Genetic Trigger Discovered For Most Common Form of Mental Disability and Autism

March 8, 2014

March 08, 1014 – The following article just appeared in PsyBlog and provides highly interesting reading in relation to newly discovered molecular mechanisms in the etiology of (possibly individualized) disease predispositions. Very exciting.

The most common form of intellectual disability is caused by a mechanism which shuts of an associated gene, a new study Gene silencingfinds.Scientists at the Weill Cornell Medical College have also shown that a drug can block the silencing mechanism, thereby preventing the most common form of mental disability: fragile X syndrome (Colak et al., 2014).This points the way towards a therapy for fragile X syndrome — a leading genetic cause of autism — and possibly for about 20 other diseases. Fragile X syndrome causes a wide range of emotional, behavioural and physical problems and occurs mostly in boys. For around twenty years scientists have known that the cause of fragile X syndrome is the excess repetition of a sequence of genetic code. The problem was understanding how this code caused the disease.

Now, in a new study, published in the prestigious journal Science, researchers have discovered that this code halts the production of a protein which is crucial to communication within the brain. To find out how to fix this problem, the researchers used human stem cells from embryos that had tested positive for fragile X syndrome to create brain neurons in the lab.

This gave them a model of how the embryonic brain develops in which to test a new drug developed by Dr. Matthew Disney of the Scripps Research Institute. After adding the drug, they found that the gene continued to produce the vital protein, instead of being deactivated as it is in fragile X syndrome.

This points the way towards a treatment for fragile X syndrome. One of the study’s authors, Dr. Samie Jaffrey, explained: The findings have implications for a range of other diseases because of the biological mechanism that has been discovered. Other diseases including Jacobsen syndrome, an intellectual disorder, and Huntington’s disease, a neurodegenerative disorder, involve similar repetitions of DNA sequences and so may be amenable to similar treatments.

Incretin Mimetic Drugs for Type 2 Diabetes: Early Communication – Reports of Possible Increased Risk of Pancreatitis and Pre-cancerous Findings of the Pancreas

May 9, 2013

May 09, 2013 – We have just stumbled upon a recent press release to the public by the American Food and Drug Administration (FDA) on a looming drug safety problem of incretin mimetic drugs related to the pancreas. Find here the unedited press releaase in full:

[Posted 03/14/2013]

AUDIENCE: Gastroenterology, Endocrinology, Oncology, Patient

ISSUE: FDA is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. FDA has asked the researchers to provide the methodology used to collect and study these specimens and to provide the tissue samples so the Agency can further investigate potential pancreatic toxicity associated with the incretin mimetics.

BACKGROUND: Drugs in the incretin mimetic class include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). These drugs work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

RECOMMENDATIONS: FDA has not reached any new conclusions about safety risks with incretin mimetic drugs. This early communication is intended only to inform the public and health care professionals that the Agency intends to obtain and evaluate this new information. FDA will participate in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Cancer Institute’s (NCI) Workshop on Pancreatitis-Diabetes-Pancreatic Cancer in June 2013 to gather and share additional information. FDA will communicate its final conclusions and recommendations when its review is complete or when the Agency has additional information to report.

The Warnings and Precautions section of drug labels and patient Medication Guides for incretin mimetics contain warnings about the risk of acute pancreatitis. FDA has not previously communicated about the potential risk of pre-cancerous findings  of the pancreas with incretin mimetics. FDA has not concluded these drugs may cause or contribute to the development of pancreatic cancer.

At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online:
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Thalidomide may fight blood vessel disorder: Nosebleeds eased with once-maligned drug

April 5, 2010

April 05, 2010 – A very recent article by indicates that thalidomide, a drug that caused birth defects when it was launched as a morning sickness pill half a century ago, may be useful for treating a hereditary condition that affects blood vessels.

In a study in the journal Nature Medicine, French researchers found giving thalidomide to patients with a disorder called hereditary hemorrhagic telangiectasia (HHT) reduced the severity and frequency of nosebleeds, one of the main symptoms.

