RxPG News : Genetic Disorders

XXYY syndrome- features and treatment options elucidated by researchers

Sun, 24 Aug 2008 01:16:17 PST

( from http://www.rxpgnews.com ) Researchers at the UC Davis M.I.N.D. Institute and The Children's Hospital in Denver have conducted the largest study to date describing the medical and psychological characteristics of a rare genetic disorder in which males have two "X" and two "Y" chromosomes, rather than the normal one of each. The study, published in the June 15, 2008, issue of the American Journal of Medical Genetics Part A, also offers treatment recommendations for men and boys with the disorder.

"We found that there are a variety of behaviors, learning disabilities and emotional problems that are unique to patients with XXYY syndrome that may be better addressed with more targeted therapies," said Randi Hagerman, medical director of the M.I.N.D. Institute and senior author of the study. "Our research is important because it provides an accurate picture of what patients are experiencing that can help physicians who treat patients with the disorder."

XXYY syndrome is a sex chromosome anomaly that is thought to occur in about one in 18,000 males in the general population. Boys with XXYY syndrome usually come to the attention of physicians because of unique facial features, developmental delays, late puberty and behavioral problems. It was once thought to be a variant of Klinefelter syndrome, in which males have one extra X chromosome. While the two disorders are similar in some ways, clinicians have become increasingly aware that they are distinct in some significant ways. The current study set out to identify the unique features of patients with XXYY for the purposes of informing the medical community and improving treatment approaches.

"Until now, physicians have had to search the medical literature to patch together a treatment plan mostly based on information on Klinefelter syndrome," said Nicole Tartaglia, an assistant professor of pediatrics at the University of Colorado Denver School of Medicine who was a fellow at the M.I.N.D. Institute when the study was conducted. "As a result, people with XXYY weren't being screened for the specific medical problems associated with their disorder. They weren't receiving therapies or medications for the behavioral and neurodevelopmental issues that are more profound for them. And they weren't receiving the types of community services that can help them live independent lives. Our research is an important resource for families and practitioners."

For the current study, Tartaglia and Hagerman examined 95 males with XXYY syndrome between the ages of one and 55 years of age. Among their medical findings were that 19.4 percent had cardiac abnormalities such as congenital heart defects and mitral valve prolapse, 87.6 percent had dental problems such as severe dental caries and malocclusion, 15 percent had seizures and 59.8 percent had asthma or other respiratory issues. Intention tremor became more common with age and was present in 71 percent of study participants over 20 years old. 45.7 percent who underwent brain MRIs showed abnormal white matter that may explain some learning difficulties.

Psychologically, the researchers found that 72.2 percent had attention-deficit/hyperactivity disorder and up to 28.3 percent had autism spectrum disorders. In the previous literature, mental retardation was the norm. This study, however, found that only 29.1 percent had IQ scores within the mental retardation range. Learning disabilities were the more common cognitive impairments, affecting 70.9 percent of study participants.

"Life skills are more of a struggle for these males, and they may need different medications, a broader array of behavioral therapies and more intensive community support than those with Klinefelter syndrome," Tartaglia said.

Lack of comprehensive information about the syndrome is what drove the current study. For years, parents of boys with XXYY syndrome supported each other over the Internet, sharing stories of heartbreak and frustration. While their sons suffered everything from heart defects to learning disabilities, they could only point doctors and teachers to a 1960s scientific paper that first identified the condition along with a few outdated notes on its outcomes.

"We knew we needed a more complete description," said Renee Beauregard, of Aurora, Col., whose 26-year-old son, Kyle, was diagnosed with XXYY syndrome at age 10. "We were tired of having our families running around the country looking for answers from people who didn't have them," said Beauregard, who is also a co-author on the study.

In 2003, Beauregard and other parents turned their frustration into advocacy and established the XXYY Project to support families.

"The more we talked, the more we realized our boys had things in common that were not addressed in the literature," said Beauregard, the project's director. "We had to do something."

The parents had their children take part in the study, and they flew Tartaglia to the United Kingdom so that she could include XXYY boys living there in the research as well.

Now, with more concrete answers, parents like Beauregard and children like Kyle can find some peace of mind.

"Kyle knows that people don't understand XXYY and therefore don't understand him as a person, she said. "The study helps the world know why he is like he is. It validates what he knows about himself and what we know about him. When he can't follow directions, it's not because he's stupid."

Switching genes to overdrive improves muscular dystrophy symptoms in mice

Sun, 01 Apr 2007 11:56:27 PST

( from http://www.rxpgnews.com ) Scientists at Dana-Farber Cancer Institute have shown in a laboratory study that revving up a crucial set of muscle genes counteracts the damage caused by a form of muscular dystrophy.

Reporting in the April 1 issue of Genes and Development, the researchers demonstrated that manipulating a genetic molecular switch increased the genesâ activity in the muscles of mice with Duchenne muscular dystrophy, slowing the disease-associated muscle wasting. The authors caution that they have not yet found a way to tweak the switch, known as PGC-1alpha, in humans.

âI think that if we could elevate the levels of PGC-1alpha in the muscles of patients with Duchenne muscular dystrophy, it is likely that we could slow or reduce the course of the disease,â said Bruce Spiegelman, PhD, the Dana-Farber researcher who led the team along with Christoph Handschin, PhD, formerly of Dana-Farber and now at the University of Zurich. Other authors are from the University of Iowa College of Medicine.

Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy in children, occurring once in about every 5,000 live births of boys, and is ultimately fatal. The average age of death is the mid-teens, and most patients die by their 30s. In the United States, about 400 to 600 boys are born each year with DMD or Becker Muscular Dystrophy, a milder form of the disease. The cause is a mutation, either inherited or occurring spontaneously, that affects a muscle protein called dystrophin.

Spiegelman, whose laboratory discovered PGC-1alpha in 1998, led the new study which was aimed at determining whether increasing levels of PGC-1alpha in the muscles of mice could increase the activity of genes that are known to behave abnormally in muscular dystrophy.

PGC-1alpha is known as a âtranscriptional coactivatorâ that functions as a switch, or perhaps more accurately, like a light dimmer that increases or decreases the activity of genes under its control. Exercising a muscle raises PGC-1alpha levels, causing the formation of more mitochondria, the chemical power plants that create energy in cells.

PGC-1alpha is also required for the normal operation of genes that control the development of neuromuscular junctions (NMJ) â sites on muscle fibers where nerves attach and signal the fibers to contract. Part of the reason that exercise builds stronger muscles is that it increases PGC-1alpha activity. Conversely, disease or lack of exercise reduces PGC-1alpha activity, causing a loss of NMJ function and weakening, or atrophying, of muscles.

Spiegelmanâs team had previously bred a strain of mice with higher-than-normal levels of PGC-1alpha in their muscles. Also available for the research was a mouse model of Duchenne muscular dystrophy, the MDX mouse. In the new experiment, the scientists bred male high-PGC-1alpha mice with female MDX mice (the muscular dystrophy gene is carried by females in mouse and in humans.) As a result, the offspring of these matings had muscular dystrophy but also had elevated PGC-1alpha. Using exercise and chemical tests, the researchers compared muscle function in the offspring with MDX mice having no additional PGC-1alpha.

Both sets of rodents were run on a treadmill for one hour, then again 24 hours later. Normal mice completed the runs easily on both days, while untreated MDX rodents were exhausted halfway through each run. The MDX mice with increased PGC-1alpha activity performed almost as well as normal mice on the first day; their performances decreased on the second day, but they still did better than the untreated MDX mice on both runs.

The exercise tests and microscopic and chemical examinations of the muscles showed that boosting PGC-1alpha caused âa clear and substantial improvement in the structure and function of skeletal muscle in this disease model,â the scientists wrote.

