Down syndrome

Overactive Gene Linked to Heart Defects in Down Syndrome

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About half of all babies born with Down syndrome have heart defects that may require high-risk surgery or ongoing monitoring depending on the severity of the condition. Now, scientists from the Francis Crick Institute and University College London have linked Dyrk1a, a gene on human chromosome 21, to heart defects in these individuals that could open a door to new therapeutic possibilities. Their findings are reported in Science Translational Medicine in a paper titled, “Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome.” 

This isn’t the first time that Dyrk1a has been linked to Down syndrome. Other studies have tied it to cognitive impairment and craniofacial dysmorphology observed in people with Down syndrome, but its link to heart defects is a novel finding. By looking at heart data from embryonic mouse models, the researchers found that Dyrk1a caused heart defects when present in three copies in mice. 

Dyrk1a codes for an enzyme called DYRK1A. The study showed that an extra copy of Dyrk1a turned down the activity of genes required for cell division in the developing heart and the function of the mitochondria. These changes were correlated with a failure to correctly separate the chambers of the heart.

Furthermore, when the researchers tested a DYRK1A inhibitor on pregnant mice with pups that model Down syndrome hearts defects as their hearts were forming, they observed that the genetic changes were partially reversed and the heart defects in the pups were less severe.  

The findings do suggest a potential therapeutic approach targeting this gene could work in humans. “However, in humans the heart forms in the first 8 weeks of pregnancy, likely before a baby could be screened for Down syndrome, so this would be too early for treatment,” noted Victor Tybulewicz, PhD, group leader of the Immune Cell Biology Laboratory & Down Syndrome Laboratory at the Crick and senior author on the paper. “The hope is that a DYRK1A inhibitor could have an effect on the heart later in pregnancy, or even better after birth. These are possibilities we are currently investigating.”

They are also investigating the possible involvement of other genes in heart defect development. While Dyrk1a is an important part of the equation, the researchers suspect it isn’t the only player. This was also reflected in the study data. The evidence shows that Dyrk1a is required in three copies to cause heart defects in mice, it was not sufficient alone. Furthermore, the inhibitor they used only partially reversed the changes in the mouse pups’ hearts. This suggests that another unknown gene must also be involved in the origin of heart defects in Down syndrome. And the team is currently searching for it.

Alongside those studies, the researchers are working with Perha Pharmaceuticals to test the DYRK1A inhibitor for treating cognitive disorders associated with both Down syndrome and Alzheimer’s disease. But they are also exploring other potential therapeutic avenues beyond Dyrk1a.

Rifdat Aoidi, PhD, a postdoctoral project research scientist at the Crick and co-first author, added, “We don’t yet know why the changes in cell division and mitochondria mean the heart can’t correctly form chambers. Dysfunction in the mitochondria has also been linked to cognitive impairment in Down syndrome, so boosting mitochondrial function could be another promising avenue for therapy.”

Hormone Treatment Improves Cognition in Down Syndrome

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Pulsatile GnRH therapy boosted brain connectivity in pilot study

A photo of a man with down syndrome working in a factory.

Regular doses of gonadotropin-releasing hormone (GnRH) boosted cognitive skills in people with Down syndrome (trisomy 21), a pilot clinical trial showed.

Cognitive performance increased in all but one of seven adult men with Down syndrome treated with pulsatile GnRH therapy, a treatment currently used in Kallmann syndrome, according to Vincent Prevot, PhD, of University de Lille in France, and colleagues.

Moreover, interventions that restored GnRH functions reversed olfactory and cognitive defects in Down syndrome mice and in a mouse model of Alzheimer’s disease, Prevot and co-authors reported in Science.

The findings suggest GnRH, a hormone associated with fertility and reproduction, may play a role in olfaction and cognition.

“This is the first study to propose a promising efficient and safe therapy to improve cognition in trisomy 21, though our data have to be validated by a larger-scale randomized clinical trial,” Prevot told MedPage Today.

“The study demonstrates that the GnRH neurons and GnRH could be used by the brain to measure the fitness of the organism and, conversely, that decline in the rhythmic release of GnRH could play a role in the pathophysiology of neurodevelopment disorders and potentially in neurodegenerative diseases in which the loss of olfaction is usually an early sign of the onset of dementia,” Prevot added.

