New Northwestern Medicine research on the genetics of diabetes could one day help women know their risk for developing gestational diabetes before they become pregnant — and lead to preventive measures to protect the health of offspring.

Gestational diabetes affects 18 percent of pregnancies but usually disappears when a pregnancy is over. Babies born to women with gestational diabetes are typically larger at birth, which can lead to complications during delivery. They are at an increased risk of developing metabolic diseases, such as diabetes, in childhood and adulthood.

This is the first study to suggest differences between the underlying genetic architecture of diabetes in and outside of pregnancy.

Gestational diabetes has been associated with type 2 diabetes, because, during pregnancy, resistance to insulin increases, similar to the effect of weight gain during a lifetime in a non-pregnant state.

But researchers found variants in two genes — HKDC1 and BACE2 — that were associated with measures of glucose and insulin levels of pregnant women but not associated with these measures in the rest of the population, including people with type 2 diabetes.

‘With additional study and verification of these and other risk genes, we could one day have genetic risk profiles to identify individuals at elevated risk for developing gestational diabetes,’ said M. Geoffrey Hayes, first author of the study.

Hayes is an assistant professor of medicine-endocrinology at Northwestern University Feinberg School of Medicine and assistant professor of anthropology at Northwestern’s Weinberg College of Arts and Sciences.

The findings suggest that the roles of the gene HKDC1 in glucose metabolism and BACE2 in insulin secretion are more important during pregnancy versus the non-pregnant state — across all ethnicities studied.

Researchers used DNA and phenotype data of more than 4,000 participants of four different ancestry backgrounds (Hispanic, Thai, Afro-Caribbean and European) from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. HAPO is a multicenter, international study of pregnant women of varied geographic, ethnic and socio-demographic backgrounds.

This study’s findings could one day help pinpoint quantitative genetic traits that predict which women may develop gestational diabetes. North Western University

A large-scale, international study on the genes involved in epilepsy has uncovered 25 new mutations on nine key genes behind a devastating form of the disorder during childhood.
Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder, for which an effective therapy already has been developed.
The findings suggest a new direction for developing genome-wide diagnostic screens for new-borns to identify who is at risk for epilepsy and potentially to develop precise therapies for the condition.
The results are the first to emerge from a set of epilepsy-genetics projects known as EPGP and Epi4K, which were launched by the National Institutes of Health in 2007 and 2012, respectively, and involve more than 40 institutions on three continents. While UC San Francisco and Duke University serve as the administrative hubs, the projects involve a team of nearly 150 scientists across 25 specialities, in the hopes of generating this type of advance on the intractable disease.
‘The limitations of what we currently can do for epilepsy patients are completely overwhelming,’ said Daniel Lowenstein, MD, a UCSF neuroscientist and renowned epilepsy expert who, along with Ruben Kuzniecky, MD, from New York University, is overseeing the Epilepsy Phenome/Genome Project (EPGP). ‘More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.’
The global team started with the most severe forms of the disorder, known as epileptic encephalopathies (EE), which affect roughly one in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities, including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.
‘We knew there was something happening that was unique to these kids, but we had no idea what that was,’ said Elliott Sherr, MD, PhD, a UCSF physician-scientist who is the principal investigator of the Epi4K Epileptic Encephalopathy project and who developed this group of patients within EPGP. ‘In a common disease like cystic fibrosis, you’re likely to see more than one child in a family affected. In this case, it is very rare to have more than one person in the entire family with this condition.’
That lack of clear, inherited links to the disease led them to propose that the condition was being caused by de novo, or brand new, mutations on certain genes.
They set out to test that hypothesis.
The team identified children with two classic forms of EE – infantile spasms and Lennox-Gastaut Syndrome – in which no other family member was affected. They excluded children who had identifiable causes of epilepsy, such as strokes at birth, which are a known risk for this group of disorders. Of the 4,000 patients whose genomes are being analysed in the Epi4K, 264 children fit that description.
The Epi4K sequencing team, led by David Goldstein, PhD, at Duke, ran a genetic scan on the children and their parents, which they compared to thousands of people of similar heritage without epilepsy. They used a cutting-edge new technique called exome sequencing to focus on the exome – the 2 percent of our genetic code that represents active, protein-making genes. Those 25,000 genes are considered to be the code for what makes us unique, including disease mutations.
The genetic analysis revealed 439 new mutations in the children, with 181 of the children having at least one. Nine of the genes that hosted those mutations appeared in at least two children with EE and five of those had shown up in previous, smaller EE studies. Of the four others, two may have been coincidental, the researchers found. But two new genes never before associated with EE – known scientifically as GABRB3 and ALG13 – each appeared with less than a one-in-40-billion statistical chance (p = 4.1×10-10) of being connected to EE by coincidence.
The findings implicated GABRB3, for the first time, as a single-gene cause of EE, and offered the strongest evidence to date for the gene’s role in any form of epilepsy, Sherr said. Knowing this about GABRB3, which is also involved with Angelman’s Syndrome, also offers the possibility that children with mutations only in this gene might benefit from the existing therapy for Angelman’s.
Another new gene, ALG13, is key to putting sugars on proteins, which points to a new way of thinking about the causes of and treatment for epilepsy.
‘The take-home is that a lot of these kids have genetic changes that are unique to them,’ Sherr said. ‘Most of these genes have been implicated in these or other epilepsies – others were genes that have never been seen before – but many of the kids have one of these smoking guns.’ University of California – San Francisco

