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Family, Friendship And Scientific Collaboration Are Part Of Research That Has Shed Light On A Rare Form Of Epilepsy
Scotty Sims and Jim Johnson's daughter suffered from nearly continuous epileptic seizures in her first month of life. Diagnosed with a KCNQ2 genetic change of uncertain significance, her parents began a search for researchers studying the gene. When their daughter was just 6 months old, they found Cooper's lab and shared her history and test results. This led Cooper and others to study the child's illness and seek better treatments. Now 12, their daughter uses an adaptive communication device to make requests and uses modified sign language. Read about their first visit to the Cooper Lab here.
Variants in the KCNQ2 gene are now known to be among the more common genetic causes of epilepsy in early infants, yet the reasons why some variants lead to mild illnesses and others more disabling have remained poorly understood.
In the current study, Abreo and his colleagues gained focus when genetic testing revealed a single amino acid change – glycine 256 changed to tryptophan (G256W) – on one copy of the KCNQ2 gene. This change was previously unknown and remained unique for several years. The team carefully characterized the clinical and developmental history of the young patient. In infancy, developmental delays became apparent, and she subsequently was diagnosed with cortical visual impairment and autism spectrum disorder.
The researchers followed the scientific literature and later found three other individuals in Asia and the EU with the same G256W variant and symptoms similar to the U.S. Patient. This observational study component allowed the team to specify the features to be modelled in the laboratory.
They analyzed the pathogenicity of the G256W variant using molecular, cellular and in vivo approaches. They modelled the structural consequences based on reported cryo-electron microscopy structures of the KCNQ2 channel and other closely related channel proteins.
Like other potassium channels, KCNQ2 possesses three critical regions called the turret, the pore helix and the selectivity filter. Disease causing variants tend to lie in residues near the selectivity filter, due to its crucial role enabling ions to flow. However, the G256 amino acid lies relatively far from the selectivity filter, which would typically indicate that a variant could be less likely to cause illness. The team uncovered evidence that G256 helps form a network of hydrogen bonds that serve to stabilize the structure of the pore-forming region. This provided a novel hypothesis for why an amino acid mutation so distant from the selectivity filter might be pathogenic.
Next, Abreo and colleagues conducted a series of experiments in which they introduced the G256W variant into cells alongside normal KCNQ2 and KCNQ3 genes. They measured electrical activity in the cells and observed that the presence of the G256W variant suppressed the function of the normal gene and reduced the ion current generated by the cells.
Finally, they used Crispr/Cas9 gene editing techniques and generated mice carrying the same G256W variant. Mice with G256W showed alterations in the distribution of KCNQ2 and KCNQ3 proteins within the brain, specifically in a region called the hippocampus that plays essential roles in learning and memory.
They found that, in the mouse models, KCNQ2 and KCNQ3 proteins were shifted from their usual location in axon initial segments to the neuronal somata, which is expected to diminish their ability to contribute to neuronal firing. Other experiments showed that the levels of KCNQ2 protein were decreased by roughly 50%, and the neurons in the CA1 region of the hippocampus showed heightened excitability, potentially indicating greater seizure susceptibility. Indeed, newborn and older G256W mice had spontaneous seizures that led to premature mortality not seen in control mice.
"Taken together, our study reveals that the presence of KCNQ2 G256W variants affects both molecular and cellular aspects of KCNQ channel activity, including their ion-conducting ability, expression and placement within cells," said Cooper, who is the study's senior author. "These changes likely play roles in the pathogenicity of the variant, and in the clinical symptoms of KCNQ2 encephalopathy observed in the individuals with this variant."
"Our results may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter," added Abreo.
In addition to caring for their child, Sims and Johnson have for a decade pursued efforts to connect and support a community of families with children living with KCNQ2 illnesses worldwide. Scotty founded the KCNQ2 parents' group on Facebook, which has grown to about 900 members, and the couple jointly founded the KCNQ2 Cure Alliance, a nonprofit organization that offers support and information to families and caregivers, information on clinical trials, and raises funds for research. Jim Johnson introduced Cooper to co-author Dr. Cathleen Lutz and colleagues at the Rare Disease Translational Center, the Jackson Laboratories (Bar Harbor, Maine), leading to the development of KCNQ2 mice including those studied by Abreo and others.