The mouse study data “suggest a similar treatment could be used in patients with Alzheimer’s disease to mobilize their cognitive reserve and improve their well-being,” he said.

Down syndrome, the most common genetic cause of intellectual disability, is caused by having three copies of chromosome 21 instead of the usual two. Many adult Down syndrome patients have symptoms similar to early-onset Alzheimer’s disease and gradual loss of olfaction.

“The loss of olfaction in Down syndrome is frequently associated with deficits in fertility, both of which start around puberty,” observed Hanne Hoffmann, PhD, of Michigan State University in East Lansing, in an accompanying editorial.

Most GnRH-positive neurons project from the hypothalamus to the median eminence and release GnRH in a pulsatile pattern to promote gonadal function and fertility, Hoffmann noted. A subset of GnRH neurons project to the hippocampus and cortex where pulsatile GnRH promotes cognitive function.

“The physiological role of this population of GnRH neurons has remained poorly understood, but now [Prevot and colleagues] have found that they are associated with memory and cognition,” she wrote.

In the pilot study, small minipumps that administered pulsatile GnRH therapy were placed under the skin of seven adult men with Down syndrome. The pumps released GnRH at a rate of 75 ng per kg of body weight per pulse at 2-hour intervals for 6 months. Six age-matched healthy male controls were also recruited to compare baseline parameters.

Pulsatile GnRH improved working memory, attention, and verbal comprehension in the Down syndrome patients. It also increased neuronal connectivity in the hippocampus and cortex.

“However, GnRH treatment did not improve olfaction nor did it change the profile of reproductive hormones, except for a reduction in follicle stimulating hormone, which was close to levels observed in controls after treatment ended,” Hoffmann noted.

“The unexpected findings of the cognition-boosting effect of GnRH have broad potential,” she added. Memory and brain fog problems that emerge during menopause, for example, might be prevented by normalizing the pulsatile release of GnRH with implantable minipumps, she suggested.

“To fully establish the value of pulsatile GnRH to enhance cognitive function, a randomized controlled study including both sexes will be required,” Hoffmann pointed out. “If GnRH neurons that project to cognitive centers in the brain lose their capacity to release GnRH at the required level in older adults, pulsatile GnRH might provide unanticipated benefits to slow down cognitive decline.”

Scientists Have Pinpointed the Gene Responsible for Down Syndrome

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IN BRIEF

A team of researchers from Singapore and the United Kingdom have discovered an enzyme that regulates sperm and egg cell production, which may be linked to Down Syndrome, Patau Syndrome, and other chromosomal aberrations.

UNDERSTANDING THE LINK

Humans have 23 pairs of chromosomes in every cell in their bodies, except for their reproductive cells or gamete cells (sperm or egg), which contain 23 chromosomes. The reason why chromosomes come in pairs is that one pair comes from the egg, and the other from the sperm. So when gametes fuse with each other, they end up as a single cell having two copies of each chromosome.

Gamete cells are produced by a process called meiosis — a type of cell division with two rounds of nuclear division, to make sure that the number of chromosomes in the parent cell is halved. Sometimes, though, errors occur during cell division, which may result to offsprings having abnormal number of chromosomes — a phenomenon called aneuploidy.

Aneuploidy causes Down Syndrome — the most common genetic condition, Patau Syndrome, and other genetic disorders. It is also the leading cause of miscarriage.

Image Credit: iStock/koya79

PLAYING A PIVOTAL ROLE

The research team, led by Dr. Prakash Arumugam from the National University of Singapore, noted how the process of meiosis can affect chromosomal irregularities: “Understanding how meiosis is regulated is of great importance to understanding the causes of aneuploidy and genetic disorders in human,” said Dr Gary Kerr and the team, writing in the journal Scientific Reports.

The researchers have discovered a particular enzyme which plays an essential role in chromosome segregation in meiosis. They identified this enzyme as PP2ACdc55, which is involved in various cellular processes. It was also shown from the research team’s previous findings that PP2ACdc55 plays a vital role in controlling the timing of meiosis, thus preventing the cells from prematurely exiting phases of cell division.

