Posts Tagged ‘epilepsy’

Reporter: Aviva Lev-Ari, PhD, RN

Australian-led Team Reports on New Nocturnal Epilepsy Gene

October 22, 2012

NEW YORK (GenomeWeb News) – An international team led by investigators in Australia has linked mutations in a sodium-gated potassium channel subunit gene to a subset of severe nocturnal frontal lobe epilepsy cases.

As they reported online yesterday in Nature Genetics, the researchers began by testing a family with autosomal dominant nocturnal frontal lobe epilepsy, or ADNFLE. Affected members of the family often had not only typical ADNFLE symptoms, but also intellectual and/or psychiatric features that don’t usually characterize the disorder.

After narrowing in on a chromosome 9 region via linkage analyses in the family, the team identified ADNFLE-associated missense mutations in the sodium-gated potassium channel subunit gene KCNT1 by whole-exome sequencing in two affected family members. Follow-up testing on more than 100 other unrelated individuals with nocturnal frontal lobe epilepsy indicated that both inherited and de novo mutations in the gene can cause severe forms of the conditions that tend to include other co-morbidities.

“KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features,” University of South Australia researcher Leanne Dibbens and the University of Melbourne’s Ingrid Scheffer, the study’s co-corresponding authors, and their colleagues wrote.

“These findings implicate the sodium-gated potassium channel complex in ADNFLE, and, more broadly, in the pathogenesis of focal epilepsies,” they added.

As the name suggests, ADNFLE is inherited in an autosomal dominant manner in affected families. Symptoms of the condition — including seizures that occur while individuals are asleep — generally appear in childhood, the researchers explained. And previous studies have implicated mutations to nicotinic acetylcholine receptor subunit genes in a subset of ADNFLE cases.

For the current study, the team focused on a multi-generational family with an especially severe form of ADNFLE that was accompanied by other symptoms such as intellectual disability and psychiatric disorders.

Genome-wide linkage analyses within the family led to a suspicious 2.36 million base stretch of sequence on chromosome 9, which housed almost 100 genes. Among them: two ion channel-coding genes, KCNT1 and GRIN1.

For two of the affected family members, the team turned to whole-exome sequencing to try to track down the most likely cause of ADNFLE. Indeed, missense mutations in KCNT1 that were predicted to be pathogenic turned up in one of the two exome sequences.

The mutation was not initially identified in the other family member’s exome sequence data, owing to low coverage, researchers explained. But it was subsequently shown to be present in both individuals by Sanger sequencing.

Consistent with the notion that this KCNT1 mutation could be related to ADNFLE pathogenesis, the investigators did not find it when they tested 111 unaffected, ancestry-matched individuals. Nor did it turn up in the dbSNP database, they reported, or in data generated for the 1000 Genomes Project or through the National Heart, Lung, and Blood Institute’s Exome Sequencing Project.

On the other hand, the team did find mutations in KCNT1 when it assessed another 108 unrelated individuals who either had ADNFLE or sporadically occurring nocturnal frontal lobe epilepsy.

That analysis helped the investigators track down two more ADNFLE-affected families with KCNT1 mutations that co-segregated with the disease, along with one case of sporadic nocturnal frontal lobe epilepsy including psychiatric features that seemed to stem from de novo mutations to KCNT1.

“[T]he phenotype associated with KNCT1 mutations is both more severe and more penetrant than that typically found with mutations affecting [nicotinic acetylcholine receptors],” the study’s authors noted.

In addition to showing more pronounced ADNFLE symptoms, they explained, the disease appears to manifest itself at a younger age in the cases linked to KCNT1 mutations.

Moreover, several cases that appear to be caused by alterations to KCNT1 also included intellectual disability, psychiatric, and/or behavioral features. The severity of such symptoms varied from one individual to the next — a pattern that the researchers speculated might be due to differences in the nature and extent of the KCNT1 mutation involved.

In addition to providing clues to help classify ADNFLE cases and offer genetic counseling for families affected by it, those involved in the study say the results should also prove useful for understanding — and potentially targeting — the processes that underlie this type of epilepsy.

“[T]his finding should provide new insights into the biological mechanisms underlying the pathogenesis of ADNFLE,” they concluded, “which may lead to targeted therapies addressing the serious co-morbidities as well as the debilitating seizure disorder.”