Gene mutation associated with X-linked mental retardation revealed

Mon, 19 Mar 2007 22:52:47 PST

( from http://www.rxpgnews.com ) Researchers have identified a novel gene mutation that causes X-linked mental retardation for which there was no previously known molecular diagnosis, according to an article to be published electronically on Tuesday, March 20, 2007 in The American Journal of Human Genetics.

Investigators F. Lucy Raymond (Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK) and Patrick S. Tarpey (Wellcome Trust Sanger Institute, Hixton, UK) describe the ZDHHC9 gene found in those with severe retardation as being mutated to the point of entirely losing function.

"ZDHHC9 is a novel gene," explains Dr. Raymond. "This gene would not have been predicted to play a role in mental retardation based on the previous genetics work. It was found only because we were systematically looking at all the genes on the X chromosome irrespective of what they do."

X-linked mental retardation is severe. Some patients require total care and may not have language ability. The condition runs in families and only affects the male offspring. So far only a few of these genes have been identified.

Working through a large, international collaboration, the researchers collected genetic samples from 250 families in which at least two boys have mental retardation to help identify novel genes that cause X-linked mental retardation. The investigators systematically analyzed the X chromosome for gene mutations.

Dr. Raymond says that the families are receiving information from the study and using it to make decisions in their lives. "We cannot currently make their children better, but knowing that we found a genetic abnormality gives them an explanation for what has happened," she explains. "We had one family that said this knowledge was the best news they had ever been given."

"We have identified the cause of problems in certain families and are able to tell whether or not women are carriers of the condition," Dr. Raymond comments. "Consequently, the families that had previously chosen to forego having children because there was no method of testing can now be tested. We have been able to test a substantial number of people to identify whether are not they are carriers, and we can offer prenatal testing to the carriers who want it."

In the broader picture, this research is not only benefiting families with X-linked mental retardation, but it is also defining the genes involved in intellectual development. "If you find genes that are abnormal, it is a reasonable assumption that the identified genes are involved in the formation of normal intellectual processing as well," concludes Dr. Raymond.

Now that a posttranslational modification enzyme has been found to be mutated in X-linked mental retardation, the researchers expect to find similar genes related to other mental retardation syndromes.

Link between Huntington's and abnormal cholesterol levels in brain discovered

Sun, 03 Dec 2006 15:10:07 PST

( from http://www.rxpgnews.com ) Mayo Clinic researchers have discovered a protein interaction that may explain how the deadly Huntington's disease affects the brain. The findings, published in and featured on the cover of the current issue of Human Molecular Genetics, show how the mutated Huntington's protein interacts with another protein to cause dramatic accumulation of cholesterol in the brain.

"Cholesterol is essential for promoting the connection network among brain cells and in maintaining their membrane integrity. Both the level of cholesterol and its delivery to the proper locations in the cell are essential for the survival of neurons," explains Mayo Clinic molecular biologist Cynthia McMurrary, Ph.D.

"Our discovery that the mutant Huntington's disease protein derails the cholesterol delivery system and causes cholesterol accumulation in neurons provides us with key results and solid clues to the mechanism of this disease," says Dr. McMurray. "Fully understanding the mechanism of toxicity is the key to developing treatments."

Huntington's disease -- sometimes called Huntington's chorea or St. Vitus' dance -- is a progressive, degenerative condition that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, emotional disturbances and mental deterioration.

The mutant protein of Huntington's attacks the railroad system of brain cells and impairs transport of essential materials required for neurons to function. When this transportation system goes awry in the parts of the brain affected in Huntington's disease, motor skills, cognitive skills and even speech can be affected. A person cannot move without shaking, and physical control gradually deteriorates, often with accompanying personality changes, depression and increased risk of suicide. Those who have Huntington's commonly die from complications of the disease, such as falls or infections.

Mouse control neuron (left) and neuron showing cholesterol accumulation in Huntington's disease.

Approximately 30,000 Americans have Huntington's disease. Another 150,000 carry the gene and have a 50 percent risk of passing it on to their children. The disease is easily diagnosed by a blood test, but symptoms usually don't appear until middle age.

Their findings, say the researchers, provide the first direct link between the Huntington's protein and the protein that controls capture and trafficking inside the cell. Their research suggests a possible means by which Huntington's disease functions.

Because no one knows how the disease is incurred or spreads, this new information is critical and establishes a clear path for investigations to move forward.

The Mayo researchers observed the abnormal accumulation of cholesterol in cultured neuronal cells in the laboratory and in the brains of animal models. They found that this happens only when the mutant Huntington's protein is expressed together with the molecule, caveolin-1. Caveolin-1 is the major structural protein of small vesicles called caveolae, which capture cholesterol and move it in and out of the neuronal membranes. When the researchers "knocked out" expression of caveolin, the neurons expressing mutant Huntington's protein stopped accumulating cholesterol.

Williams Syndrome, the brain and music

Thu, 05 Oct 2006 00:57:37 PST

( from http://www.rxpgnews.com ) Children with Williams syndrome, a rare genetic disorder, just love music and will spend hours listening to or making music. Despite averaging an IQ score of 60, many possess a great memory for songs, an uncanny sense of rhythm, and the kind of auditory acuity, than can discern differences between different vacuum cleaner brands.

A study by a multi-institutional collaboration of scientists, published in a forthcoming issue of NeuroImage, identified structural abnormalities in a certain brain area of people afflicted with Williams syndrome. This might explain their heightened interest in music and, in some cases, savant-like musical skill.

Professor Ursula Bellugi, director of the Laboratory for Cognitive Neuroscience at the Salk Institute for Biological Studies the central hub of this unique scientific alliance explains, "Understanding the connections between missing genes, the resulting changes in brain structure and function, and ultimately behavior may help us to reveal how the brain works."

The current study is just the latest chapter in a story that's been unfolding for quite some time gaining increasing momentum in recent years. It all started when Bellugi reached out across disciplines and assembled a team of experts under the umbrella of a Program Project from the National Institutes of Child Health and Human Development to help her trace the influence of individual genes on the development and functioning of the brain.

Along with co-author Albert Galaburda, a professor at the Harvard Medical School's Department of Neurology, Professor Allan L. Reiss, Director of the Center for Interdisciplinary Brain Sciences Research at Stanford University and senior author of the current study, focuses on the overall morphology of the brain, zooming in on the cellular architecture of the brain. Molecular geneticist Julie R. Korenberg, a professor in the Department of Pediatrics at UCLA, digs even deeper and studies the genes missing in people with Williams syndrome, whereas Debra Mills, an associate professor in the Department of Psychology at Emory University, concentrates on the neurophysiology, the electrical activity of behaving neural networks. Says Bellugi, who studies the cognitive aspects of the disorder: "Things are really starting to come together now."

Identified more than 40 years ago, Williams syndrome arises from a faulty recombination event during the development of sperm or egg cells. As a result, almost invariably the same set of about 20 genes is deleted from one copy of chromosome seven, catapulting the carrier of the deletion into a world where people make much more sense than objects do.

"Williams syndrome is a perfect example where a genetic predisposition interacts with the environment to sculpt the brain in unique ways," says Reiss. "It provides a unique window of understanding on how the brain develops under typical and atypical conditions," he adds.

People with Williams syndrome are irresistibly drawn to strangers, remember names and faces with ease, show strong empathy and have fluent and exceptionally expressive language. Yet, they are confounded by the visual world around them: While they can't scribble more than a few rudimentary lines to illustrate an elephant, they can verbally describe one in almost poetic detail.

"The discrepancy between their engaging social use of language and their poor visual-spatial skills is startling," says Bellugi. "I am confident that once all the evidence is in, we will have identified genes and pathways in the Williams syndrome deletion that underlie these drastic differences in modalities," she adds.