The scientists tracked the enzyme on yeast models using fluorescent tagging, and analyzed the resulting mutant yeast strains, characterized the mutations and determined the role of the Cdc55 gene. Their results suggest that the gene might have a role in meiotic chromosome segregation. This is, without a doubt, a step forward, but we still don’t know what causes the process to go wrong.

BPA Damages Chromosomes, Disrupts Egg Development

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When a woman experiences a miscarriage or has a baby born with a birth defect like Down Syndrome, the cause is usually a mystery. Modern medicine simply does not have an explanation in most cases, although there are some clues coming in.

BPA Products

Story at-a-glance –

  • An animal study found BPA exposure damaged chromosomes and interfered with egg development, which could lead to spontaneous miscarriage or birth defects such as Down Syndrome
  • In animals exposed to continuous low doses of BPA, there were not only problems with initial egg development, but also in the fetal eggs that were developing; the fetal eggs were not “packaged” properly in the follicles, which means they would have difficulty developing and maturing normally
  • Chemical exposures that we’re seeing today have the potential to impact not only your health, but they are also likely changing future generations to come, even if they’re not directly exposed to the chemical
  • One recent study found that pregnant rats exposed to dioxin passed on diseases to their third-generation offspring (or great-grandchildren) via epigenetic transgenerational inheritance, cellular changes that influence the expression of various genes
  • In order to avoid any number of chemical toxins leaching into your food and beverages, choose glass over plastic, especially when it comes to products that will come into contact with food or beverages, or those intended for pregnant women, infants and children

Environmental Chemicals Like BPA May Have Serious Reproductive Effects

Bisphenol-A (BPA) is one of the world’s highest production-volume chemicals and as a result of its widespread use has been found in more than 90 percent of Americans tested. BPA is an endocrine disrupter, which means it mimics or interferes with your body’s hormones and “disrupts” your endocrine system.

The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.

The strongest evidence showing that exposure to environmental chemicals like BPA can lead to disruption of endocrine function comes from bizarre changes seen in a number of wildlife species, such as intersex fish, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.

But evidence is also very strong showing these chemicals are influencing humans, too, and leading to decreased sperm quality, early puberty, stimulation of mammary gland development, disrupted reproductive cycles and ovarian dysfunction, among numerous other health problems, like cancer and heart disease, as well.

In the latest study, researchers found disruptions to egg development after rhesus monkeys, which have human-like reproductive systems, were exposed to either single, daily doses of BPA or low-level continuous doses. The BPA appeared to damage chromosomes, which could lead to spontaneous miscarriage or birth defects.

In the group exposed continuously to BPA, there were not only problems with initial egg development, but also in the fetal eggs that were developing.1 The fetal eggs were not “packaged” properly in the follicles, which means they would have difficulty developing and maturing normally.

Washington State researcher Patricia Hunt noted:2

“The concern is exposure to this chemical that we’re all exposed to could increase the risk of miscarriages and the risk of babies born with birth defects like Down Syndrome. The really stunning thing about the effect is we’re dosing grandma, it’s crossing the placenta and hitting her developing fetus, and if that fetus is a female, it’s changing the likelihood that that female is going to ovulate normal eggs. It’s a three-for-one hit.”

Similar results have been revealed in humans, as women undergoing in vitro fertilization who had higher levels of BPA in their blood had 50 percent fewer fertilized eggs, according to one study, which suggests the chemical is compromising the quality of women’s eggs and perhaps contributing significantly to fertility problems.3

You May be Impacted by Your Great-Grandmothers’ Chemical Exposures

The statement that “no man is an island” is coming all the more true now that we’re seeing regular evidence that our health is intricately tied to the lives of not only our parents but also our grandparents and great-grandparents …The chemical exposures that we’re seeing today have the potential to impact your health for sure, but they are also likely changing future generations to come, even if they’re not directly exposed to the chemical.

One recent study found that pregnant rats exposed to dioxin, a known carcinogen and endocrine disruptor, passed on diseases to their third-generation offspring (or great-grandchildren) via epigenetic transgenerational inheritance, cellular changes that influence the expression of various genes.4 The great-grandkids had high rates of kidney disease, ovarian disease and early-onset of puberty, while males had changes in sperm.

