drawbacks (short half-life and poor brain penetration). Sodium channel blockers such as carbamazepine are particularly effective (39; 48).
Studies suggest that the disappearance of the developmentally regulated giant depolarizing potential is partly due to the increase in M-current during the neonatal period (55). This raises the possibility that seizures in benign familial neonatal convulsions resolve with development because of the increase in M-current expression during this period (30). Another study identified that two anti-inflammatory drugs, meclofenamic acid and diclofenac, act as novel KCNQ2/Q3 channel openers that enhance the M-current. One of these agents, diclofenac, exhibits anticonvulsant properties in the maximal electroshock model (43). These promising results may open new avenues for treating benign familial neonatal seizures.
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