Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.  These are a wide-ranging collection of conditions that affect the brain.  They include autism, intellectual impairments, developmental delays, attention deficits, tic disorders and language difficulties.

To better understand how gene-disrupting mutations contribute to the biology of neurodevelopmental disorders, researchers recently conducted a large, international, multi-institutional study.   

More than 11,700 affected individuals and nearly 2,800 control subjects underwent targeted DNA sequencing of 208 suspected disease-risk genes. The candidate genes were chosen based on previously published studies.  By looking at greater numbers of cases and using a reliable yet inexpensive molecular inversion probe, the project team wanted to measure the statistical significance of individual, implicated genes.

The study leaders were Holly A. F. Stessman, Bo Xiong and Bradley P. Coe, of the genome sciences laboratory of Evan Eichler at the University of Washington School of Medicine and the Howard Hughes Medical Institute.  Stessman is now at Creighton University.

Their samples were collected through the Autism Spectrum/Intellectual Disability 15-center network spanning seven countries and four continents.  An advantage of this collection, the researchers said, is the ability to check back on a large fraction of cases to try to relate genetic results to clinical findings.  

In their study population, the researchers associated 91 genes with the risk of a neurodevelopmental disorder. These included 38 genes not previously suspected of playing a role.  Based on some of the family studies, however, mutations even in two or more of the risk genes may not be necessary or sufficient to cause disease.

Of the 91 genes, 25 were linked with forms of autism without intellectual disability. The scientists also described a gene network that appeared to be related to high-functioning autism.  Individuals with this form of autism have average to above average intelligence, but may struggle in learning to talk, interact socially, or manage anxiety and sensory overload.  
While observing that some genes were more closely associated with autism and others with intellectual or developmental impairments, the researchers found that most of the genes implicated were mutated in both conditions.  This result reinforces the substantial overlap among these conditions in their underlying genetics and observable characteristics.

“Most of these genes are clearly risk factors for neurodevelopmental disorders in a broad sense,” the researchers explained.  “But analysis of both the genetic and subsequent patient follow-up data did single out some genes with a statistical bias towards autism spectrum disorder, rather than an intellectual disability or developmental delay.”

Additional findings suggest that less severe mutations may be behind autism that is not accompanied by intellectual disability.

University of Washington Health Systemhsnewsbeat.uw.edu/story/sorting-out-risk-genes-brain-development-disorders

EUROIMMUN and Roche announced early April 2017 that they have entered into an option agreement under which Roche gains access to intellectual property in the field of Zika virus immunodiagnostics assigned to EUROIMMUN.
In January 2016, EUROIMMUN became the first company in the world to launch antibody tests that are capable of indicating both an acute Zika virus infection (usually from the fifth day after the onset of symptoms) and previous episodes of the illness. The EUROIMMUN Anti-Zika Virus ELISA is also the first commercial serological Zika test to receive CE (Europe) and ANVISA (Brazil) Mark registrations.
Infectious diseases represent a major cause of death worldwide. Every year, 1.45 million people die of viral hepatitis and in 2014, 1.2 million died of AIDS-related causes. After the 2014 Ebola outbreak, Zika is the latest virus to create significant public health concern. There is growing body of evidence that links the Zika virus to birth defects in fetuses and newborns, and neurological complications in adults. Public health officials and experts in the field consider these associations valid based on a number of epidemiological studies, modelling, and use of predefined criteria. Concern among public health bodies is high since there are currently no effective interventions to control vector mosquitoes.
In order to prepare for the growing health emergency, EUROIMMUN launched the Anti-Zika Virus ELISA (IgM or IgG), a fully automated, highly specific test with reduced cross-reactivity to other flaviviruses. The Anti-Zika Virus ELISA (IgM or IgG) is based on a highly specific, recombinant non-structural viral protein (NS1), which avoids the cross reactivity typically associated with serological tests based on whole virus antigens. Data from panels of well-characterised sera have confirmed that there is no cross reactivity with flaviviruses including dengue, West Nile, yellow fever, tick-borne encephalitis and Japanese encephalitis viruses. In studies on clinically and serologically characterised samples the IgM and IgG ELISAs showed nearly 100% specificity. Furthermore, the combination of IgM and IgG ELISAs provides highest sensitivity of 97%. Serological testing provides a much longer window for diagnosis compared to direct detection methods. This type of testing helps assess a recent infection even when ribonucleic acid (RNA) is no longer detectable – if, for example, the infection is resolved or has moved into the chronic phase. It is therefore critical that any serology assay be extremely specific to Zika to reduce cross-reaction with these other viruses, thus avoiding a potential false positive that could lead to erroneous interpretation of a patient’s immune status.
“Until now it has been virtually impossible to distinguish a Zika virus infection by antibody testing from infections with other flaviviruses like dengue or West Nile virus,” said Dr. Wolfgang Schlumberger, Vice Chairman of the EUROIMMUN’s Board. “Our test may be used by travellers to areas with Zika virus outbreaks to assess any health risks and to take appropriate precautions upon return, and cooperating with Roche will help us make it available to the broadest possible spectrum of patients.”
Learn more about the Anti-Zika Virus ELISA.

