Ava Begley’s parents say they feel “deeply grateful” that the researchers, from 91ֱ�� University NHS Foundation Trust (MFT) and The University of Manchester (UoM), have made this discovery, which is one of the most common genetic causes of severe epilepsy.

Delivered through the this groundbreaking work is already transforming the lives for many children and young people around the world, providing long-awaited answers and hope for the future.

Ava’s parents, Daniel Begley and Elizabeth Dowd, from Sydney, Australia, said: “Our first reaction was a mixture of emotion – relief at finally having a diagnosis, but also sadness in understanding the seriousness of the condition and how rare it is. Above all, we felt grateful that Ava’s experience may contribute to greater knowledge and future progress and treatment.”

This new condition, which the researchers have named as “Recessive RNU2-2-related neurodevelopmental disorder”, results in difficult-to-control seizures and severe developmental delays in children, often appearing within their first year of life.

Published in the journal , the research has so far identified 84 individuals living with the new condition, while experts estimate that thousands more remain undiagnosed across the world.

The team estimates that millions of people globally could be ‘carriers’ of the faulty gene behind this disorder.

91ֱ�� lead and first author of the paper Dr Adam Jackson, Academic Clinical Fellow at the 91ֱ�� Centre for Genomic Medicine, part of MFT, and The University of Manchester, explained: “We believe that as many as in 1 in 100 people could unknowingly be carriers of this condition. If both parents are carriers, there is a 1 in 4 chance with every pregnancy that their child could be affected. We estimate roughly 1 in 40,000 people may be living with this condition, making it one of the most common neurodevelopmental disorders currently known. Our discovery brings hope for many patients and families who have been searching for answers and is already having a positive impact around the world.”

This major advance builds on in which they showed the importance of the RNU genes in brain development and function.

The research team made the new discovery by analysing changes in several hundred RNU genes in data of individuals who took part in the 100,000 Genomes Project, a Genomics England initiative to sequence and study the role genes play in health and disease.

Dr Jackson, who is also an early career researcher in the NIHR 91ֱ�� BRC’s Rare Conditions Theme, explained: “What makes this discovery even more remarkable is that RNU2-2 is extremely small in comparison to other genes. Unlike most other genes, RNU2-2 does not even make a protein. We were astonished to discover how changes in this tiny gene can have such profound effects in so many individuals.”

Children with the condition experience severe early on in life, often in their first year. This means they have seizures – sudden surges of electrical activity in the brain which can cause the body to stiffen, jerk, shake and lose consciousness. These seizures can be difficult to fully control with medication, highlighting the urgent need for improved therapies.

The condition also has a profound impact on brain development, causing delays or inability to achieve key milestones such as walking or talking. Almost all affected individuals have significant learning problems.

Ava’s story

6-year-old Ava has lived with complex neurological symptoms from early childhood and requires full-time care and ongoing medical support.

Ava’s condition includes developmental delay, profound intellectual disability and severe epilepsy with frequent seizures. She would often experience 100 to 200 seizures per day, but these are now more controlled with medication.

Ava is non-verbal and cannot communicate through speech or gestures. She requires full-time support with daily life, including bathing, toileting and feeding. She also experiences major motor and balance difficulties, can only walk short distances and falls frequently. Ava often bites and pulls hair out and screams in frustration.

Collaborating with 91ֱ�� researchers, the Sydney Children’s Hospital Clinical Genetics Team who support Ava and her family, were able to link Ava’s condition to the newly identified recessive RNU2-2-related disorder.

Ava’s dad, Daniel and mum, Elizabeth, said: “Ava is a beautiful little girl with a bright presence. She loves looking through books, music, sensory play, being outdoors, and spending time with her family. Even with the immense challenges she faces, Ava brings extraordinary love and meaning into our lives. She has a deep presence about her that touches everyone who meets her.

“For many years we have been through extensive medical investigations, specialist appointments, and genetic testing, hoping to find an answer that could explain Ava’s condition and guide her care. Like many rare disease families, we have lived with a long period of uncertainty.

“Having a diagnosis is incredibly meaningful. It gives Ava a name and a place in the medical world, rather than being an unanswered mystery. It helps us feel that we are getting closer to the starting point of being able to find a cure/treatment, and provides hope that research and awareness may lead to better understanding and support in the future.

“We believe that rare disease research is vital, not only for families like ours, but for the broader medical community. Ava’s journey has been challenging, but she is deeply loved, and we are committed to advocating for her and for all children living with rare and complex conditions.”