Potential Treatment For Genetic Epilepsy Identified
A novel therapeutic focus has emerged for CDKL5 deficiency disorder (CDD), a prevalent form of genetic epilepsy. (1✔ ✔Trusted SourceCell type-specific expression, regulation and compensation of CDKL5 activity in mouse brainGo to source)CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function. In research published today in Molecular Psychiatry, the scientists studied mice that don't make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. 'Targeting a calcium channel may present a viable therapeutic approach for addressing CDKL5 deficiency disorder (CDD), a widespread genetic epilepsy variant. #worldepilepsyday #epilepsy ' The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn't produced.Interestingly, even in mice that don't produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.
By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.
The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remainingTheir research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development.
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Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory at the Crick, said, "CDD is a devastating condition that impacts young children from birth, and we don't know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we've identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse."The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD.
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Reference:Epilepsy Not Caused By Spiritual Attack – Neurologists
Neurologists and brain health advocates have dismissed the long-standing myth that persons living with epilepsy are under a spell, curse or spiritual attack.
In Nigeria, epilepsy is usually attributed to witchcraft attacks, demonic possession, destiny and heredity.
However, the experts, in separate interviews with PUNCH Healthwise, stated that epilepsy was a brain disease that had a traceable scientific cause.
The experts, speaking on the sidelines of the International Epilepsy Day, which is commemorated on the second Monday in February, called for an end to the stigma and unfounded myths associated with the disease and persons living with it.
It was celebrated on February 12 with the theme, "Milestones on My Epilepsy Journey."
According to the World Health Organisation, epilepsy is the most common chronic brain disease that affects people of all ages.
America's National Institute of Neurological Disorders and Stroke, notes that epilepsy is a brain disorder in which groups of nerve cells in the brain sometimes send the wrong signals and cause seizures.
The WHO stated that more than 50 million people globally have epilepsy and nearly 80 per cent of them live in low and middle-income countries.
The global health body, however, noted that 70 per cent of people living with epilepsy could be seizure-free if properly diagnosed and treated.
To celebrate IED, the Sub-Saharan Africa Brain Health Initiative in its Global Action for Brain Health Series, organised a virtual event themed, Epilepsy: Epidemiology, Language and Policy.
Speaking during the event, the co-founder of SSABHI, Laz Eze, stated that epilepsy was a brain health issue that affected all of the dimensions of brain health cognitive, mental, social, emotional, and physical components.
He clarified that epilepsy was not a psychiatric and mental health problem but a neurological disorder and brain health.
"So we need to rethink these disorders from the perspective of brain health. Even in the presence of a brain disease, like epilepsy, you can have brain health and you can promote brain health.
"The concept of Brain Health provides far greater opportunities for innovation research, and prevention. It also enhances interdisciplinary work and learning and has the potential to reduce stigma and exclusion.
"So, the word epilepsy, I would say, reframing and rethinking epilepsy for prospective brain health is very powerful. It's very possible to think about how we can address the social, emotional, mental, and cognitive impacts of epilepsy that are impacting people who are living with this condition of their quality of life. It also allows us to think about the potential for prevention," Eze said.
Commenting on the issue, a professor of Clinical Neurology and Internal Medicine at the University of Nigeria, Nsukka, Enugu State, Ikenna Onwuekwe, debunked claims that epilepsy was as a result of witchcraft or ancestral curses, spiritual problems or attacks.
He asserted that epilepsy was a disease that affected the brain and had clear causes.
Onwuekwe also said that although epilepsy was preventable and treatable, it was also a genetic condition that could be inherited.
The don added, "Some causes of epilepsy are due to genetic causes. These types usually appear as epilepsy syndromes because they are also associated with other complications like learning difficulty, intellectual decline or other organ abnormalities such as skeletal shape etc. Such genetic abnormality-associated epilepsy is often passed down to offspring and hence hereditary. Most causes of epilepsy are not normal genetic and are often preventable or treatable such as meningitis.