Franck Lebrin, who led the study with colleagues from the National Institute for Health and Medical Research in Paris, said experiments on mice with HHT showed thalidomide treatment was able to repair blood vessel wall defects through a mechanism involving proteins involved in cell growth. “Biopsies of the nasal surface tissue from patients with HHT showed that similar mechanisms may explain the effects of thalidomide treatment in humans,” he wrote in the study.

HHT affects about one in 5,000 people. Many patients develop recurrent, difficult-to-treat nosebleeds which can significantly harm their quality of life.

Thalidomide was used to treat nausea during pregnancy in the 1960s. The drug was taken off the market after severe teratogenic congenital defects appeared in the newborns of mothers who had taken it (referred to as “contergan scandal” in germany).

More recently, thalidomide – which has powerful anti-cancer properties – experienced a revival and is now being used to treat certain forms of cancer such as multiple myeloma, and the drug is on the market in the US as Thalidomide [Thalomed]. U.S. drugmaker Celgene has developed a successor drug to thalidomide, called Lenalidomide [Revlimid], which is also approved to treat multiple myeloma.

Regulatory Science Update: FDA and International Serious Adverse Events Consortium (SAEC) Complete Third Data Release

February 21, 2010

February 21, 2010 – In the field of pharmaco- and toxicogenetics of serious adverse drug reactions (sADRs) in humans, we learn today from a press release by the US Food and Drug Administration (FDA) of the completion and release by the FDA and the International Serious Adverse Events Consortium (SAEC) of the third data set with  focus on the genetic basis of drug-induced liver injury (DILI) and serious skin reactions (SSRs).

The data focus on the genetics associated with DILI and SSR and may help researchers to better predict an individual’s risk of developing these serious complications.

Drug induced liver injury occurs in a small subset of patients and is often associated with a drug that is an unpredictable liver toxin, and may be the cause of acute liver failure in some patients. Although the exact mechanism behind drug-induced liver injury is unknown, research suggests that a person’s genes contribute to their likelihood of developing this injury.

Drug-induced SSRs, such as Stevens-Johnson, present as allergic-like skin reactions (blistering and peeling of the skin) and are considered serious enough to discontinue treatment with the medication. These reactions can be fatal if the signs and symptoms are not quickly recognized.

The released research data relating to drug-induced liver injury (368 cases) and serious skin reactions (15 cases), complement the already released data from the SAEC’s December, 2008 and May, 2009 data releases.

“FDA is pleased with the Consortium’s progress,” said ShaAvhree Buckman, M.D., Ph.D., director of the Office of Translational Sciences in the FDA’s Center for Drug Evaluation and Research. “The continued accumulation of scientific information on the genetic basis of adverse drug events provides researchers with invaluable tools for understanding why some people respond to medicines differently than others.”

The SAEC is a nonprofit partnership of 10 international pharmaceutical companies, the Wellcome Trust, and academic institutions focused on research relating to the genetics of drug-induced serious adverse events.

Researchers who enter into a data use agreement can obtain free access to the data to generate custom data inquiries and obtain immediate results on the genetic basis of adverse drug events.

For more information on the International Serious Adverse Event Consortium (SAEC), go to

Information on previous SAEC data releases, follow the links below:, or

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Mutant genes linked to Parkinson’s disease in some patients of Japanese or European descent

November 20, 2009

November 20, 2009 – Two independent studies which tried to uncover genetic associations behind Parkinson’s disease have been published in the latest issue of Nature Genetics. They are the largest studies of this type to date and involved more than 25’000 participants.

The two research teams have found that people of Japanese and European descent who have mutant versions of five genes may be at higher risk of developing Parkinson’s disease.

The first study in Japan looked at ethnic Japanese  only while the second study, performed in the United States, focused on people of European heritage only.