As Scientific American reported:5

“Scientists have long known that environmental exposures can cause genetic mutations. But now epigenetics experts are finding that some exposures seem capable of changing how genes are expressed, or turned on and off, without actually damaging the genes. These changes then can be inherited by future generations.

… ‘The cause of the higher rates of disease in these [third generation] animals was not due to direct exposure, but rather through transmission of changes in the code that regulates gene expression,’ said Abby Benninghoff, who specializes in epigenetics at Utah State University. She was not involved with the study.”

BPA is Disturbingly Common

Thanks to the U.S. Food and Drug Administration’s (FDA) refusal to ban BPA from food packaging in the United States, the chemical will continue to experience steady growth in 2012, with an estimated 4.7 million tons set for production this year. This, in turn, will earn BPA manufacturers a handsome profit of $8 billion.6

So even though some forward-thinking manufacturers have removed BPA from their products, this chemical is still disturbingly common in food and drinks packaging, as well as in other places you probably wouldn’t expect, like thermal printer receipts. So we are all lab rats, in a sense, being subjected to BPA exposures with unknown consequences for ourselves and future generations, whether we like it or not. This is why it’s so important to boycott the common sources of BPA that you can control, such as:

  • Canned foods and soda cans
  • All BPA-containing plastics
  • Certain tooth sealants
  • Certain BPA-free plastics (which can contain similar endocrine-disrupting chemicals)
  • Thermal printer receipts and paper currency (while you can’t “boycott” these, seek to limit or avoid carrying receipts in your wallet or purse, as it appears the chemical is transferring onto other surfaces it touches. It would also be wise to wash your hands after handling receipts and currency, and avoid handling them particularly if you’ve just put lotion or have any other greasy substance on your hands, as this may increase your exposure)

In addition, one way to help protect yourself from the adverse effects of inevitable BPA exposure is by eating traditionally fermented foods, such as raw grass-fed organic kefir, organic fermented veggies like sauerkraut or kimchi, or taking a high-quality probiotic supplement. These foods contain “friendly bacteria,” some of which have the ability to break down BPA, as well as reduce your intestinal absorption of it.7

This is important for everyone, but if you’re pregnant, nursing or planning to become pregnant, avoiding BPA as much as possible becomes all the more crucial.

Switching to BPA-Free Products May Not be Enough …

As a result of widespread consumer backlash, many companies have rolled out “BPA-free” plastic products, ranging from bottles and sippy cups to reusable water bottles, meant to appeal to those health-conscious consumers looking to avoid toxins.

Unfortunately, this may be just a ruse, as studies now show another bisphenol, bisphenol-S (BPS), is now showing up in human urine concentrations at levels similar to those of BPA.8 This suggests that many manufacturers are simply swapping one bisphenol for another. Research suggests BPS has similar hormone-mimicking characteristics as BPA, but it may be significantly less biodegradable, and more heat-stable and photo-resistant, which means it may cause even more health and environmental damage over time.

If you’re interested in avoiding any number of chemical toxins leaching into your food and beverages, choose glass over plastic, especially when it comes to products that will come into contact with food or beverages, or those intended for pregnant women, infants and children. This applies to canned goods as well, which are a major source of BPA (and possibly other chemicals) exposure, so whenever you can, choose jarred goods over canned goods, or opt for fresh instead. Another good idea is to ditch plastic teething toys for your little ones and choose natural wood or fabric varieties instead.

Fewer Complex Heart Defects Seen in Children With Down Syndrome

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Complex congenital heart defects are less common today than previously in children with Down syndrome, Swedish researchers report.

“With the introduction of antenatal screening, many fetuses diagnosed with Down syndrome are aborted,” write Dr. Stefan Johansson of Karolinska Institutet in Stockholm and colleagues in Pediatrics, online June 1. Therefore, “little (was) known about the cardiovascular phenotype in infants with Down syndrome born today.”
To investigate whether risks of specific types of congenital heart defects changed among infants with Down syndrome when antenatal screening was introduced in Sweden, the researchers analyzed data from national health care registers covering the period 1992 to 2012.

