A multi-institutional group of researchers, led by investigators at Children’s Hospital Los Angeles and the University of Michigan, have identified a simple and inexpensive tool for assessing the prognosis of paediatric brain tumours called ependymomas. Their study, which demonstrates the epigenetic mechanism behind these tumours, may offer future opportunities for novel therapeutic options.

Childhood posterior fossa ependymomas (PF) are tumours found largely in the hind brain (consisting of the cerebellum, pons and the brainstem) of children. Routine assessment of tumour grade and other markers in PF ependymomas do not correlate well with outcomes in these tumours, highlighting the need for new prognostic markers. Genomic sequencing efforts have not identified mutations in these tumours, and the origin of PF ependymomas remains obscure.

While lacking recurrent genetic mutations, a subset of these tumours exhibit alterations in DNA methylation. In this study, the researchers looked at modification of histones – protein components of the chromatin around which DNA winds, and which play a role in gene regulation – in particular, histone H3.

Co-lead investigator, Sriram Venneti, MD, PhD, of the Department of Pathology at the University of Michigan, observed that histone H3 is modified differently in paediatric posterior fossa ependymoma. Specifically, 80 percent of these tumours exhibited loss of the H3K27me3 a repressive mark, while 20 percent of tumours retained H3K27me3.  Researchers went back and looked at MRIs and outcomes of children treated for these tumours and identified that tumours with loss of H3K27me3 tumours behaved more aggressively and showed poor overall survival.  This suggests that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.

“Detection of H3K27me3 by immunohistochemical staining is a widely available and cost effective surrogate molecular marker.  This test can be readily implemented in most departments of pathology and provides a much-needed tool to risk stratify and identify ependymoma patients who would potentially benefit from epigenetic therapies,” said co-lead investigator Alexander R. Judkins, MD, of the Department of Pathology and Laboratory Medicine at CHLA and Keck School of Medicine of the University of Southern California.

This loss in H3K27me3, along with other epigenetic changes, was similar to that observed in another type of paediatric brain tumour of the hind brain region termed diffuse intrinsic pontine gliomas (DIPGs).  This suggests that both of these tumours arise from similar epigenetic states. Intriguingly, researchers found that certain progenitor cells in this part of the brain also showed low H3K27me3, suggesting – as both tumours share epigenetic similarities – that low methylation of H3K27me3 is important to the development of tumours in this region of the brain.

Children’s Hospital of Los Angeles www.chla.org/press-release/biomarker-identified-aid-prognosis-pediatric-ependymomas

Researchers from Trinity College Dublin have shown for the first time that Motor Neurone Disease (MND) — also known as Amyotrophic Lateral Sclerosis (ALS) — and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked.
By analysing the genetic profiles of almost 13,000 MND cases and over 30,000 schizophrenia cases, the researchers have confirmed that many of the genes that are associated with these two very different conditions are the same.
In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between MND and psychiatric conditions has been shown.
Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said: “This study demonstrates the power of genetics in understanding the causes of diseases."
"While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.”
Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre at Beaumont Hospital Dublin, Orla Hardiman, is the senior author and lead investigator on the project.
Professor Hardiman said: “Our work over the years has shown us that MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.”
She continued: “So instead of thinking of MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilise the failing brain networks." 
“The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one. We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock-on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions."
The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman. These studies showed that people with MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide.
This was first noted as family histories were ascertained from people with MND in the National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013.
This led the Trinity group to team up with European collaborators in MND including the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia to see if these epidemiological observations could be due to a genetic overlap between MND and schizophrenia.
The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.

Trinity College Dublin
www.tcd.ie/news_events/articles/scientists-discover-shared-genetic-origin-for-mnd-and-schizophrenia/7681

The Wellcome-funded diagnostic – developed by researchers at University College London (UCL) and the Western Eye Hospital – allows doctors to see individual nerve cell death in the back of the eye.
Early detection means doctors can start treatment before sight loss begins. The test also has potential for early diagnosis of other degenerative neurological conditions, including Parkinson’s, Alzheimer’s and multiple sclerosis.
Professor Francesca Cordeiro, at UCL Institute of Opthamology, who led the research, said: "Although detection has been improving, most patients have lost a third of vision by the time they are diagnosed.
"Now, for the first time, we have been able to show individual cell death and detect the earliest signs of glaucoma. While we cannot cure the disease, our test means treatment can start before symptoms begin."
Glaucoma affects 60 million people worldwide and one in ten go blind.
The new technique means patients could be diagnosed up to ten years earlier than is currently possible.
Bethan Hughes, Wellcome’s Strategic Development Lead for Innovation, said: "This innovation has the potential to transform lives for those who suffer loss of sight through glaucoma, and offers hope of a breakthrough in early diagnosis of other neurodegenerative diseases."
Loss of sight in patients with glaucoma is caused by the death of cells in the retina at the back of the eye – apoptosis.
The new technique is called DARC, which stands for detection of apoptosing retinal cells.
It uses a specially developed fluorescent marker which attaches to cell proteins when it’s injected into patients. Damaged retinal cells appear as white fluorescent spots during eye examination.
Initial clinical trials were carried out on a small number of glaucoma patients and compared with tests on healthy people to establish the test’s safety.
DARC uses equipment that is already part of routine hospital eye examinations.
The researchers hope that eventually it may be possible for opticians to do the tests. This would mean even earlier detection of the disease.
Treatment for glaucoma is much more successful when it is begun in the early stages of the disease.
Further studies will now be carried out into DARC and how it could be used to detect other neurodegenerative conditions where increasing numbers of nerve cells are lost as the disease progresses.