Thus, in the first study, researchers at the Kobe University in Japan and sequenced the genes of 2’011 participating patients with Parkinson’s disease and 18’381 other study participants without the disease. They found that those with the disease were carriers of genetic variants of the PARK16, BST1, SNCA and LRRK2 genes. In the second study, researchers at the National Institutes of Health’s (NIH) Laboratory of Neurogenetics in the US analyzed the genes of more than 5’000 patients of European ancestry who suffer from the disease and detected strong links between Parkinson’s and genetic variants of the genes SNCA and MAPT. The two teams later compared their data and found that variants of PARK16, SNCA and LRRK2 carry risk of Parkinson’s disease in both Japanese and European populations, while genetic variants of BST1 and MAPT, repectively, seemed to specific for patients of Japanese or European descent.

The researchers hope that the better understanding of the underlying genetic variants involved in the progress of Parkinson’s disease will lead to better insights into the causes and underlying biology of this disease. Eventually, this knowledge will one day provide physicians with strategies to delay, or even prevent, the development of Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disease that affects one to two percent of people over the age of 65. It is characterized by tremors, sluggish movement, muscle stiffness, and difficulty with balance. Although medical treatments today may improve symptoms, there are none that can slow down or halt the progression of the disease.

Considerable stroke risk linked to anemia drug; Darbepoetin-α [Aranesp] nearly doubled risk in people with diabetes

November 1, 2009

November 1, 2009 – A new study raises fresh safety concerns about widely used anemia medicines, finding that the drug Darbepoetin-α [Aranesp] nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis. The study is the largest ever of these blood-boosting drugs and the only one that compared them to a dummy treatment. The medicines have become blockbuster sellers because they lessen the need for transfusions, but their ability to prevent heart attacks, kidney failure or other problems have not been proven.

Over the last two years, the federal Food and Drug Administration has repeatedly strengthened warning labels not only on Darbepoetin-α [Aranesp] , but on the similar drug products Epoetin-α [Epogen] and Epoetin-α [Procrit] as concerns rose that they may worsen survival in certain cancer patients, especially at higher doses.

The new study tested Darbepoetin-α [Aranesp] in a different group of patients: 4,038 people with Type 2 diabetes, kidney problems and moderate anemia  problems that often go hand in hand. The goal was to see if the drug could prevent heart attacks, heart failure, strokes or the need for dialysis. The leader of the study, Dr. M. Pfeffer, noted that the study did not only fail to do that, but a susbstantial  hightened risk for stroke was uncovered.  Strokes occurred in 101 patients given Aranesp and 53 patients given dummy shots. Looked at another way, the risk of suffering a stroke was about 1 percent per year in the placebo group and about 2 percent in those given Aranesp. Results were published online Friday by the New England Journal of Medicine (NEJM). For many patients, this risk will outweigh its potential benefits, the study’s authors concluded.

On a positive note, in the present study, Darbepoetin-α [Aranesp] did reduce the need for transfusions;  297 people on the drug needed them versus 496 of those getting dummy shots. However, there was only a modest improvement in how fatigued people said they felt in the Aranesp group.

For your convenience, you find the abstract of the study be Pfeffer M.A., et al., published at October 30, 2009 (10.1056/NEJMoa0907845). Please read the full study result at the link provided.

Background Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.

Methods In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

Results Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.

Conclusions The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. ( number, NCT00093015 [] .)

Sperm donor passed on sudden death heart defect

October 24, 2009

October 24, 2009 – Sperm donation is an increasingly common practice for achieving pregnancy in the absence of a male partner or when fertility is problematic. The unintended consequence in which genetic diseases are unwittingly transmitted to offspring is an underrecognized public health issue not previously prioritized by US Food and Drug Administration guidelines.

An asymptomatic 23-years old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel β-myosin heavy-chain mutation that caused hypertrophic cardiomyopathy (HCM), after an offspring was clinically diagnosed with this disease.

Of the 24 children known to be offsprings of the donor, including 22 children who were products of fertilization via sperm donation and 2 children conceived by the donor’s wife, a total of 9 genetically affected children, age 2 to 16 years (6 of them being male), have been identified with HCM.  Three of the 9 gene-positive children have currently expressed phenotypic manifestions of HCM, including one child who died at the age of 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at the age of 15 years. The latter two children and the donor are judged likely to be at increased risk for sudden death.