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The eTNS System. (PRNewsFoto/NeuroSigma)

Reporter: Howard Donohue, PhD (EAW)

Following the arrival in the 1990s of a drug for treating depression called fluoxetine (better known by its brand name, Prozac) – a “selective serotonin reuptake inhibitor” (SSRI) – it’s probably fair to say that not many drugs have become as deeply engrained in the public’s general awareness as those of this type. Perhaps one reason for this could be the sheer number of people affected by depression and to whom SSRIs are relevant as a possible treatment (one study has estimated that depression affected upwards of 30 million Europeans in the year 2010 [1]). Perhaps another reason could be the various controversies that have surrounded SSRIs over the years, from stories of increased suicide risk in children [2] to evidence of biases and the “selective” publishing of clinical data favoring the effectiveness of these drugs [3]. Of course, despite the controversies, SSRIs (along with other classes of antidepressant drug) continue to be a mainstay, but let’s not forget, amid their popularity, that there are other ways to treat depressive illnesses. And in maximizing the benefits of treatment for the individual, it’s important to realize that any one of these approaches might work well for one person, but not for another. Among the non-pharmacologic ways to treat depression are psychological approaches, for example cognitive behavioral therapy, or alternatively, “brain stimulation” approaches such as electroconvulsive therapy (ECT). ECT is a method to induce a mild seizure in the patient by means of electrical activity applied to the brain via electrodes connected to the temples.

On the subject of ECT; you could be forgiven for thinking that it’s not very nice, especially if you’ve seen the plights of characters like Randle Patrick “Mac” McMurphy, portrayed by Jack Nicholson in One Flew Over the Cuckoo’s Nest or Russell Crowe’s portrayal of Dr. John Nash (based on the real-life Nobel Laureate in Economics by the same name) in A Beautiful Mind. Nonetheless, despite the treatment in Hollywood of ECT as a sinister, repressive, and even brutal procedure, the reality is obviously different and it continues to have a place in medical practice for the treatment of severely depressed patients to this day. This isn’t to say that controversies don’t exist within the medical community concerning certain side effects (such as memory loss), but in balancing this, we should remember that many – if not most – medical procedures have their drawbacks (hopefully, the benefits will far outweigh the drawbacks). Putting aside any thoughts on whether ECT is good or bad, it is recognition and consideration of the drawbacks that helps drive the evolution of medical technologies.

So, in illustrating the evolution that is happening in the field of brain stimulation for treating neurological disorders (in this case, depression and also epilepsy), the recent approval in Europe of an “external Trigeminal Nerve Stimulation” (eTNS) technique provides an excellent example. The technique, called the MonarchTM and exclusively licensed to Neurosigma Inc. (a Los Angeles-based medical device company) “for the adjunctive treatment of epilepsy and major depressive disorder, for adults and children 9 years and older”, is a non-invasive form of neuromodulation therapy [4]. It was invented at the University of California, Los Angleles (UCLA) and has been in development for over 10 years [4]. It works by using a low-energy stimulus to stimulate branches of the trigeminal nerve, a nerve that can affect the activity of several key brain regions believed to be involved in depression and epilepsy. In contrast to ECT, the stimulus is restricted to the soft tissues of the forehead without direct penetration to the brain, which thereby facilitates a non-invasive form of neuromodulation [4]. Following European approval, Neurosigma affirmed in a press release that eTNS is “supported by years of safety and compelling efficacy data generated in clinical trials conducted at UCLA and the University of Southern California (USC)” [4]. In realizing the future potential of eTNS, Neurosigma’s business strategy is now geared toward steps for its adoption at major epilepsy and depression centers in the EU, as well as endeavors to make it available to patients in the US and other countries [4].

To answer the question of whether eTNS will rise to prominence as an effective treatment in the fight against depression and epilepsy, only time will tell. But if it does, as well as being a valuable addition to the armamentarium against these debilitating diseases, maybe its non-invasive nature will mean that the film directors have a harder time in “demonizing” it for dramatic effect. Well anyway, let’s hope so.