Despite whole brain volumes that are about 15 percent smaller than normal, the temporal lobe, which lies above the ear canal and, among other things, is involved in processing sounds and interpreting music and language, is of approximately normal volume in people with Williams syndrome. In their study, the researchers tried to answer the question of whether an atypical development of the planum temporale, which is part of the temporal lobe and thought to be involved many auditory tasks, including perfect pitch, may underlie the unusual musical and language skills.

First author Mark Eckert, formerly at Stanford and now an assistant professor at the Medical University of South Carolina, and his colleagues used data from brain scans of 42 individuals with Williams syndrome and 40 control participants to compare the surface folds of the planum temporale. In most people, the structure, a slender inch-long piece of tissue, is larger on the left side of the brain than the right.

In people with Williams syndrome, however, both sides tended toward symmetry. "There are different possible explanations: Either the left side didn't grow enough or the right side grew larger than usual," says Galaburda. The folding pattern, in particular one groove called the Sylvian fissure, pointed to an increase size of the right planum temporale.

But size alone might not explain the unusual auditory strengths of people with Williams syndrome. A more general explanation includes variations in the connectivity of certain brain regions that might contribute to the specific strengths and weaknesses in Williams syndrome."

In recent studies, Galaburda had found that cells in the primary visual cortex of carriers of the Williams deletion are smaller and more densely packed -- allowing for fewer connections between cells. Neurons in the primary auditory cortex, on the other hand, were larger and loosely packed, denoting increased "connectedness."

"These differences in cell size and density may underlie the strengths in auditory phonology, language and possibly music, and the difficulties in visual spatial construction for primary visual areas," says Bellugi, adding, "This is really just part of the overall effect of the genes' deletion on brain development."

"Relatively subtle developmental defects can have a significant impact on neurological function," says Dennis O'Leary, a Salk neurobiologist who studies the development of the visual system. "This work opens the door to explaining how genes works through the brain and make us who we are," he adds.

Exploring genetics of congenital malformations

Sat, 19 Aug 2006 21:41:37 PST

( from http://www.rxpgnews.com ) New research published in the August issue of the Journal of Cell Biology explains for the first time why congenital heart defects so often occur with limb deformities.

In their research into the molecular mechanisms that control embryonic limb and heart development, Northwestern University researcher Hans-Georg Simon and his laboratory group recently identified a new protein, LMP4, which binds and regulates activity of the Tbx4 and Tbx5 transcription factors. Tbx5 and Tbx4 proteins play a key role in limb and heart formation in virtually all vertebrates, from fish to birds to mice to humans.

Mutations in the respective Tbx5 and Tbx4 genes can cause severe birth defects characterized by upper limb and heart defects (Holt-Oram syndrome) or patella, hip and foot malformations (small patella syndrome), respectively, Simon explained.

"Despite the importance in embryogenesis and disease, the mechanisms by which the transcription factors encoded by these genes exert their functions are not well understood," Simon said.

In studies using chicken and zebrafish model systems, Simon and his lab members are trying to gain a complete picture of how the Tbx and LMP4 proteins interact in order to control the growth and particular shaping of the limbs and heart.

LMP4 apparently regulates Tbx protein activity in the cell by keeping the Tbx transcription factors bound to the actin cytoskeleton or releasing them to the nucleus. Actin is a contractile protein of muscle and is a major component of the cytoskeleton the "scaffolding" of the cell.

As the researchers wrote in their paper, this is the first demonstration of a Tbx transcription factor to be localized outside the cell nucleus by a specific protein. In addition, they demonstrate that removal of Tbx5 from the nucleus represses the transcription factor's ability to activate target genes in the limbs and heart.

"We are just beginning to understand the multitude of different cellular process that the Tbx proteins are involved in," concluded Simon. "The next step will be to identify the signals that regulate the dynamic interaction between LMP4 and Tbx5."

FDA Approves Idursulfase As First Treatment for Hunter Syndrome

Wed, 02 Aug 2006 12:29:37 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) approved Elaprase (idursulfase), the first product for the treatment of Hunter syndrome (Mucopolysaccharidosis II, or MPS II), a rare inherited disease which can lead to premature death. Elaprase is a new molecular entity, which is an active ingredient never before marketed in the United States.

Hunter Syndrome, which usually becomes apparent in children one to three years of age, is a disease in which the person's body is defective in producing the chemical iduronate-2-sulfatase, which is needed to adequately breakdown complex sugars produced in the body. Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, neurological deficits, and death.

Elaprase was designated as an orphan product by FDA. Orphan products, such as Elaprase, are generally developed to treat rare diseases or conditions that affect fewer than 200,000 people in the U.S. The Orphan Drug Act provides a seven-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan product. Hunter syndrome is diagnosed in approximately one out of 65,000 to 132,000 births.

"This is the first product that brings help to a very small group of seriously ill patients who have no other treatment option," said Dr. Steven Galson, Director, Center for Drug Evaluation and Research. "This approval is a good example of how the Orphan products program can benefit the public health with urgently needed products that would otherwise not be commercially available."

Elaprase was approved after a randomized, double-blind, placebo-controlled study of 96 patients with Hunter syndrome showed that the treated participants had an improved capacity to walk. At the end of the 53week trial, patients who received Elaprase infusions experienced on average a 38-yard greater increase in the distance walked in six minutes compared to the patients on placebo.

The most serious adverse events reported during the trial were hypersensitivity reactions to Elaprase that could be life-threatening. They included respiratory distress, drop in blood pressure, and seizure. Other frequent, but less serious adverse events included fever, headache and joint pain.

Because of the potential for severe hypersensitivity reactions, appropriate medical support should be readily available when Elaprase is administered. Patients and their physicians are encouraged to participate in a voluntary Hunter Outcome Survey which has been established to monitor and evaluate the safety and effects of long-term treatment with Elaprase.

PARP1 inhibitors can protect Huntington's disease affected cells from damage

Sun, 30 Jul 2006 02:40:37 PST

( from http://www.rxpgnews.com ) An enzyme known to be critical for the repair of damaged cells and the maintenance of cellular energy may be a useful target for new strategies to treat Huntington's disease (HD) and other disorders characterized by low cellular energy levels. In the August issue of Chemistry & Biology, a research team from the MassGeneral Institute for Neurodegenerative Disease (MIND) describes their discovery of a novel inhibitor of Poly (ADP-ribose) polymerase (PARP1) and their findings that PARP1 inhibitors can protect HD-affected cells from damage in laboratory assays.

"While PARP1 is essential for the repair of damaged DNA, we also know that, if overactivated, it can cause cell death by excessive energy depletion," says Aleksey Kazantsev, PhD, director of the MIND High Throughput Drug Screening Laboratory, who led the current study. "It has recently been shown that neurons from patients with Huntington's appear to be energy-deficient, so we hypothesized that modest stresses that would be tolerated by healthy cells could send HD cells below a viable energy threshold and that blocking PARP1 activation could be protective."

To test this hypothesis the MIND researchers first ran a computer search of their small-molecule library for potential novel inhibitors of PARP1, searching for those with structural similarities to known inhibitors. "Safety and efficacy of human drugs depends on many factors, so it's hard to predict which inhibitor would be most effective against a specific disorder. The more diverse novel inhibitors can be identified, the more chances there are of developing safe and effective drugs," Kazantsev explains.

Two candidate molecules were identified as potential PARP1 inhibitors based on their structure, and both of them were confirmed to inhibit the enzyme's activity in an in vitro assay. However, when tested using cultured human and rat cells, only one of the candidate molecules, K245-14, successfully prevented the death of cells in which PARP1 had been overactivated.