This case series underscore the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (e.g., HCM) such as consideration for 12-lead electrocardiograms.

Hypertrophic cardiomyopathy (HCM) thickens the heart and makes it harder to pump blood. It affects about one in 500 people; many more likely have the genetic defect without symptoms, Symptoms can include an irregular heartbeat and shortness of breath but many cases go undetected until sudden death. The condition is often the culprit when young athletes collapse and die suddenly. Treatment includes medication and an implanted defibrillator to prevent sudden death.

Neither the sperm bank nor the donor were identified. The donor, now 42, had no symptoms of genetic heart disease and no obvious family history when he donated sperm in the early 1990s. His own condition wasn’t diagnosed until after a child born through sperm donation was diagnosed. Maron declined to provide more details on the donor’s health, citing privacy concerns.

Access the full study report at JAMA, the Journal of the American Medical Association.

Gene May Predict Response to Hepatitis C Therapy

August 19, 2009

August 18, 2008 – A slight difference in a person’s genetic code could determine whether they respond to a grueling round of treatment for hepatitis C infection or not.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of Peginterferon-2b (PegIFN-2b) or Peginterferon-2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment was and continues to be a high priority. A recent study, led by D.B. Goldstein and published in the Journal Nature reported that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10-25) and African-Americans (P = 2.06 x 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Genetic tests looking for that particular genetic variant could be used to help treating physicians decide which patients are most likely to benefit from the current PegIFN-2b or PegIFN-2a based therapies. Of course, the findings of this study do not mean poor responders should not be offered therapy but it may alter their decision-making.

Gene Responsible For Acetaminophen-induced Liver Injury Identified

May 15, 2009

May 14, 2009 – Drugs containing the pharmacologically active ingredient acetaminophen are among the most commonly used over-the-counter (OTC) drugs in the United States (US).

Acetaminophen is considered safe over long-term use, but recent studies have indicated that even over a relatively short period, the maximum allowable dose can induce elevated levels of the liver enzyme ALT in blood serum in approximately one third of healthy individuals, suggesting possible liver injury. It is possible that if given high doses, many of these individuals would be susceptible to acute liver failure. There is likely to be a genetic predisposition, but finding the responsible variant genes by scanning human subjects alone may be very difficult, requiring large studies with many participants.

A team of researchers at the North Carolina State University used the help of mouse genetics in the search for candidate genes linked to acetaminophen-induced liver injury in humans.  The group used a genetically diverse population of mice to model human genetic variation, taking advantage of the known genetic differences in these strains to find genes linked to variable responses to acetaminophen treatment. Once the researchers narrowed their search to a few candidate genes in mouse, they sequenced the genetic code of the counterparts of the same genes in human patients exhibiting elevated levels of serum ALT in response to acetaminophen. They found that a single letter change (i.e. a so called single nucleotide polymorphism (SNP) to the DNA sequence in one of these candidate genes, called CD44, is significantly associated with elevated serum ALT in these patients. While the role of this gene in liver toxicity is not yet known, CD44 could serve as a potentially useful marker to identify people at risk for acetaminophen-induced liver damage.

There is still some research  to be done in order to determine the allele frequency of the CD44 T-Allele in the general population versus its abundance in patients with acetaminophen-induced liver damage (measured by elevated serum ALT-levels) as well as both the positive and the negative predictive values for the association of the CD44 T-Allele with acetaminophen-induced liver damage.

This article is adapted from materials at Cold Spring Harbor Laboratory. “Gene Responsible For Acetaminophen-induced Liver Injury Identified.” ScienceDaily 11 May 2009. 15 May 2009 < /releases/2009/05/090504171943.htm>. See also the full journal article  reference: Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Contractor, T., Wiltshire, T., Rusyn, I., and Threadgill, D.W. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res, DOI: 10.1101/gr.090241.108

See also the drug labels for  FDA-approved  drugs  and generics containing  the pharmacologically active ingredient acetaminophen at Drugs@FDA or at DailyMed.

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