Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.
A team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.
De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.
Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analysing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.
‘Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,’ said Gleeson. Realising they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.
The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.
‘We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly,’ said Gleeson. ‘These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.’
The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.
‘Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere,’ said Mathern. ‘Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere.’
But a less-invasive drug therapy would still be more appealing.
‘We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly,’ said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. ‘We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?’ EurekAlert

Virginia Commonwealth University School of Medicine researchers have discovered that changes in the gene expression of a key enzyme may contribute to high blood pressure and increase susceptibility to forming blood clots in pregnant women with preeclampsia.
These findings could provide clues to the best treatment approaches for high blood pressure and the formation of blood clots that can block blood flow to a pregnant woman’s internal organs and lead to organ failure.
Researchers have been working to determine the root cause of preeclampsia on the molecular level and have now identified that epigenetic mechanisms may be at play. Epigenetics refers to changes in gene expression that are mediated through mechanisms other than changes in the DNA sequence.
In a study published, the VCU team reported that thromboxane synthase – an important inflammatory enzyme – is increased in the blood vessels of expectant mothers with preeclampsia. The thromboxane synthase gene codes for this enzyme, which is involved in several processes including cardiovascular disease and stroke. This enzyme results in the synthesis of thromboxane, which increases blood pressure and causes blood clots.
‘The present work is unique because it opens up a new concept as to the cause and subsequent consequences of preeclampsia relating to epigenetics,’ said corresponding author Scott W. Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology. ‘It is the first study to show that epigenetic alterations in the blood vessels of the mother are related to preeclampsia.’
According to Walsh, one of the main epigenetic mechanisms is methylation of the DNA, which controls the expression of genes. The increase of this enzyme in the blood vessels is related to reduced DNA methylation and the infiltration of neutrophils into the blood vessels. Neutrophils are white blood cells that normally help fight infection.
In the future, Walsh said some potential treatments for preeclampsia may include inhibition of thromboxane synthase, blockade of thromboxane receptors or dietary supplementation with folate. He said that folate supplementation could increase methylation donors to protect against adverse changes in DNA methylation that affect expression of the thromboxane synthase enzyme. Virginia Commonwealth University

BlueGnome is pleased to announce the results of the first randomised prospective IVF study of pre-implantation chromosome analysis using their 24sure array platform. The study by Yang et al (Pacific Reproductive Center,Torrance, USA) has demonstrated that selectively implanting euploid embryos, with a normal number of chromosomes, significantly increases pregnancy rates.
The study blindly randomised 103 IVF cycles. In the treatment group of 55 cycles, 24sure analysis of day 5 biopsies was used to selectively implant a single euploid embryo (as recommended by IVF regulatory bodies such as the HEFA), while in the control group of 48 cycles single embryos were selected using existing morphological scorecard approaches. The ongoing pregnancy rate, after 20 weeks, per cycle started was 69.1% in the 24sure treatment group vs 41.7% in the control group. This extremely promising result provides direct evidence that 24sure analysis can deliver a 65% increase in pregnancy rates, even in younger patients with more favourable IVF outcomes. Further randomised studies are needed and are underway.
‘This study provides crucial evidence that 24 chromosome aneuploidy screening, using 24sure, can offer a dramatic benefit to IVF success rates. While further studies are still needed, this result is incredibly exciting because it indicates for the first time that 24 chromosome screening and single embryo transfer has the potential to become the default standard of care for all IVF cycles worldwide.’ Nick Haan, CEO, BlueGnome Ltd, BlueGnome

Scientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’ The Centre for Addiction and Mental Health