They calculated risk ratios for congenital heart defects for each three-year period and adjusted for maternal age, parity, BMI, smoking, diabetes and hypertensive disease, and infant gender.

They found that a congenital heart defect was diagnosed in 54% of infants with Down syndrome. Although year of birth was not associated with the overall risk of any congenital heart defect, the risk of complex congenital heart defects decreased significantly over time.

Compared with 1992 to 1994, the risk in 2010 to 2012 was reduced by almost 40% (adjusted risk ratio, 0.62). By contrast, risks for isolated ventricular septal defect (VSD) or atrial septal defect showed significant increases during later years.

Overall, the three most common congenital heart defect diagnoses were atrioventricular septal defect (42%), VSD (22%) and atrial septal defect (16%). Although atrioventricular septal defect was far more common than VSD in 1992 to 1994, they were equally common in 2010 to 2012.
“Many parents whose newborn babies have Down syndrome are being informed that the risk of complicated heart malformations is high. Therefore, all infants with Down syndrome should undergo heart ultrasound after birth,” Dr. Johansson told Reuters Health by email.

“However, our study shows that the risk of a complicated heart malformation has dropped by 40%. Despite the same underlying genetic abnormality – a third copy of chromosome 21 – the ‘expression’ of Down syndrome has changed in a more favorable direction. The lower risk of complicated heart malformations likely leads to less need of thoracic surgery, a great advantage for many families and babies,” he said.

“Although we did not have access to such data, we speculate that the introduction of prenatal diagnostics of chromosomal abnormalities explains much of the risk reduction. Pregnancies complicated by both Down syndrome and a congenital heart defect may be more often terminated,” Dr. Johansson concludes.

Pediatric cardiologist Dr. Shaji C. Menon of the University of Utah, Salt Lake City, told Reuters Health by email, “The most important finding of this study was the significant reduction over time in the proportion of Down syndrome infants born with complex congenital heart defects like atrioventricular septal defect, while the proportion of infants with simple congenital heart defects like atrial septal defect and isolated ventricular septal defect increased.”

Like the authors, Dr. Menon noted that “this drastic reduction . . . is likely secondary to selective termination of a higher proportion of Down syndrome fetuses with complex congenital heart defects.”

He added, “Even with significant advancements in the management of Down syndrome and its associated defects, the selective termination rates of fetuses with Down syndrome have not decreased. For many parents, the challenges of raising a child with Down syndrome seem overwhelming. (But at the same time), there are couples who are on a waiting list for adopting a child with Down syndrome.”

Pregnancy Test That Can Predict Down Syndrome, Miscarriage, And Twins May Be Available In Just 2 Years

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pregnancy test
The MAP Test hopes to provide expectant parents with accurate information faster.

The days of wondering what to expect when you’re expecting may soon be over. Researchers in the UK are working on eliminating much of the mystery surrounding pregnancies by developing a mail-in test that can predict everything from whether or not a couple is having twins to if an unborn child may have Down syndrome, using nothing more than a urine sample.

MAP Diagnostics is the company behind the first-of-its-kind pregnancy test that would reveal intricate details of both a mother and child’s health months before the actual due date, Smithsonian reported. The test, known as the MAP test, was originally developed to analyze proteins in a mother’s urine to predict chances of having an aneuploid pregnancy, or a pregnancy in which the child has an abnormal number of chromosomes in his cells (the cause of Down syndrome ). The Telegraph reported that the technique is similar to that used in IVF when screening for the best embryo to implant.

However, according to the company’s website, the researchers soon realized that the same technology used to predict Down syndrome could be used to predict other conditions, including: preeclampsia, hyperemesis gravidarum, ectopic pregnancies, gestational diabetes, assisted reproduction, intrauterine growth restriction, and gestational cancer.

According to MAP’s founder and chief scientific officer, Stephen Butler, this ultimate pregnancy test would provide expectant parents with more accurate test results than those currently available. “What we’re trying to do is create more information so people can make better decisions,” Butler explained, as reported by Smithsonian.