91ֱ�� lead and senior author Consultant Clinical Geneticist at the 91ֱ�� Centre for Genomic Medicine at MFT, Professor of Genomic Medicine and Rare Diseases at UoM and Rare Conditions Theme Co-Lead at the NIHR 91ֱ�� BRC said: “Our work helps expand knowledge of conditions related to RNU genes, an emerging group of diseases which potentially affect around 1 in 10,000 individuals globally. It also shines a light on the regions of the human genome sometimes dismissed as ‘junk DNA’. We now see that so-called ‘dark regions’ are vital for health.”

Prof Banka, who is also Clinical Director of the , a virtual centre based at MFT which aims to improve the lives of people with rare conditions, added: “At MFT, we have established a dedicated RNU clinic to identify and support more patients with these conditions. Looking to the future, this discovery paves the way to help unlock life-changing treatments for the recessive RNU2-2-related neurodevelopmental disorder.”

Professor Marian Knight, Scientific Director for NIHR Infrastructure, said: “Discovering the cause for conditions like Ava’s is the first step to personalised treatment and improved lifelong health and quality of life. This breakthrough is a testament to the robust research infrastructure the NIHR has developed over the last 20 years, enabling us to turn world-class genomic science into better care.”

• The paper 'Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy is published in DOI: . 

is a spin-out company from the Catalan Institute of Nanoscience and Nanotechnology () and the Catalan Institution for Research and Advanced Studies (), partners of - and supported by - the European Commission’s programme.

INBRAIN’s work involves the decoding of brain signals by implanting innovative, flexible nanoscale graphene electrodes, developed in conjunction with researchers at 91ֱ��’s Nanomedicine Lab and the  (NGI).

These signals may then be used to produce a therapeutic, personalised response for patients with epilepsy, Parkinson’s and other neurological disorders.

This new investment is co-led by Barcelona-based venture capitalists Asabys Partners and Alta Life Sciences, joined by: Vsquared Ventures, a deep tech-focused early-stage venture capitalist based in Munich; TruVenturo GmbH, Germany’s most successful internet company builders; and CDTI, the Spanish Ministry of Science and Innovation.

Fruits of long collaboration

Kostas Kostarelos, Professor of Nanomedicine at The University of Manchester , the NGI and co-founder of INBRAIN Neuroelectronics, said: ‘’This investment for INBRAIN is a testament that graphene-based technologies and the properties of 2D materials have a unique set of propositions to offer for clinical medicine and the management of neurological disorders.

“This did not happen suddenly, though, or by a stroke of good luck in the lab,” he added. “It is the culmination of many years of persistent and consistent work between at least three research institutions, one of which is the Nanomedicine Lab in 91ֱ��, the other two in Barcelona, all working closely and cooperatively under the critically important funding of the Graphene Flagship project.”

The Graphene Flagship is the European Commission’s €1bn research funding spearhead and a key partner of ICN2, ICREA and Graphene@91ֱ��, with a mission is to accelerate advanced 2D materials research and commercialisation.

High costs of brain disease

The high incidence of brain-related diseases worldwide and their huge annual cost - around £700bn in Europe alone, according to a 2010 study by the European Brain Council - call for greater investments in basic research in this field, with the aim of developing new and more efficient therapeutic and diagnostic tools.

Existing brain interfaces are based on metals such as platinum and iridium, which significantly restrict miniaturisation and signal resolution, and are therefore responsible for considerable side effects.

As a consequence, there is a 50% rejection rate of these implants in candidate patients. INBRAIN Neuroelectronics has a disruptive technology proposition, based on the novel material graphene, that overcomes the current limitations of metal-based neural interfaces.

Graphene electrodes allow miniaturisation to nanoscale, with the potential to reach single-neuron resolution. The extraordinary properties of graphene - which is light, biocompatible, flexible and extremely conductive - are harnessed in much smaller devices, which are safer to implant and can be programmed, upgraded and recharged wirelessly.

Driven by artificial intelligence, the implant can learn from the brain of the specific patient and trigger adaptive responses to deliver a personalised neurological therapy. In addition, the use of big data management will permit remote monitoring of the device and data processing.

Better patient outcomes

Carolina Aguilar, founder and CEO of INBRAIN (pictured centre with team, above), said: “Patients with chronic conditions are alone with their diseases, at most they see their physician 1-4 times per year for a follow-up. With less invasive and more intelligent neuroelectronic therapies, we aim to provide safer and real-time adaptive therapies to empower them and improve the outcomes that matter to them.