The next assays examined whether blocking PARP1 activity with K245-14 could reduce energy depletion in cells with the HD genetic mutation. Using cells from human HD patients and from a mouse model of the disorder, the MIND researchers compared the reactions of HD cells to oxidative stress caused by the application of hydrogen peroxide with the reactions of normal cells. Although all of the cells reacted with a loss of ATP, a key source of cellular energy, the HD cells which had much lower ATP levels to begin with were much more vulnerable to stress-induced energy loss. Inhibiting PARP1 by means of K245-14 reduced ATP loss in all tested cells and significantly protected against both energy loss and cell death in the HD cells.

"While we were pleased to observe these predicted protective effects in our experiments, validation of PARP1 as a useful HD drug target will require the testing of inhibitors in animal trials," Kazantsev explains. "The process of identifying the best candidates for trials will be very complex, since any drug treating a central nervous system disorder needs to penetrate the blood-brain barrier. We will be working with our collaborators at the Scripps Research Institute world leaders in computational chemistry to conduct a more comprehensive virtual screen and select additional promising candidates for drug development.

"Inhibition of PARP1 activity is thought to be potentially beneficial for treatment of cancer, neurodegenerative conditions such as Parkinson's disease, and over twenty other human disorders," he adds. "We envision broad therapeutic applications for small molecule inhibitors of PARP1." Kazantsev is an assistant professor of Neurology at Harvard Medical School.

Gene therapy protects neurons in Huntington's disease

Fri, 30 Jun 2006 03:01:37 PST

( from http://www.rxpgnews.com ) Researchers at Rush University Medical Center, Chicago, and Ceregene Inc., San Diego, have successfully used gene therapy to preserve motor function and stop the anatomic, cellular changes that occur in the brains of mice with Huntington's disease (HD). This is the first study to demonstrate that, using this delivery method, symptom onset might be prevented in HD mice with this treatment.

"This could be an important step toward a disease modifying therapy," says co-author Jeffrey H. Kordower, PhD, director of the Research Center for Brain Repair at Rush. "We could potentially be stopping the disease process in its tracks, delaying symptoms from ever showing up."

Huntington's disease is an inherited degenerative disease that progressively robs patients of the ability to think, judge appropriately, control their emotions and perform coordinated tasks. HD typically begins in mid-life, between the ages of 40 and 50. There is no effective treatment or cure for this fatal illness that affects 30,000 Americans and places another 75,000 at risk.

Kordower says this research, if eventually applied to humans, could help those who have HD or, due to the presence of a genetic test, are known to be destined to get HD.

"Each child of an affected parent has a 50 percent risk for inheriting the disease. Genetic testing can identify mutated gene carriers destined to suffer from HD. Unlike other neurodegenerative disorders, identification of the genetic markers provides a unique opportunity to intercede therapeutically before or extremely early in the disease processonly a small fraction of potential carriers get tested. But, if there was a treatment, especially one that altered the natural course of disease, potentially halting it, we would hope every potential patient would get tested so they could avail themselves to the therapy."

Researchers used a defective virus, adenoassociated viral vector, (AAV) to deliver gene therapy (glial-derived neurotrophic factor (GDNF) directly to the brain cells of mice.

GDNF is one of two closely related, naturally-occurring nutrients that strengthen and protect brain cells that would normally die in this disease. The other neural nutrient is called neurturin (NTN). GDNF and NTN also increase production of the chemical neurotransmitter dopamine, which sends signals in the brain that enable people to move smoothly and normally. Ceregene, Inc, whose scientists co-authored this paper, is developing AAV-NTN (called CERE-120) as a potential treatment for several neurodegenerative diseases, while using AAV-GDNF for 'proof of principle' research studies.

The mice in this study were injected with the gene for GDNF encased in a harmless viral coating, which protects the gene and facilitates its delivery to brain cells. The virus coating (AAV vector) that carries the gene is well studied and has been used in several other gene transfer studies to deliver different genes for Parkinson's disease and Alzheimer's disease patients. The vector is no longer a true virus as it cannot replicate on its own and no longer contains any of its own genes. The vector has been engineered to transfer the gene for the brain nutrient selectively to the area of the brain where it is needed to protect the degenerating cells.

Three groups of mice were involved in the 4 month study. All mice were modeled to have the genetics of HD. The HD mice exhibited symptoms of motor deficits including loss of control, gait abnormalities, hypokinesia (abnormally decreased mobility and motor function), hind limb clasping behaviors and muscle weakness. One control group of mice did not receive any gene therapy. A second control group was injected with a placebo gene therapy. The third group received the active GDNF gene therapy.

To measure fine motor coordination, balance and fatigue, researchers evaluated mice walking on a rotating rod. Mice injected with the gene therapy performed significantly better than the other mice. These mice also showed diminished hind limb clasping, (a simulation of motor control behavior in HD patients). Perhaps most importantly, gene delivery of GDNF provided neuroprotection in the brain, with reduced density of brain inclusions and less cell death.

The authors wrote "Although GDNF's exact role in preventing cell death in mice modeled with HD remains to be established, we speculate the increase trophic support and inhibiting apoptosis (programmed cell death) via these two pathways likely played integral roles."

Kordower says the study suggests a new approach to forestall disease progression in newly diagnosed HD patients by delivering potent trophic factors with effects that are long-term and non-toxic." "If these results can be replicated in HD patients, it would represent a significant advance in the treatment of this tragic disease", agreed Dr. Jeffrey Ostrove, President and CEO of Ceregene.

"We are pleased with the results of this 'proof of concept' study with AAV-GDNF in HD mice", stated Raymond T. Bartus, Ph.D., Sr. Vice President, Clinical and Preclinical R&D and COO, Ceregene. "We now look forward to completing ongoing studies with our product, AAV-NTN (CERE-120), in HD mice, also performed in collaboration with Dr. Kordower and Rush University Medical Center", Bartus added.

Ceregene's lead program with CERE-120 is in Parkinson's disease (PD). The company completed enrollment of a Phase I trial with CERE-120 at UCSF and Rush University Medical Center, which was reported to be safe and well tolerated in PD patients at the American Association of Neurology meeting last spring. Initial efficacy results of this Phase I trial are expected to be presented this fall and a double-blinded, controlled Phase II trail in PD patients is planned for later this year.

Huntingtin cleavage is caused by caspase-6

Sat, 17 Jun 2006 20:09:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of British Columbia's Centre for Molecular Medicine and Therapeutics (CMMT) have provided ground-breaking evidence for a cure for Huntington disease in a mouse offering hope that this disease can be relieved in humans.

Published today in Cell journal, Dr. Michael Hayden and colleagues discovered that by preventing the cleavage of the mutant huntingtin protein responsible for Huntington disease (HD) in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. This is the first time that a cure for HD in mice has been successfully achieved.

"Ten years ago, we discovered that huntingtin is cleaved by 'molecular scissors' which led to the hypothesis that cleavage of huntingtin may play a key role in causing Huntington disease", said Dr. Michael Hayden, Director and Senior Scientist at the Child and Family Research Institute's Centre for Molecular Medicine and Therapeutics. Dr. Hayden is also a Canada Research Chair in Human Genetics and Molecular Medicine.

Now a decade later, this hypothesis has resulted in a landmark discovery. "This is a monumental effort that provides the most compelling evidence of this hypothesis to date", said Dr. Marian DiFiglia, Professor in Neurology, Massachusetts General Hospital, Harvard Medical School and one of the world's leading experts on Huntington disease. "Dr. Hayden and his team have shown in convincing fashion that many of the changes seen in HD patients can be erased in HD mice simply by engineering a mutation into the disease gene that prevents the protein from getting cleaved at a specific site".

To explore the role of cleavage, Dr. Hayden's team established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. In the study, researchers confirmed that the deadly cleavage is caused by a key enzyme called caspase-6. By blocking the action of this target, they showed that the mouse did not develop any symptoms of Huntington disease.