Jennifer Cochran and Matthew Scott have created a bioengineered peptide that has been shown in mice to provide better imaging of a type of brain tumour known as medulloblastoma.
In a breakthrough that could have wide-ranging applications in molecular medicine, Stanford University researchers have created a bioengineered peptide that enables imaging of medulloblastomas, among the most devastating of malignant childhood brain tumours, in lab mice.
The researchers altered the amino acid sequence of a cystine knot peptide — or knottin — derived from the seeds of the squirting cucumber, a plant native to Europe, North Africa and parts of Asia. Peptides are short chains of amino acids that are integral to cellular processes; knottin peptides are notable for their stability and resistance to breakdown.
The team used their invention as a ‘molecular flashlight’ to distinguish tumours from surrounding healthy tissue. After injecting their bioengineered knottin into the bloodstreams of mice with medulloblastomas, the researchers found that the peptide stuck tightly to the tumours and could be detected using a high-sensitivity digital camera.
‘Researchers have been interested in this class of peptides for some time,’ said Jennifer Cochran, PhD, an associate professor of bioengineering and a senior author of the study. ‘They’re extremely stable. For example, you can boil some of these peptides or expose them to harsh chemicals, and they’ll remain intact.’
That makes them potentially valuable in molecular medicine. Knottins could be used to deliver drugs to specific sites in the body or, as Cochran and her colleagues have demonstrated, as a means of illuminating tumours.
For treatment purposes, it’s critical to obtain accurate images of medulloblastomas. In conjunction with chemotherapy and radiation therapy, the tumours are often treated by surgical resection, and it can be difficult to remove them while leaving healthy tissue intact because their margins are often indistinct.
‘With brain tumours, you really need to get the entire tumour and leave as much unaffected tissue as possible,’ Cochran said. ‘These tumours can come back very aggressively if not completely removed, and their location makes cognitive impairment a possibility if healthy tissue is taken.’
The researchers’ molecular flashlight works by recognising a biomarker on human tumours. The bioengineered knottin is conjugated to a near-infrared imaging dye. When injected into the bloodstreams of a strain of mice that develop tumours similar to human medullublastomas, the peptide attaches to the brain tumours’ integrin receptors — sticky molecules that aid in adhesion to other cells.
But while the knottins stuck like glue to tumours, they were rapidly expelled from healthy tissue. ‘So the mouse brain tumors are readily apparent,’ Cochran said. ‘They differentiate beautifully from the surrounding brain tissue.’
The new peptide represents a major advance in tumour-imaging technology, said Melanie Hayden Gephart, MD, neurosurgery chief resident at the Stanford Brain Tumor Center and a lead author of the paper.
‘The most common technique to identify brain tumours relies on preoperative, intravenous injection of a contrast agent, enabling most tumours to be visualised on a magnetic resonance imaging scan,’ Gephart said. These MRI scans are used like in a computer program much like an intraoperative GPS system to locate and resect the tumors.
‘But that has limitations,’ she added. ‘When you’re using the contrast in an MRI scan to define the tumour margins, you’re basically working off a preoperative snapshot. The brain can sometimes shift during an operation, so there’s always the possibility you may not be as precise or accurate as you want to be. The great potential advantage of this new approach would be to illuminate the tumour in real time — you could see it directly under your microscope instead of relying on an image that was taken before surgery.’
Though the team’s research focused on medulloblastomas, Gephart said it’s likely the new knottins could prove useful in addressing other cancers. Stanford University