The pregnancy test we’re familiar with today was patented in 1972, but humans have recorded their efforts to predict pregnancies for nearly a thousand years. In the 1920s, scientists discovered the pregnancy hormone, human chorionic gonadotropin (hCG), and pregnancy tests started to become a little more accurate. The MAP test works off a similar concept as traditional pregnancy tests but goes one step further by analyzing the hCG for proteins that can indicate other health conditions.

Unlike at-home pregnancy tests, the MAP test would need to be sent to a lab for proper analysis. Also, a woman would need to be at least eight weeks into her pregnancy to get an accurate result. Currently, an amniocentesis procedure, where a doctor draws amniotic fluid from the mother’s uterus using a needle, is the most common way to predict Down syndrome in unborn children. The new test would theoretically provide a non-invasive way to arrive at the same answer.

The test for Down syndrome may take up to two years before becoming available to the public, but MAP Diagnostics developers hope their simpler tests, such as those for preeclampsia, will become available to the global market within six months. According toSmithsonian, the most recent developments on the MAP test were presented at the European Society of Human Reproduction and Embryology in Lisbon in June. Researchers are expected to release further information on their developments at the American Society for Reproductive Medicine conference in Baltimore this fall.

DNA Blood Test is Accurate for Detecting Down Syndrome

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A blood test for pregnant mothers that detects an unborn child’s DNA is better than standard tests at detecting Down syndrome, and returns fewer false positives, US researchers said Wednesday.

DNA Blood Test is Accurate for Detecting Down Syndrome

The cell-free DNA blood test, which finds small amounts of floating DNA from the fetus in the mother’s blood sample, can be given to a woman when she is between 10 and 14 weeks pregnant.

Researchers studied nearly 16,000 women, and found that the cell-free DNA blood test correctly identified all 38 fetuses with Down syndrome in the group, said the study in the New England Journal of Medicine.

However, standard screening given to the same women found only 30 of the 38 cases of Down syndrome.

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Standard screening consists of drawing blood to test for hormones and proteins associated with chromosomal defects, combined with an ultrasound that checks for excess fluid in the back of the fetus’s neck, in an area called the nuchal fold.

Standard screening also returned far more misdiagnoses, with 854 false positive results, compared to nine false positive with the cell-free DNA tool.

When it came to identifying other, less common chromosomal abnormalities, the cell-free DNA test was more accurate than standard screening.

“Among 10 cases of trisomy 18, also known as Edwards syndrome, the cell-free DNA technique pinpointed nine and flagged one false positive,” said the study led by Mary Norton, professor of clinical obstetrics and gynecology at the University of California, San Francisco.

“With standard screening, eight were identified and there were 49 false positives,” it added.

Cell-free DNA testing found two cases of another disorder, trisomy 13, also known as Patau syndrome, and flagged one false positive.

Standard screening found just one case of trisomy 13 and mistakenly diagnosed 28 fetuses.

Researchers cautioned, however, that the cell-free DNA test is unable to find a range of abnormalities that can show up in standard screening.

The team also found that “a surprisingly high number” of disorders turned up in 488 pregnant women whose plasma was disqualified for testing because it had inadequate or an immeasurable quantity of fetal DNA, or other problems interpreting test results. A total of 2.7 percent of these fetuses were found to have chromosomal defects, “markedly higher than the 0.4 prevalence in the overall group,” said the findings.

Since this group was excluded from the final analysis, the success rates of the cell-free DNA test may be skewed high in the report, the authors said.

“Those women who do opt for cell-free DNA testing should be informed that it is highly accurate for Down syndrome, but it focuses on a small number of chromosomal abnormalities and does not provide the comprehensive assessment available with other approaches,” said Norton.

Opioids Prove Effective for Restless Legs Syndrome.

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In a new, placebo-controlled study, prolonged-release opioid treatment with an oxycodone-naloxone combination product produced impressive relief of symptoms in patients with severe restless legs syndrome for whom other therapies had failed.

The study, published online October 18 in Lancet Neurology, was led by Claudia Trenkwalder, MD, Paracelsus-Elena Hospital, Kassel, Germany.