Hayden's team is now trying to test this model of prevention in a mouse using drug inhibitors and then ultimately in humans. "Our findings are important because they tell us exactly what we need to do next", said Dr. Rona Graham, Post Doctoral Fellow at the CMMT and lead author in the study.

This work is also pivotal for the individuals and families affected by Huntington disease. "Patients of this disease should know that this is a research milestone for all and that this work brings the field closer to finding effective treatment for a devastating disorder", said Dr. DiFiglia.

The Huntington Society of Canada (HSC), a national network of volunteers and professionals united in the fight against HD, echoed this sentiment. "This ground-breaking research provides great hope for the Huntington community", said Don Lamont, the Society's CEO and Executive Director. "This research brings us closer to treatment and ultimately a cure".

Huntington disease is a degenerative brain disease that affects one in every 10,000 Canadians. One in 1,000 is touched by HD -- for example, as a person with HD, a family member, a person at risk, caregiver or friend. The disease results from degeneration of neurons in certain areas of the brain causing uncontrolled movements, loss of intellectual faculties, and emotional disturbances. Currently, there is no treatment to delay or prevent HD in patients.

The risk of transmission of genetic disorders through donor's sperm

Fri, 19 May 2006 19:24:37 PST

( from http://www.rxpgnews.com ) As medical technology continues to advance, fertility procedures such as in-vitro fertilization and donor insemination are becoming more commonplace. However, a study in the May issue of The Journal of Pediatrics warns that, even after thorough screenings of sperm donors, genetic disorders can be transmitted to the conceived children.

Laurence Boxer, MD, and colleagues from the University of Michigan and the Severe Chronic Neutropenia International Registry investigated the cases of five children conceived by in-vitro fertilization or donor insemination who had severe congenital neutropenia (SCN)--a genetic disorder characterized by abnormally low levels of certain white blood cells in the body. Because these white blood cells help fight bacterial infections by destroying invading bacteria, people with SCN are more susceptible to recurring infections and are at greater risk for developing leukemia.

The study results showed that the same sperm donor was used for all five pregnancies. After conducting advanced genetic testing, the authors established that the donor was the carrier of the gene, not the mothers. The sperm bank was informed of this evidence, and all remaining samples were discarded.

The authors conclude that, because it is presently difficult to screen for all conceivable genetic disorders, it is imperative that potential mothers be properly counseled and informed prior to the procedures. "The mothers need to be prepared that there is always an inherent risk of a genetic disorder being transmitted by the donor's sperm," says Dr. Boxer.

Liver transplants provide metabolic cure for maple syrup urine disease

Tue, 11 Apr 2006 22:27:37 PST

( from http://www.rxpgnews.com ) Liver transplants cured the metabolic symptoms of 11 patients with a rare but devastating genetic condition known as Maple Syrup Urine Disease (MSUD), according to a study by researchers from Children's Hospital of Pittsburgh and the Clinic for Special Children.

All patients from the study (ranging in age from 1-20) are alive and well with normal liver function, according to the researchers. Amino acid levels in the study patients stabilized within 6-12 hours of transplant and remained stable since transplant despite unrestricted intake of protein.

MSUD is a metabolic disease which causes amino acids from proteins to accumulate in the body. The disease gets its names from the sweet smell of the urine. The accumulation of amino acids in the blood can cause metabolic crisis at any age, which can lead to brain swelling, stroke and even sudden death. Over a patient's lifetime, chronic instability of blood amino acids can result in serious learning disabilities and mental illness.

Before transplant, the only treatment was strict adherence to a diet almost devoid of protein. Despite adherence to this diet, patients were still at risk of metabolic crisis from something as simple as a common cold, which can disrupt the body's metabolism and cause rapid neurological deterioration.

In 1997, an MSUD patient at another hospital received a liver transplant due to an unrelated medical condition and physicians noticed the symptoms of her MSUD were alleviated.

Based on this serendipitous result, physicians from Children's and the Clinic for Special Children, located in Strasburg, Pa., began working collaboratively to develop a liver transplant protocol for MSUD which optimized patient safety. With a comprehensive, multidisciplinary protocol established, Children's transplant surgeons began performing liver transplants on MSUD patients in May 2004. Children's has performed 18 MSUD liver transplants since then.

The study by Children's and the Clinic for Special Children involved 11 of these MSUD patients, including the original patient. Results of the study are published in the March issue of the American Journal of Transplantation.

"The development of liver transplantation as a treatment for MSUD has dramatically improved our patients' quality of life," said George V. Mazariegos, director of Pediatric Transplantation at Children's and one of the study authors. "Our MSUD patients and their families had lived in fear of everything from a chicken nugget to a common cold. Liver transplantation is not without risks, but for some patients, it is the best option and it has allowed these recipients and their families to live without fear of simple things most people take for granted."

Kevin A. Strauss, MD, a pediatrician at the Clinic for Special Children and a co-author of the study, said that over the past 15-20 years, early diagnosis of MSUD followed by careful nutritional therapy have improved the health and developmental outcome of affected individuals.

"Nevertheless, the risk for metabolic crisis and acute neurological injury is always present, and many older individuals with MSUD suffer from depression, anxiety, and impaired concentration and learning," Dr. Strauss said. "Liver transplantation protects patients from these acute and chronic neurological complications. It is a reasonable alternative to nutritional therapy, particularly for patients with poor access to specialized medical care. However, liver transplantation is not without serious risks, and decisions about the best course of therapy will vary on an individual basis."

Spinocerebellar ataxia type 5 (SCA5) gene pinpointed

Mon, 23 Jan 2006 16:11:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of Minnesota Medical School have discovered the gene responsible for a type of ataxia, an incurable degenerative brain disease affecting movement and coordination.

This is the first neurodegenerative disease shown to be caused by mutations in the protein â-III spectrin which plays an important role in the maintaining the health of nerve cells. The scientific discovery has historical implications as well--the gene was identified in an 11-generation family descended from the grandparents of President Abraham Lincoln, with the President having a 25 percent risk of inheriting the mutation.

"We are excited about this discovery because it provides a genetic test that will lead to improved patient diagnoses and gives us new insight into the causes of ataxia and other neurodegenerative diseases, an important step towards developing an effective treatment," said Laura Ranum, Ph.D., senior investigator of the study and professor of Genetics, Cell Biology and Development at the University of Minnesota.

Understanding the effects of this abnormal protein, which provides internal structure to cells, will clarify how nerve cells die and may provide insight into other diseases, including amyotrophic lateral sclerosis (Lou Gehrig's disease) and Duchenne muscular dystrophy. The research will be published in the February print issue of Nature Genetics, and posted online Jan. 22, 2006.

Ataxia is a hereditary disease that causes loss of coordination resulting in difficulty with everyday tasks such as walking, speech, and writing. About 1 in 17,000 people have a genetic form of ataxia.

Spinocerebellar ataxia type 5 (SCA5) is a dominant gene disorder; if a parent has the disease, each of their children has a 50 percent chance of inheriting the mutation and developing ataxia sometime during their lifetime. The onset of SCA5 usually occurs between the ages of 30 and 50, but can appear earlier or later in life, with reported ages of onset ranging from 4 to more than 70 years of age.

Now that researchers have identified the specific mutation that causes SCA5, testing of patients at risk of developing this disease is possible before any symptoms appear. The availability of predictive testing allows people with a family history of the disease to determine whether they will develop the disease and whether their children are at risk of inheriting the mutation. In addition, the prognoses of the different types of ataxias vary greatly, so identifying the specific type of ataxia provides patients with a more accurate picture of what the future holds.

Ranum added: "Finding the SCA5 mutation in Lincoln's family makes it possible to test Lincoln's DNA if it becomes available to unequivocally determine if he carried the mutation and had or would have developed the disease." Biographical texts of Lincoln include descriptions of his uncoordinated and uneven gait, suggesting the possibility that he showed early features of the disease.