What are some of the most troubling numbers in mental health? Six to 10 — the number of years it can take to properly diagnose a mental health condition. Dr. Elizabeth Osuch, a Researcher at Lawson Health Research Institute and a Psychiatrist at London Health Sciences Centre and the Department of Psychiatry at Western University, is helping to end misdiagnosis by looking for a ‘biomarker’ in the brain that will help diagnose and treat two commonly misdiagnosed disorders.
Major Depressive Disorder (MDD), otherwise known as Unipolar Disorder, and Bipolar Disorder (BD) are two common disorders. Currently, diagnosis is made by patient observation and verbal history. Mistakes are not uncommon, and patients can find themselves going from doctor to doctor receiving improper diagnoses and prescribed medications to little effect.
Dr. Osuch looked to identify a ‘biomarker’ in the brain which could help optimise the diagnostic process. She examined youth who were diagnosed with either MDD or BD (15 patients in each group) and imaged their brains with an MRI to see if there was a region of the brain which corresponded with the bipolarity index (BI). The BI is a diagnostic tool which encompasses varying degrees of bipolar disorder, identifying symptoms and behavior in order to place a patient on the spectrum.
What she found was the activation of the putamen correlated positively with BD. This is the region of the brain that controls motor skills, and has a strong link to reinforcement and reward. This speaks directly to the symptoms of bipolar disorder. ‘The identification of the putamen in our positive correlation may indicate a potential trait marker for the symptoms of mania in bipolar disorder,’ states Dr. Osuch.
In order to reach this conclusion, the study approached mental health research from a different angle. ‘The unique aspect of this research is that, instead of dividing the patients by psychiatric diagnoses of bipolar disorder and unipolar depression, we correlated their functional brain images with a measure of bipolarity which spans across a spectrum of diagnoses.’ Dr. Osuch explains, ‘This approach can help to uncover a ‘biomarker’ for bipolarity, independent of the current mood symptoms or mood state of the patient.’
Moving forward Dr. Osuch will repeat the study with more patients, seeking to prove that the activation of the putamen is the start of a trend in large numbers of patients. Lawson Health Research Institute
　

A recent study by members of the Children’s Oncology Group reports results of a large trial showing that children whose leukaemia cells have amplification of a portion of chromosome 21 may require more aggressive treatment for Acute Lymphoblastic Leukaemia (ALL) than children without this gene amplification.

‘This helps identify patients who need more therapy than they may otherwise get,’ says Stephen Hunger, MD, investigator at the University of Colorado Cancer Center, professor of paediatrics at the University of Colorado School of Medicine, and director of the Center for Cancer and Blood Disorders at Children’s Hospital Colorado.

Hunger notes that this genetic abnormality was first described in 2003 and has subsequently been found in about 2 percent of pediatric ALL patients. Initial reports described poor outcomes for small groups of children with this abnormality, but the current study is by far the largest and shows the importance of this genetic abnormality even with modern treatments. The study documents the treatments and outcomes of more than 8,000 cases of pediatric ALL.

‘What we found is that when this genetic abnormality is present in children with good risk features who get a standard level of treatment, there is more treatment failure than with similar, low-risk kids who don’t have this genetic marker. But with kids whose risk features already dictate more aggressive treatment, this genetic abnormality doesn’t seem to be associated with a worse outcome, because kids are already getting the appropriate treatment. Recognising this abnormality could help us treat even otherwise low-risk kids more aggressively up front leading to improved cure rates,’ Hunger says.

Specifically, the genetic abnormality is defined as four or more copies of the gene RUNX1, located on an abnormal chromosome 21. And this amplification is already detected as a by-product of another genetic test standard in pediatric ALL, namely a test for fusion of this RUNX1 gene with the gene ETV6.

‘In a sense, the testing comes for free with other testing you’re already doing,’ Hunger says.

A study published by the same group in 2012 showed that pediatric ALL cure rates are at or above 90.4 percent.

‘In early 1960s this disease was incurable,’ Hunger says. ‘Then in the late 1960s, the cure rate was 10 percent. Now 90 percent of children and adolescents diagnosed with ALL will be cured. Still, a 90-percent survival rate is little consolation to the 10 percent of families whose child doesn’t survive. There’s still more work to be done.’ University of Colorado Cancer Center