“We found an 8-point reduction in the mean International RLS Study Group rating scale sum score vs placebo,” Dr. Trenkwalder commented to Medscape Medical News. “This is the most effective treatment response ever seen in restless legs syndrome. A reduction of more than 3 points is thought to be clinically significant. While between-study comparisons are always difficult, dopaminergic drugs ― the main agents used ― are associated with reductions of about 4 to 6 points vs placebo. A reduction of 8 points has never been seen before.”

Professor Trenkwalder explained that there has been much interest in using opioids in restless legs syndrome for many years, after a small study conducted in 1993 showed a positive effect in 8 patients. This has been followed by other small case series and anecdotal reports, but there has never been a controlled clinical trial before.

“This trial is long overdue. It has taken us 20 years to get it done, largely because no one wanted to pay for it. But we eventually managed to get funding from MundiPharma and have now definitely proven that this opioid-based combination works and works very well in reducing all symptoms of restless legs syndrome ― sensory, restlessness, pain, and sleep,” she said.

She added that doctors have been using different opioids at different dosages over the years, but this study provides solid evidence in support of one combination product used at a low dosage and given twice a day.

Professor Trenkwalder noted that the inclusion of the opioid antagonist naloxone counters peripheral side effects of the oxycodone in the gastrointestinal system and so minimizes constipation, the major side effect of long-term opioid therapy. She also highlighted the importance of taking the drug combination twice a day ― morning and evening. “Some people just take medication for restless legs syndrome at night, but you then get high levels at night and a trough during the day. It is important to have stable levels of opiates in the brain to get good symptom improvement.”

In an accompanying commentary, Arthur S. Walters, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, says that the data are “especially convincing because the study included patients who were refractory to other treatments. Such patients would normally be much more likely to fail an alternative treatment than patients who have not had previous treatment failure.”

Although he notes that no direct comparisons can be made between drugs, “the treatment difference between groups of 8.15 points is much greater than that for most approved drugs for restless legs syndrome.”

For the study, Professor Trenkwalder and colleagues randomly assigned 306 patients who had had symptoms for at least 6 months and whose International RLS Study Group severity rating scale sum score was at least 15 to study drug or placebo. Study drug was oxycodone 5 mg, naloxone 2.5 mg twice daily, up-titrated according to investigator’s opinion to a maximum of oxycodone 40 mg, naloxone 20 mg twice daily.

The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at the end of the 12-week double-blind phase.

Mean score at baseline was 31.6. This was reduced by 16.5 points in the oxycodone-naloxone group vs 9.4 points in the placebo group ― a difference of 8.15 points.

Primary Outcome: International RLS Study Group Severity Rating Scale Sum Score at 12 Weeks

Oxycodone-Naloxone Placebo Treatment Difference (95% CI) PValue
Mean sum score at 12 weeks 15.1 22.1 8.15 (5.46 – 10.85) <.0001

Researchers turn off Down’s syndrome genes.

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Silencing extra chromosome in cell cultures could lead to new treatments for the disorder.

The insertion of one gene can muzzle the extra copy of chromosome 21 that causes Down’s syndrome, according to a study published today inNature1. The method could help researchers to identify the cellular pathways behind the disorder’s symptoms, and to design targeted treatments.

down's

“It’s a strategy that can be applied in multiple ways, and I think can be useful right now,” says Jeanne Lawrence, a cell biologist at the University of Massachusetts Medical School in Worcester, and the lead author of the study.

Lawrence and her team devised an approach to mimic the natural process that silences one of the two X chromosomes carried by all female mammals. Both chromosomes contain a gene called XIST(the X-inactivation gene), which, when activated, produces an RNA molecule that coats the surface of a chromosome like a blanket, blocking other genes from being expressed. In female mammals, one copy of the XIST gene is activated — silencing the X chromosome on which it resides.

Lawrence’s team spliced the XIST gene into one of the three copies of chromosome 21 in cells from a person with Down’s syndrome. The team also inserted a genetic ‘switch’ that allowed them to turn on XIST by dosing the cells with the antibiotic doxycycline. Doing so dampened expression of individual genes along chromosome 21 that are thought to contribute to the pervasive developmental problems that comprise Down’s syndrome.