Ranum started this historical and scientific journey more than a decade ago. She and her colleagues John Day, M.D., Ph.D., University of Minnesota, and Larry Schut, M.D., CentraCare Clinic in St. Cloud, Minn., examined and collected DNA samples from more than 300 Lincoln family members who live across the country, tracking descendants from two major branches of the family.

Scientists probe connection between regulatory DNA and disease

Sat, 17 Dec 2005 15:33:38 PST

( from http://www.rxpgnews.com ) Through the Human Genome Project, the HapMap Project and other efforts, we are beginning to identify genes that are modified in some diseases. More difficult to measure and identify are the regulatory regions in DNA the 'managers' of genes that control gene activity and might be important in causing disease.

Today, a team led by the Wellcome Trust Sanger Institute, together with colleagues in the USA and Switzerland, provide a measure of just how important regulatory region variation might be in a pilot study based on some 2% of the human genome. As many as 40 of 374 genes showed alteration in genetic activity that could be related to changes in DNA sequence called SNPs.

"We were amazed at the power of this study to detect associations between SNP variations and gene activity," commented Dr Manolis Dermitzakis, Investigator, Division of Informatics at the Wellcome Trust Sanger Institute. "We were even more amazed at the number of genes affected: more than 10% of our sample or perhaps 3000 genes across the genome could be subject to modification of activity in human populations due to common genetic variations."

The study combined the map of genetic variation developed through the HapMap with estimates of gene activity obtained from cell cultures from 60 individuals who provided samples for the HapMap. More than 630 genes were studied, of which 374 were active in the cell cultures. If gene activity in a cell culture was skewed from the average, it was investigated further.

These genes were correlated with more than 750,000 SNPs sequence differences between individuals in the sample collection. A series of statistical tests were carried out to provide increased confidence in the association between gene activity and sequence variation.

"Our sample size of 60 individuals is relatively small," continued Dr Dermitzakis, "and we might expect not to detect rare variations. However, our pilot project gives us greater confidence to take on a genome-wide survey of gene activity."

A global map of sequence variation and gene activity will be an important tool in the interpretation of variation and disease. Such genome-wide association studies will be able to identify some regions of the genome with strong disease effects.

"The HapMap is proving to be useful in a wide range of applications," commented Dr Panos Deloukas, Senior Investigator, Division of Medical Genetics, Wellcome Trust Sanger Institute. "The journey for our biomedical research is from DNA sequence to individual people and individual disease. The HapMap is a bridge from sequence data to the differences in individuals."

The project focused on three regions of the human genome. The first, called the ENCODE regions, and about 30 million base-pairs of DNA, are being intensively studied around the world as a group of 'typical' human genome regions. The second was 35million base-pairs of chromosome 21 sequence: three copies of chromosome 21 lead to Down Syndrome. The third was a region of chromosome 20 10 million base-pairs that is known to be associated with diabetes and obesity.

In comparison with gene sequences that contain the instructions to make proteins, regulatory regions that control genes are relatively poorly understood. Their structure is variable and their distance from the genes they control also varies among genes.

New tools are needed in the search of our genome for the sequences that contribute to disease, tools that will harness the massive amounts of DNA information and transform them into information of real biomedical utility. The methods described here, with the power of the HapMap data and the cell cultures available, will speed that transformation.

Farnesyl Transferase Inhibitors in Hutchinson-Gilford progeria syndrome

Wed, 28 Sep 2005 13:19:38 PST

( from http://www.rxpgnews.com ) The new Hopkins research, and similar results from other labs, shows that a class of drugs known as farnesyl transferase inhibitors, or FTIs, can reverse an abnormality in laboratory-grown cells engineered to mimic cells from progeria patients. In the laboratory, however, treating these engineered cells with an FTI already in clinical trials in cancer patients restored the cells to a normal appearance, the researchers report Sept. 26 in the advance online section of the Proceedings of the National Academy of Sciences. The drug blocks the first step in processing the faulty protein that causes the syndrome.

"We've been hopeful that our two decades of research on how proteins are processed and modified in cells might ultimately help people with certain forms of cancer," says Susan Michaelis, Ph.D., professor of cell biology at Johns Hopkins' Institute for Basic Biomedical Sciences.

"But for progeria, we and others only recently learned that it involves the one of the modified proteins we've been studying, a nuclear protein called lamin A. As a basic scientist, it is really exciting to have leapfrogged from studying a fundamental process to finding evidence that an existing drug might be useful in treating a devastating disease in children," she says.

Michaelis emphasizes that no one knows whether making the cells' nuclei look normal will be enough to reverse the disease process or slow it down. The class of drugs they tested prevents the first step in cells' processing of certain critical proteins in yeast and mammals. For more than 20 years, Michaelis has been studying this complex process.

The process starts with a fully assembled protein, then adds a fatty appendage called farnesyl very close to the protein's end, and then a tiny modification called a methyl group to a nearby building block. In yeast, the protein that gets the full treatment helps the single-celled organisms reproduce -- and the useful protein is the smaller part with all the fancy modifications. In cells' processing of lamin A in mammals, however, the plain, big chunk is the active part, and it's critical for the proper function and organization of cells' nuclei.

In children with progeria, however, a genetic mutation causes a piece of the original lamin A protein to be deleted, a discovery made by National Institutes of Health researchers and reported in 2003. "The normal mammalian protein, lamin A, doesn't have all those modifications; the modified part is thrown away," says Michaelis. So Michaelis and postdoctoral fellow Monica Mallampalli, Ph.D., set out to test that idea. Mallampalli genetically engineered a human cell line (HeLa) to have either of two mutations in the gene for lamin A. One mutation halted the process at the very beginning, by preventing addition of the fatty farnesyl appendage. The other affected the end of the process by preventing cleavage of the otherwise normal, fully modified protein.

"Neither has the correct lamin A protein, but only one has a modified protein hanging around," says Michaelis. "We found that only the cells with the farnesyl-modified protein had the problems seen in cells with the HGPS mutation."
Mallampalli also altered the version of the gene that produces the abnormal, persistently modified, disease-causing protein, called progerin, to uncover the effect of preventing the addition of farnesyl. Sure enough, even though the cells still didn't have normal lamin A, their nuclei looked normal when the faulty protein couldn't get modified.

"We were thrilled that, as our genetic studies predicted, the experimental drug did the trick," says Michaelis. "Because FTIs are already in advanced clinical trials with cancer patients and seem to be quite well-tolerated, it's hopeful that they could be tested in patients with progeria fairly quickly."

FTIs prevent addition of farnesyl to all proteins that have a particular molecular tag. In cancer, the key target among these proteins is one called Ras, which is activated by the same farnesyl-triggered process as lamin A and which promotes cancerous growth when there's too much of it.

Clioquinol, an antibiotic shows new promise for Huntington's Disease

Mon, 12 Sep 2005 18:13:38 PST

( from http://www.rxpgnews.com ) Clioquinol, an antibiotic that was banned for internal use in the United States in 1971 but is still used in topical applications, appears to block the genetic action of Huntington's disease in mice and in cell culture, according to a study reported by San Francisco VA Medical Center (SFVAMC) researchers.

The study, led by principal investigator Stephen M. Massa, MD, PhD, a neurologist at SFVAMC, was reported in the August 16, 2005 issue of Proceedings of the National Academy of Sciences.

Huntington's disease is a hereditary, degenerative, and ultimately fatal disease of the brain that causes changes in personality, progressive loss of memory and cognitive ability, and a characteristic uncontrolled jerking motion known as Huntington's chorea. There is no known cure or effective treatment. A person who carries the mutant Huntington's gene may pass it on unknowingly because the disease often manifests in early to late middle age after the carrier's children have already been born.

