Autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an epileptic disorder that results in frequent violent seizures during sleep. The seizures often involve complex motor movements, including hand clenching, arm raising/lowering, and knee bending. Vocalizations, such as shouting, moaning, or crying, are also common. ADNFLE is often misdiagnosed as nightmares. The attacks typically occur in clusters and first manifest in childhood. There are four known loci for ADNFLE, with three having known causative genes. These genes, CHRNA4, CHRNB2, and CHRNA2, encode various nicotinic acetylcholine receptor α and β subunits.

Signs and symptoms

ADNFLE is a partial epilepsy disorder characterized by brief violent seizures during sleep. The seizures are complex, involving arm and leg movements, fist clenching, and vocalizations such as yelling and moaning. These seizures often occur in clusters and can first manifest in childhood. Diagnosis is often initially incorrect, with conditions such as nightmares, night terrors, parasomnias, and various psychiatric disorders being mistaken for ADNFLE.

Causes

While the exact cause of ADNFLE is not well understood, it is believed that malfunction in thalamocortical loops plays a vital role in the disorder. This belief is based on three primary factors: the importance of thalamocortical loops in sleep and the frontal cortex as the origin of ADNFLE seizures; the fact that both the thalamus and cortex receive cholinergic inputs and acetylcholine receptor subunits comprise the three known causative genes for ADNFLE; and the presence of K-complexes at the start of seizures. It is thought that epilepsy is caused because these receptor subunits are expressed presynaptically by neurons that release the inhibitory transmitter GABA. As a result, the mutation in the α4 subunit could lead to reduced GABA release, causing hyperexcitability.

Pathophysiology

CHRNA4

The first mutation associated with ADNFLE is a serine to phenylalanine transition at position 248 (S248F), which is located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor α4 subunit. Receptors containing this mutant subunit are functional, but desensitize at a much faster pace compared to wild-type only receptors. These mutant-containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. These mutant receptors also have a decreased single channel conductance compared to wild-type and have a lower affinity for acetylcholine. Importantly, this mutation, along with the others in CHRNA4, produces receptors less sensitive to calcium.

Other mutations in CHRNA4 associated with ADNFLE include L259_I260insL, S252L, and T265M, all of which are located in the second transmembrane spanning region. Electrophysiological experiments have shown various effects on receptor sensitivity, desensitization, and calcium permeability as a result of these mutations.

15q24

Some families have been shown to not have mutations in CHRNA4 and, furthermore, to show no linkage around it.

CHRNA2

The third known causative gene for ADNFLE is CHRNA2, which encodes a nicotinic acetylcholine receptor α2 subunit. One mutation identified in CHRNA2 is I279N, which resides in the second transmembrane spanning region. Functional studies of this mutation have shown that receptors containing the I279N mutation display a lower sensitivity to acetylcholine and exhibit altered desensitization kinetics compared to wild-type receptors.

Genetic heterogeneity

Although three causative genes have been identified, there are still families with ADNFLE that do not have mutations in any of these genes. This suggests that there is further genetic heterogeneity in ADNFLE, and more causative genes are yet to be discovered.

Diagnosis

Diagnosing ADNFLE can be challenging due to its initial presentation, which is often mistaken for nightmares, night terrors, parasomnias, or various psychiatric disorders. A thorough clinical history, including a detailed description of seizure semiology and family history, is essential for an accurate diagnosis. Video-electroencephalogram (video-EEG) monitoring during sleep may also help to capture seizures and confirm the diagnosis. In some cases, genetic testing can be useful to identify mutations in the known causative genes.

Treatment

Treatment for ADNFLE typically involves the use of antiepileptic drugs (AEDs). The choice of AED may vary depending on the specific seizure characteristics and the individual patient's response to medication. Commonly used AEDs for ADNFLE include carbamazepine, oxcarbazepine, and topiramate. In some cases, other medications such as benzodiazepines, gabapentin, or lamotrigine may also be effective. It is important to work closely with a healthcare professional to determine the most appropriate treatment plan.

Prognosis

The prognosis for individuals with ADNFLE is generally favorable. Most patients experience a significant reduction in seizure frequency and severity with appropriate treatment. Some individuals may even achieve complete seizure control. However, it is important to note that the response to treatment can vary among patients, and some individuals may continue to experience seizures despite medication. In such cases, alternative treatment options or a combination of medications may be considered. It is also worth noting that the severity and frequency of seizures may change over time, with some individuals experiencing improvement as they age.

Cognitive and psychiatric comorbidities

Although the primary symptom of ADNFLE is seizures during sleep, some individuals with the condition may also experience cognitive or psychiatric comorbidities. These can include attention deficit hyperactivity disorder (ADHD), learning difficulties, anxiety, and depression. In some cases, these comorbidities may have a significant impact on an individual's quality of life and daily functioning. It is essential for healthcare professionals to assess and address these comorbidities as part of the overall treatment plan for individuals with ADNFLE.

Impact on daily life

ADNFLE can have a significant impact on an individual's daily life, particularly if seizures are not well-controlled. Sleep disturbances due to frequent nocturnal seizures can lead to daytime sleepiness, impaired cognitive function, and reduced quality of life. In addition, the presence of cognitive and psychiatric comorbidities can further complicate daily functioning and social interactions.

Early diagnosis and appropriate treatment are essential to minimize the impact of ADNFLE on an individual's daily life. With proper management, many individuals with ADNFLE can achieve good seizure control and maintain a high quality of life.

Summary

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare genetic epilepsy syndrome characterized by sleep-related seizures. It is caused by mutations in the CHRNA4, CHRNB2, and CHRNA2 genes, although additional causative genes may still be undiscovered. Diagnosis can be challenging due to the variable presentation of the condition, but a thorough clinical history, video-EEG monitoring, and genetic testing can aid in accurate diagnosis. Treatment typically involves the use of antiepileptic drugs, and the prognosis is generally favorable with appropriate treatment. Early diagnosis and management are essential to minimize the impact of ADNFLE on an individual's daily life and overall well-being.

Further reading

• GeneReviews/NCBI/NIH/UW entry on Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

External links

Classification	OMIM: 600513 Online Mendelian Inheritance in Man (OMIM) 603204 Online Mendelian Inheritance in Man (OMIM) 605375 Online Mendelian Inheritance in Man (OMIM) 610353

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