First steps

The experiment used induced pluripotent stem cells, which can develop into many different types of mature cells, so the researchers hope that one day they will be able to study the effects of Down’s syndrome in different organs and tissue types. That work could lead to treatments that address degenerative symptoms of Down’s syndrome, such as the tendency of people with the disorder to develop early dementia.

“The idea of shutting off a whole chromosome is extremely interesting” in Down’s syndrome research, says stem-cell researcher Nissim Benvenisty of Hebrew University in Jerusalem. He anticipates future studies that split altered cells into two batches — one with the extra chromosome 21 turned on, and one with it off — to compare how they function and respond to treatments.

Researchers have previously removed the extra chromosome in cells from people with Down’s syndrome using a different type of genetic modification2. That technique relied on the fact that induced pluripotent stem cells that carry the third copy of chromosome 21 occasionally boot it out naturally — but “it’s a pain in the neck”, says Mitchell Weiss, a stem-cell researcher at the Children’s Hospital of Philadelphia in Pennsylvania. “You can’t control it.”

However, Weiss says that the latest method has its own drawbacks: turning on XIST may not block all gene expression in the extra chromosome, and that could muddle experimental results.

Still, Weiss thinks that the approach could yield fresh treatments for Down’s syndrome — and prove useful for studying other chromosome disorders such as Patau syndrome, a developmental disorder caused by a third copy of chromosome 13.

Source: Nature

 

Genetic advance in Down’s syndrom.

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US scientists say they have moved a step closer to being able to treat disorders caused by an extra chromosome.

They have “switched off” the chromosome that causes the symptoms of Down’s syndrome in human cells in the lab.

The research, published in Nature, could one day lead to new medical treatments for the condition.

Future work may be of real benefit to people with Down’s syndrome, said the UK Down’s Syndrome Association.

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, making a total of 46 in each cell.

People with Down’s syndrome have three – rather than two – copies of chromosome 21.

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This is an exciting breakthrough, but this process is still at a very early [cellular] stage and we are nowhere near seeing this procedure being used in the treatment of Down’s syndrome in people”

Dr Lucy RaymondUniversity of Cambridge

This causes symptoms such as learning disabilities and early-onset Alzheimer’s disease, as well as a greater risk of blood disorders and heart defects.

Gene therapy, which uses genes to treat illnesses, has been attempted for problems caused by a single defective gene. But until now, the idea of being able to silence the effects of a whole chromosome had appeared beyond the realms of possibility, even in the lab.

Now scientists at the University of Massachusetts Medical School have shown that, in theory, this might be possible but would take decades of research.

A team led by Dr Jeanne Lawrence inserted a gene called XIST into the stem cells of a person with Down’s syndrome grown in the lab.

‘Exciting research’

The gene plays a role in normal cell development by switching off one of the two X chromosomes present in female embryos, ensuring daughters avoid a double dose of X chromosome genes.

The experiments showed that the gene was able to silence the extra copy of chromosome 21, helping correct unusual patterns of growth in the cells.

Dr Lawrence told BBC News: “The research means that we have a new way – right away – to study the cellular basis for Down’s syndrome, that could help identify drugs for Down’s syndrome.

“At the same time we have made it conceivable – not necessarily possible or effective, that still needs to be proven – but conceivable that you could use just a single gene to correct the over-expression of the whole chromosome. So it makes genetic therapy for Down’s syndrome more conceivable where it really wasn’t before.”

Commenting on the study, Carol Boys, chief executive of the Down’s Syndrome Association, said it was exciting new research from a very well-respected team.

“The findings could have serious implications for future work that may be of real benefit to people with Down’s syndrome,” she said.

“We are a very long way from understanding how these findings might translate into clinical applications but it could be that they will be of great assistance in the search for conventional treatments for some of the health conditions that affect people with Down’s syndrome.”

Dr Lucy Raymond, from the department of medical genetics at the University of Cambridge, said the group had demonstrated an important proof of concept.

“This is an exciting breakthrough, but this process is still at a very early [cellular] stage and we are nowhere near seeing this procedure being used in the treatment of Down’s syndrome in people.”

Source: BBC