  1. Wittchen et al. Eur Neuropsychopharmacol 2011: 21:655-79.
  2. http://news.bbc.co.uk/2/hi/health/3656110.stm
  3. Turner et al. N Engl J Med 2008; 358:252-60.
  4. http://www.prnewswire.com/news-releases/neurosigma-receives-ce-certification-168578146.html

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Reporter: Howard Donohue, PhD (EAW)

The hypothalamic-pituitary-adrenal (HPA) axis – which can be thought of as a series of closely linked endocrine structures in the brain – has a key role in triggering the body’s stress response through the secretion of cortisol. In explaining how the HPA axis is itself regulated, for example how its activity is increased in response to a perceived environmental threat, we can infer that the diverse brain areas with which it shares neural interconnections have a crucial role (for a review, see [1]). An equally important question relates to how the activity of the HPA axis is returned to normal when the stress response is no longer needed. To answer this, it is well known that the same “neurosteroid” hormones released by the HPA axis that trigger stress-related biological adaptations also serve to dampen its activity through a “negative feedback” mechanism. In re-defining the biological model of how neurosteroids control the HPA axis, a study led by Jamie Maguire, PhD at Tufts University (Boston, MA) provides some fascinating insights [2]. Moreover, this study has some extremely interesting and counter-intuitive implications for understanding the functions of the “inhibitory” brain chemical gamma-aminobutyric acid (GABA), which is best known for opposing the effects of “excitatory” brain chemicals in order to balance the flow of electrical activity in the brain.

To study how the HPA axis is regulated by neurosteroids, Maguire’s team performed investigations in mice using the neurosteroid tetrahydrodeoxycorticosterone (THDOC). The investigators found that THDOC, when applied to a discrete population of cells in the thalamus called the paraventricular nucleus (PVN), resulted in a decrease in blood levels of corticosterone (the mouse equivalent of the human stress hormone, cortisol). This finding highlights the importance of the PVN as a key anatomical locus in the brain where neurosteroids act, and is consistent with the traditional view of neurosteroids as “negative regulators” of the HPA axis. However, in mice that underwent a stressful “restraint” procedure, it was found that a prior treatment with THDOC (thirty minutes before the stressful experience) resulted in augmentation of corticosterone levels (i.e. relative to mice that underwent the stressful experience but did not receive prior THDOC treatment). In parallel, it was shown that while application of THDOC normally decreased the electrical activity of PVN cells, it actually led to increases in mice that had undergone restraint. Taken together, these findings provide evidence that neurosteroids can have opposite effects on the HPA axis depending on the “stressed” state of the organism.

Thinking about how a neurosteroid hormone can exert opposite effects on PVN cells in the thalamus may be confusing, but what may be more confusing is that these different actions depend on the same “inhibitory” brain chemical, GABA (a neurotransmitter), as well as the same molecular “machinery” (or receptors) with which GABA interacts. This was demonstrated by using mice in which a particular sub-component (or subunit) of the GABA receptor, the gamma subunit, had been genetically deleted; neurosteroids had absolutely no effect on the activity of the HPA axis (neither positive nor negative) in these gamma subunit-deficient mice.

How is it possible to explain the seemingly paradoxical finding that neurosteroids can exert opposite effects on the HPA axis through the same neurotransmitter system? In addressing this question, it is important to remember that although neurotransmitters may be thought of as excitatory or inhibitory, their ability to trigger these effects depends solely on the molecular and cellular apparatus with which they interact. Normally, the inhibitory actions of GABA upon the electrical activity of nerve cells depend on the maintenance of an “electrochemical” gradient by a “transporter” molecule called KCC2 (which transports chloride ions out of cells). Maguire’s team showed that “dephosphorylation” (i.e. the removal of a small chemical moiety – the phosphate group – which is covalently bound at a specific site on the molecule) of KCC2 resulted in lower detectable levels of this transporter in the PVN. Similarly to innumerable other examples in biology where dephosphorylation (or the reverse, phosphorylation) serves as an exquisite regulatory mechanism for controlling the activity of molecular networks, removal of the phosphate group from KCC2 acts as a molecular “switch” that causes the breakdown of the electrochemical gradient. The outcome is that GABA has an excitatory influence on neural activity instead of the inhibitory influence with which it is usually associated.

In common with many important contributions to scientific understanding, these findings should serve as a reminder that it is often necessary to challenge and question what is already “accepted” in our theoretical models, in the light of unexpected and sometimes counter-intuitive experimental results. Whatever the line of scientific inquiry may be, the reward for doing so will be a deeper and more comprehensive understanding of the natural phenomena being studied. The findings of Maguire and colleagues, published in the Journal of Neuroscience, have possible therapeutic implications for disorders associated with disrupted function of the HPA axis, including epilepsy and depression.


1. http://www.nature.com/nrn/journal/v10/n6/full/nrn2647.html

2. http://www.jneurosci.org/content/31/50/18198.long


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