“This way patients can better deal with their condition between follow-up visits, by getting the right therapy and support when they need it.”

The technology has already been validated in vitro and in vivo, with extensive biocompatibility and toxicity tests mainly performed in 91ֱ�� using preclinical models. This significant investment will be dedicated to bring the technology to human patients, with the execution of multiple clinical trials in collaboration with key neurosurgical and neurological groups in Europe, including various NHS hospitals.

 is one of The University of Manchester’s  - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet. #ResearchBeacons

A new study has shown that people diagnosed with epilepsy in England and Wales are at increased risk of dying from suicide and accidents.

Though the risks of dying unnaturally for people with epilepsy are low in absolute terms (0.3-0.5%), they are higher than in people without epilepsy says from The University of Manchester.

The research conducted at the University of Manchester and Swansea University, and funded by the NIHR, is published in the journal JAMA Neurology today.

The team analysed data from 44,678 people with epilepsy compared to 891,429 persons without epilepsy in England and 14,051 people with epilepsy compared to 279,365 individuals without epilepsy in Wales.

The data shows that compared to people without epilepsy, people with epilepsy are specifically:

• Twice as likely to die by suicide
• Three times more likely to die accidentally
• Five times more likely to die specifically by accidental medication poisoning
• Three and a half times as likely to die by intentional medication poisoning

Opioid painkillers and medicines for mental illness were most commonly taken in fatal poisonings among people with and without epilepsy, whereas fatal overdoses involving antiepileptic drugs were comparatively rare. Antiepileptic drugs were involved in about 10% of poisoning deaths among people with epilepsy.

Dr Gorton said: “Though unnatural death occurs rarely among all groups in the population, people with epilepsy are almost three times more likely to die from any unnatural cause than those without the condition.

“We already know that people with epilepsy are at increased risk of dying prematurely, but such a detailed examination of specific types of unnatural death has not been carried out until now.

“However, the direct causes of these increased mortality risks are not yet fully understood.

“And though the paper identifies an association between mortality and epilepsy, we cannot say for certain what causal mechanisms are implicated.”

Dr Gorton added: “Because of these risks, it’s important that people with epilepsy are adequately warned so they can take measures to prevent accidents.

“We urge clinicians to advise their patients about unintentional injury prevention and monitor them for suicidal thoughts and behaviour.

“We would also advise doctors to assess suitability and toxicity of medication when prescribing medicines for other associated conditions to these individuals .”

The study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014).

Patients with epilepsy who need more information about risks should visit the  and  websites

The study – led by University of Manchester psychologists – is the first of its kind to assess the similarities and differences in how the left and right sides of the brain process semantic memory.

The research, led by Dr Grace Rice and Professor Matthew Lambon Ralph from The University of Manchester, was funded by the Engineering and Physical Sciences Research Council and the Medical Research Council.

The team – working with neuropsychologists at Salford Royal and The Walton Centre for neurology in Liverpool – worked with 41 patients who had part of their brains removed to treat their long-standing epilepsy.

The patients – who now experience fewer seizures and are able to go back to work and learn to drive as a result of the surgery - had their verbal and visual semantic memory tested.

The surgery removes part of the brain that causes the seizures, but also removes tissue which researchers believe is involved in storing semantic memories. Twenty of the patients had surgery to remove part of the brain, called the anterior temporal lobe, on the right side, and 21 had surgery to remove the left anterior temporal lobe.

To test their verbal semantic memory, the team’s assessments included testing patients’ ability to name pictures and celebrities (including Brad Pitt, Princess Di and the Queen), and their ability to match words in terms of their meaning.

And to test their visual memory, the patients were asked to identify emotions of people in photographs and say if a face was familiar to them.

The test results were compared with 20 more people who did not have any neurological problems.

Dr Grace Rice, from The University of Manchester said: “Popularly, there is a lot of interest in whether there are similarities or differences between the left and right sides of the brain.

“Our research for the first time shows that - at least for semantic memory - both sides of the brain play an important role in visual and verbal semantic memory.

“But there is a significance difference when it comes to verbal expression of this knowledge, which was effected more by surgery to the left side of the brain.

“Our research provides an important insight both into what effects this particular kind of epilepsy surgery has on behaviour, but also helps us to understand where in the brain memory is stored.”

‘The roles of left vs. right anterior temporal lobes in semantic memory: a neuropsychological comparison of postsurgical temporal lobe epilepsy patients’ is published in the journal Cerebral Cortex and is available