During the course of the disease, the Huntington's gene causes the production of a toxic protein, mutant huntingtin, in neurons (brain cells). Eventually the protein kills the neurons, causing the disease's degenerative effects.

In Massa's study, Clioquinol appeared to interrupt the production of mutant huntingtin. In the first part of his study, Massa and his research team tested the effect of Clioquinol on neurons in cell culture that contained a form of the mutant Huntington's gene. "We found that not only did cells look better and survive a bit longer when exposed to the drug, but they also seemed to make less of the toxic protein," observed Massa, who is also a clinical assistant professor of neurology at the University of California, San Francisco (UCSF).

Based on the in vitro results, Massa decided to test the drug in vivo, on mice bred to express the toxic huntingtin protein. The mice were given approximately 1 milligram of Clioquinol per day in water. After eight weeks of treatment, they had accumulated four times less toxic protein in their brains than control mice given water alone. The experimental animals lived 20 percent longer than the control animals, did better on tests of motor coordination, and had less weight loss.

"It's a limited study, in that we used the same drug dose on all the animals as opposed to comparing different doses, but fairly convincing," Massa concluded. "Together, the in vitro and in vivo results suggest that Clioquinol has an effect of decreasing the symptoms of Huntington's, its pathology, and perhaps even the actual production of the toxic protein."

However, he noted, "the drug's mechanism of action remains unclear." The clearer the mechanism of the drug, he explained, the better the chance that researchers might eventually be able to create a medication that is both safe and effective.

Like some other antibiotics, Clioquinol is known to be a chelator -- that is, it binds metals in body tissues, particularly copper and zinc, and removes them when it is excreted. Massa and other researchers believe that this chelation effect may interfere with production of the mutant huntingtin protein in some way. "But there are still a couple of explanations we need to rule out," he said.

To that end, Massa's next studies will involve the creation of an in vitro system in which toxic and non-toxic forms of huntingtin are made in the same cell. He and his team will then evaluate the effects of Clioquinol on several phases of protein synthesis within the cell. Massa hopes these experiments will confirm initial indications that Clioquinol preferentially interferes with synthesis of the toxic form of the protein. "Then we can move on to trying to isolate the actual mechanism of the drug," he predicted.

"However," Massa cautioned, "the record of successfully translating drugs from animal to human use is not good."

Clioquinol has shown promise as a potential treatment for Alzheimer's disease in recent studies in mice and humans. Apparently through chelation, it interferes with the creation of beta-amyloid plaque in the brain, which has been implicated in the progression of Alzheimer's symptoms.

Currently, Clioquinol is banned for internal use in many countries because of its side effects. In Japan in the late 1950s and 60s, the drug was found to cause a neurologic condition called subacute myelo-optico-neuropathy (SMON), with symptoms including visual loss, muscle weakness, and numbness, in several thousand people. However, noted Massa, the doses given in current clinical trials are much smaller than were commonly prescribed in Japan. In addition, he explained, it has been found that vitamin B12, when taken along with the drug, protects against its potential toxic effects.

Anti-cancer drugs might work in aging disease

Tue, 30 Aug 2005 19:44:38 PST

( from http://www.rxpgnews.com ) Working together, scientists at the National Institutes of Health and the University of North Carolina at Chapel Hill have developed a promising new strategy for treating a form of progeria. That rare but deadly and heartbreaking genetic disease causes children to age remarkably fast and die almost always before they complete their teens.

The average lifespan of victims, who eventually resemble very old bald people or, some might say, Hollywood's conception of space aliens, is 12 years.

Along with their staffs and students, Dr. Francis S. Collins, director of the National Human Genome Research Institute, has collaborated with Drs. Channing J. Der and Adrienne D. Cox of the UNC School of Medicine in laboratory studies.

They have shown that certain anti-cancer drugs known as FTIs can block some of the complex biochemical processes that result in progeria's symptoms. The collaboration came about because the UNC scientists have been working on the drugs for more than a decade, and Collins' group has been actively investigating progeria of childhood, which also is known as Hutchinson-Gilford syndrome.

The potential treatment has not been used with patients yet but had a strong positive effect on progeria patients' cells, they said.

Respectively, Cox and Der are associate professor of radiation oncology and pharmacology and professor of pharmacology and members of UNC's Lineberger Comprehensive Cancer Center. Collins, a UNC medical graduate, attracted widespread attention in 1989 as the discoverer of the defective gene that causes cystic fibrosis, another fatal illness that afflicts children.

A report on the research appears in the Sept. 6 issue of the Proceedings of the National Academy of Sciences. Other authors of the report include M.D.-Ph.D. student Brian C. Capell of Collins' NIH laboratory; NIH staff members Drs. Michael R. Erdos, Renee Varga and Leslie B. Gordon (also medical director of the Progeria Research Foundation); doctoral student James P. Madigan of Cox's laboratory; Dr. James Fiordalisi, assistant professor of radiation oncology at UNC; and Dr. Karen N. Conneely of the University of Michigan School of Public Health.

"Fortunately, progeria is very rare, and only about one child in four million comes down with it," Der said. "It was first identified in the early 1900s. Since then only 100 or so cases have been found. Still, it is quite devastating for those children who have it and their families."

He and Cox concentrate on FTIs, or farnesyltransferase inhibitors, which block the action of the enzyme farnsyltransferase. Currently, several chemical variations are undergoing clinical trials with cancer patients.

"There's a lot of interest in FTIs now because they target an enzyme that's required for a protein called RAS to cause cancer," Der said. "The idea that these FTIs also might be useful in treating progeria came up because it turns out that the gene that is mutated in that rare illness also requires this enzyme for generating an active protein known as lamin A."

In progeria patients, he said, the process that results in the normal, mature form of lamin A doesn't work correctly because of the genetic mutation, so a damaged form of lamin A is made instead. Researchers reasoned that the anti-cancer drugs might block the enzyme and hence interfere with the mutated lamin A gene's haywire actions.

"In the paper, we describe experiments showing that the mutant form of lamin A was indeed sensitive to these drugs," Der said. "The second thing we found was that some of the aberrant biology that this mutant protein causes can be stopped when we treat the cells with the inhibitors."

Because the drugs already are undergoing clinical trials and much is known about their action and safety, scientists have a significant head start in getting the possible treatment to patients, Cox said.

"We are very excited about the possibility that a drug class whose actions we have been working so hard to understand in cancer might soon be useful for this devastating 'orphan disease,'" she said. "Progeria is clearly an illness that would otherwise get no attention from pharmaceutical companies due to the tiny numbers of children afflicted."

The next step will be to test the enzyme inhibitors in mouse models of the disease which already have been made, Cox said. If those experiments succeed, then scientists could start clinical trials with patients.

Lamin research project provides clues about premature aging

Tue, 30 Aug 2005 19:41:38 PST

( from http://www.rxpgnews.com ) A step towards understanding cell mutations that cause a variety of human diseases, particularly in children -- including that which brings about premature aging and early death -- has been taken by researchers at the Hebrew University of Jerusalem Silberman Institute of Life Sciences and the John Hopkins University School of Medicine.

The scientists have focused their research on a study of induced mutations in the nuclear envelope of cells from the tiny C. elegans worm. Their aim is to thus provide clues towards a better understanding of mutations in proteins of the envelope of the cell nucleus in humans.

Such mutations, particularly in lamin (nuclear envelope) proteins A and C, cause many different diseases, including Hutchison Gilford progeria syndrome. Children with this disease develop premature aging and die usually before the age of 13. Other diseases brought about by these mutations include a form of muscular dystrophy, cardiomyopathy (a weakening of the heart muscle), and various other forms of irregular or retarded growth in childhood.