Wellcome Trust
wellcome.ac.uk/news/new-eye-test-detects-earliest-signs-glaucoma

The scientists from the Montreal Neurological Institute and Hospital at McGill University, led by Peter McPherson, along with collaborators in Saudi Arabia, Jordan, Germany, and at SickKids Hospital and the University of Toronto, have discovered that a severe form of epileptic encephalopathy is caused by recessive loss-of-function mutations in the gene DENND5A.
Epileptic encephalopathy is a rare but devastating sub-form of epilepsy that results in severe mental and physical disabilities in children from birth. It is often caused by improper development of the brain. Individuals with epileptic encephalopathy caused by mutations in DENND5A present with serious anomalies in brain structure along with calcifications in the brain and altered facial features.
Researchers performed whole exome sequencing on three children with epileptic encephalopathy from two families, one from Saudi Arabia and another from Jordan. Both families were consanguineous, meaning the parents were related to each other. This greatly increases the chance that rare mutations that are recessive and that cause no harm to the parents are expressed in the children. The whole exome sequencing, along with extensive and complex genetic analysis, revealed that recessive mutations in DENND5A were responsible for the disease, with the Saudi family and the Jordanian family having different mutations but in the same DENND5A gene. They found that mutations in DENND5A lead to a lack of the DENND5A protein, resulting in underdevelopment of the central nervous system. The protein expressed from the DENND5A gene is present at highest levels in the nervous system especially while the brain is developing, corroborating the evidence that mutations in the gene cause epileptic encephalopathy.
The researchers discovered that the DENND5A protein controls the movement of receptors for key developmental factors called neurotrophins. Disruption of DENND5A function leads to altered levels of these receptors, which could explain why loss of DENND5A leads to the severe neurological developmental defects in the patients.
Epilepsy affects approximately three per cent of the world population, and epileptic encephalopathy is a rare sub-form of the disease. It is difficult to say how many children with epileptic encephalopathy have the DENND5A mutations, but now that the gene has been identified as a cause, researchers around the world can begin to test patients for mutations in this gene.
This finding also improves our understanding of neuronal development. The observation that loss-of-function mutations in DENND5A causes epileptic encephalopathy suggests that DENND5A protein controls membrane trafficking pathways critical for normal neuronal development and strengthens the argument that protein trafficking processes in cells are critical for normal neuronal development and function.
“Our study demonstrates the importance of membrane trafficking in neuronal development and it provides a new pathophysiological mechanism for this disease type. This will allow physicians around the world to test if mutations in DENND5A are causing the disease in their patients, and also to provide genetic counselling for affected families,” says Dr. Chanshuai Han, the lead author on the study.

The Montreal Neurological Institute and Hospital http://tinyurl.com/jfb7aho

Malaria is a leading cause of death for children living in Sub-Saharan Africa. Many children in rural areas seek care at local community health clinics, but these clinics lack reliable tests to distinguish severe and uncomplicated malaria. Working at a health centre in rural Uganda, researchers from the University of North Carolina at Chapel Hill demonstrated for the first time the potential of using a low-cost, routinely available rapid diagnostic test to detect severe malaria in children.
 “In many areas of rural areas of sub-Saharan Africa, malaria is inevitable. Children will be infected,” said Ross Boyce, M.D., MS.c., study author and a fellow in the UNC Division of Infectious Diseases. “Ensuring that those with the most severe form of the disease are quickly identified and treated, even when hours from the nearest hospital, is critically important to reducing the number of deaths.”
Over a period of six months, a total of 2,678 children with fever underwent testing for malaria using a rapid diagnostic test at the Bugoye Level III Health Center in the Kasese District of Western Uganda. Nearly half tested positive for malaria and 83 satisfied criteria for severe malaria. The sensitivity and specificity of the rapid diagnostic test for detecting severe malaria was 97.6 percent. The test was especially sensitive for children less than 5 years of age. Knowing when a child is suffering from severe malaria allows for a referral to a health centre better equipped to handle the disease’s grave manifestations.
“Rapid diagnostic tests have been around for awhile, and are generally considered standard of care in most malaria-endemic settings,” said Boyce. “However, what we’ve done is show that these relatively simple tests can be used in new ways to provide important information beyond just a positive or negative result. While it’s not perfect, the approach could help first-line healthcare workers – many of who have no formal medical training – make potentially lifesaving triage decisions.”
Boyce said further work is needed to validate and operationalize diagnostic and treatment algorithms so as not to overwhelm fragile referral networks.

University of North Carolina
globalhealth.unc.edu/2017/08/rapid-diagnostic-test-malaria/