A single blood test and basic information about a patient’s medical status can indicate which patients with myelodysplastic syndrome (MDS) are likely to benefit from a stem cell transplant, and the intensity of pre-transplant chemotherapy and/or radiation therapy that is likely to produce the best results, according to new research by scientists at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

In a study, the investigators report that genetically profiling a patient’s blood cells, while factoring in a patient’s age and other factors, can predict the patient’s response to a stem cell transplant and help doctors select the most effective combination of pre-transplant therapies. The findings are based on an analysis of blood samples from 1,514 patients with MDS, ranging in age from six months to more than 70 years, performed in collaboration with investigators from the Center for Blood and Marrow Transplant Research.

MDS is a family of diseases in which the bone marrow produces an insufficient supply of healthy blood cells. Treatments vary depending on the specific type of MDS a patient has; donor stem cell transplants are generally used for patients with a high risk of mortality with standard treatments.

“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said the study’s lead author, R. Coleman Lindsley, MD, PhD, of Dana-Farber. “As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”

Researchers have long known that the specific genetic mutations within MDS patients’ blood cells are closely related to the course the disease takes. The current study sought to discover whether mutations also can be used to predict how patients will fare following a donor stem cell transplant.

Analysis of the data showed that the single most important characteristic of a patient’s MDS was whether their blood cells carried a mutation in the gene TP53. These patients tended to survive for a shorter time after a transplant, and also relapse more quickly, than patients whose cells lacked that mutation. This was true whether patients received standard “conditioning” therapy (which includes chemo- and/or radiation therapy) prior to transplant or received reduced-intensity conditioning, which uses lower doses of these therapies. Based on these results, doctors at Dana-Farber are now working on new strategies to overcome the challenges posed by TP53 mutations in MDS.

In patients 40 years old and over whose MDS didn’t carry TP53 mutations, those with mutations in RAS pathway genes or the JAK2 gene tended to have a shorter survival than those without RAS or JAK2 mutations. In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in reduced-intensity conditioning. This suggests that these patients may benefit from higher intensity conditioning regimens, the researchers indicated.

The study also yielded key insights about the biology of MDS in specific groups of patients. Surprisingly, one in 25 patients with MDS between the ages of 18 and 40 were found to have mutations associated with Shwachman-Diamond syndrome (a rare inherited disorder that often affects the bone marrow, pancreas, and skeletal system), but most of them had not previously been diagnosed with it. In each case, the patients’ blood cells had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after transplantation.

Dana Farber Cancer Institutewww.dana-farber.org/Newsroom/News-Releases/genetic-profiling-can-guide-stem-cell-transplantation-for-patients-with-myelodysplastic-syndrome-study-finds.aspx

Research led by scientists at the University of Birmingham has revealed a new cause of high blood pressure which could lead to major changes in managing the disease.
High blood pressure, also known as hypertension, often goes unnoticed but if left untreated can increase the risk of heart attack and stroke.
Studies estimate that one in four adults suffer from hypertension, but most patients have no identifiable cause for the condition.
However, it is known that in up to 10 per cent of hypertensive patients the overproduction of the adrenal hormone aldosterone – a condition known as primary aldosteronism or Conn syndrome – is the cause of disease.
Now the University of Birmingham-led study has, for the first time, made the important discovery that a large number of patients with Conn syndrome do not only overproduce aldosterone but also the stress hormone cortisol.
Professor Wiebke Arlt, Director of the Institute of Metabolism and Systems Research (IMSR) at the University of Birmingham, said: “Our findings show that the adrenal glands of many patients with Conn syndrome also produce too much cortisol, which finally explains puzzling results of previous studies in Conn patients.
“These previous studies had found increased rates of type 2 diabetes, osteoporosis and depression in Conn patients – problems typically caused by overproduction of cortisol, also termed Cushing syndrome, and not by too much aldosterone.”
The authors of the University of Birmingham-led study, conducted in collaboration with a group of scientists from Germany, decided to name this new cause of hypertension – the combined overproduction of aldosterone and cortisol – as Connshing syndrome.
At present, many Conn syndrome patients are treated with drugs that are directed against the adverse effects of aldosterone. However, this leaves the cortisol excess untreated.
Second author of the study, published in JCI Insight, Dr Katharina Lang – an academic clinical lecturer at IMSR – said: “These findings are very likely to change clinical practice.
“Patients will now need to undergo more detailed assessment to clarify whether they suffer from Conn or Connshing syndrome.

University of Birmingham
www.birmingham.ac.uk/news/latest/2017/04/connshing-syndrome.aspx