"In many cases of epilepsy, at least 70 per cent are so responsive to medical treatment that they can be taken off medications and remain seizure-free for life. About 30 per cent will need to be on maintenance medications to enable them to live a near normal life as much as possible."
Speaking on the popular myth that epilepsy was communicable, Onwuekwe said, "Epilepsy is not a communicable disease. It cannot be contracted by touching a person or by contact with body fluids."
Onwuekwe, who is a researcher in Stroke/Vascular Neurology and Epilepsy, said that a difficult pregnancy and childbirth, lack of access to routine immunisations, newborn infections and inflammations were some causes of childhood epilepsy.
The neurologist noted, "Many cases of epilepsy can be prevented especially those cases due to babies being born in difficult pregnancy and labour settings due to either ignorance or lack of suitable maternal and child health services that permit safe pregnancy, safe deliveries, proper care of the newborn, adequate nutrition for mother and child as well as access to routine immunisations. Perinatal causes of epilepsy due to maternal or newborn infections/inflammations and birth trauma are major causes of epilepsy in children which persist into adult life.
"Some cases of epilepsy, called benign types of epilepsy, may be limited to childhood and not be present in adulthood."
He, however, stated that epilepsy in children could give rise to complications that may persist or manifest later in life.
The don also noted that although a few seizure types could be outgrown, not every epilepsy seizure type can be outgrown with age.
He advised individuals around persons having epileptic seizures to "get the person to be free and safe from dangerous nearby objects. Remove any tie or piece of clothing that is threatening the airway and lie the individual in a semi-prone position with the head face down and supported on a soft material.
"Do not allow a crowd around him or her as this may reduce good quality air supply for breathing. Call the Emergency line or make arrangements to take the individual to a nearby hospital where proper medical attention can be given.
"The individual's personal belongings are often at this stage best safeguarded to prevent theft or damage. Most seizures begin and end within 5 minutes, though they may be recurrent."
Also speaking on International Epilepsy Day, Onwuekwe said that people living with epilepsy can have normal and fun-filled lives.
"Children and adults with epilepsy need not suffer stigma or discrimination. Ignorance is the enemy while information is key. Remember that epilepsy is not due to witchcraft or village people and has nothing to do with marine spirits or ancestral curses. Also, know that epilepsy is not infectious and cannot be transmitted by physical contact or body fluids. Our pastors and clerics should be enlightened to stop spreading such nonsense. Support and love people living with epilepsy. Bring your family members and friends who you suspect have epilepsy to the Neurologist for care. Bring epilepsy out of the shadows!" the neurologist strongly stated.
Also, a Prof of Neurology at Ahmadu Bello University, Kaduna, Onyeadumarakwe Obiako, noted that epilepsy, like stroke and Parkinson's, was a disease of the brain and not a spiritual disease.
He also noted while epilepsy could be a familial trait, the majority of the cases were due to brain injury.
The don said, "Epilepsy is a disease of the brain just like stroke, Parkinson etc, so it is not a spiritual disease. However, since the brain houses the spirit of the body, diseases of the brain can be said to be spiritual.
"Some are familial (grandmal) while the majority is due to brain injury (focal epilepsy)."
Obiako, who is also a researcher on stroke & epilepsy, noted epilepsy was not curable, stating that most of the time, treatment was for life.
To further reduce the incidence of crisis, the neurologist urged persons living with epilepsy to regularly take antiepileptic drugs.
Obiako further dismissed popular claims that the spittle or foamy secretions from epileptic patients during their crisis could infect people close by with the condition.
He added, "It is not a communicable disease, because it is not an infection and has no vector. It can start from childhood if the child suffers brain injury in the uterus or from birth or after birth and can be prevented if the brain is protected and injury is prevented.
"Once brain injury leads to epilepsy, it cannot be outgrown, although there could be some remission for years with regular treatment."
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