A report on the lamin research project was published in a recent issue of the Proceedings of the National Academy of Sciences in the U.S. The project was carried out primarily by Ayelet Margalit, a doctoral student in genetics at the Hebrew University, working under the supervision of Prof. Yosef Gruenbaum, and in cooperation with Prof. Katherine L. Wilson and Dr. Miriam Segura-Totten of Johns Hopkins University.

Experimenting with removal of the worm's lamin protein or its interacting protein partners emerin, MAN1 or BAF, the researchers have described "down-the-line" consequences, including the disruption of various proteins necessary for normal cell reproduction. Even though the C. elegans worm has only one lamin protein and few proteins that interact with it, the processes that occur there are similar to what happens in humans and provide clues to the laminopathic diseases affecting people..

The results seen from these lamin complex disruptions are a halted process of cell division, resulting in a static "bridge" structure between cells that should have separated, plus damage to the gonad cell structure. In both cases, the ability of the organism to grow and to reproduce is severely impaired.

The researchers hope that through further laboratory experimentation with the worm they will be able to better understand the functions of lamin-based complexes, and why mutations in these proteins cause a variety of different laminopathic diseases, such as progeria and muscular dystrophy in humans.

Drug prevents cell abnormality leading to progeria

Tue, 30 Aug 2005 19:38:38 PST

( from http://www.rxpgnews.com ) BACKGROUND: One in 4 million children are born with progeria, a genetic disease marked by accelerated aging and early cardiovascular disease. The children suffer from dwarfism, baldness, wrinkles, hardened arteries and osteoporosis. Most die from heart disease before age 15.

The rare disorder stems from a mutation in a gene that produces an abnormal cellular protein, which attaches itself to structures in the cell's nucleus. The accumulated protein deforms the nucleus, sparking miscommunications with other cells and leading to the genetic disease.

FINDINGS: UCLA scientists studied cells isolated from people with progeria and cultured the cells with a drug that blocked the mutant protein from attaching to the cells' nuclei. The drug significantly reduced the number of human cells with misshapen nuclei. The UCLA team earlier used the same approach to improve the shape of abnormal nuclei from mice genetically engineered to develop progeria.

IMPACT: The findings offer new clues into how progeria develops and could lead to new drugs to treat the disease and its related disorders, including osteoporosis and hardening of the arteries. UCLA's next step will be to test whether returning the shape of the nuclei to normal stops development of progeria in mice.

Farnesyltransferase inhibitors (FTIs) might be useful in Hutchinson-Gilford Progeria Syndrome

Tue, 30 Aug 2005 19:32:38 PST

( from http://www.rxpgnews.com ) In a surprising development, a research team led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has found that a class of experimental anti-cancer drugs also shows promise in laboratory studies for treating a fatal genetic disorder that causes premature aging.

In a study published Monday in the online edition of the Proceedings of the National Academy of Sciences (PNAS), Brian Capell and his colleagues at NHGRI reported that drugs known as farnesyltransferase inhibitors (FTIs), which are currently being tested in people with myeloid leukemia, neurofibromatosis and other conditions, might also provide a potential therapy for children suffering from Hutchinson-Gilford Progeria Syndrome, commonly referred to as progeria. A related study from Stephen Young, M.D., and colleagues at the University of California at Los Angeles is being published in the same issue of PNAS.

There are currently no treatments for progeria, which is a genetic disorder estimated to affect one child in 4 million. When they are born, children with progeria appear normal. But, as they grow older, they experience growth retardation and show dramatically accelerated symptoms of aging -- namely hair loss, skin wrinkling and fat loss. Accelerated cardiovascular disease also ensues, typically causing death from heart attack or stroke at about the age of 12.

"Our findings show that FTIs, originally developed for cancer, are capable of reversing the dramatic nuclear structure abnormalities that are the hallmark of cells from children with progeria. This is a stunning surprise, rather like finding out that the key to your house also works in the ignition of your car," said NHGRI Director Francis S. Collins, M.D., Ph.D., who is the study's senior author.

The new work involved using FTIs to treat skin cells taken from progeria patients and grown in laboratory conditions. If upcoming studies in a mouse model validate the results of the cell experiments and translate into improvements in the animals' conditions, a clinical trial of FTIs in children with progeria may begin as early as next spring, researchers said.

Dr. Collins and his colleagues discovered in April 2003 that mutations in the lamin A (LMNA) gene cause progeria, spurring renewed interest among researchers to study this rare syndrome. Among those were Capell, a New York University medical student participating in the Howard Hughes Medical Institute/NIH (HHMI/NIH) Research Scholars Program. In July 2004, he joined Dr. Collins' lab and immediately set his sights on understanding the molecular basis of progeria.

"What really interested me in this research in the first place were the potential links to aging and atherosclerotic disease," said Capell. Indeed, understanding progeria at the molecular level may illuminate the general processes involved in normal human aging.

The LMNA gene codes for a protein called lamin A, which constitutes a major component of the scaffold-like network of proteins just inside the cell's nuclear membrane, called the lamina. The gene mutation implicated in progeria causes a section of 50 amino acids within the lamin A protein to be deleted, resulting in a mutated protein that is called progerin. This protein fails to integrate properly into the lamina, thereby disrupting the nuclear scaffolding and causing gross disfigurement of the nucleus. Cells with progerin have a nucleus with a characteristic "blebbed," or lobular, shape.

To find its way to the lamina, lamin A carries two tags, rather like ZIP codes, that help to direct the protein's travels. One tag at the end of lamin A instructs another protein to modify it through a process called farnesylation. Farnesylation tethers lamin A to the inner nuclear membrane. Once there, a second tag within the protein signals an enzyme to cleave off the terminal portion of the protein, including the farnesyl group, freeing lamin A to integrate properly into the nuclear lamina.

Because progerin carries the farnesylation tag but lacks the second cleavage tag, Capell speculated that progerin was becoming permanently stuck to the inner nuclear membrane. There, he suspected, it enmeshed other scaffolding proteins, preventing their proper integration into the lamina. If progerin's tendency to stick to the inner nuclear membrane is indeed the culprit in nuclear blebbing and the root of the progeria defect, Capell and his colleagues reasoned that they could prevent these defects by blocking farnesylation of progerin.

The researchers' hunch proved correct. When they changed one amino acid within progerin's farnesylation tag to prevent the addition of a farnesyl group and tested the effect in cells grown in the laboratory, progerin did not anchor itself to the inner nuclear membrane and instead clumped within the nucleus. Moreover, they observed no nuclear blebbing.

The researchers then tried treating the cells carrying progerin with FTIs, which are drugs originally developed to inhibit certain cancer-causing proteins that require farnesylation for function. FTIs are now being tested in phase III clinical trials of patients with myeloid leukemia. So far, clinical trials using FTIs have found little toxicity, even when the drug treatment significantly raises levels of unfarnesylated proteins.

After FTI treatment, the progerin-carrying cells showed no blebbing. More importantly, researchers saw the same effect when they used FTIs to treat cells grown from skin biopsies of progeria patients: Cell blebbing decreased to near normal levels.

Lorenzo's oil (LO) reduced the risk of developing severe X-linked adrenoleukodystrophy (ALD)

Tue, 12 Jul 2005 12:25:38 PST

( from http://www.rxpgnews.com ) Treatment of boys with X-linked adrenoleukodystrophy (ALD) with Lorenzo's oil (LO) reduced their risk of developing the severe debilitating form of the disease, according to a study in the July issue of the Archives of Neurology, one of the JAMA/Archives journals.

Individuals with ALD accumulate high levels of saturated very long-chain fatty acids (VLCFA) in their brains. The course of the disease results in a number of different manifestations [phenotypes], according to background information in the article. The rapidly progressive cerebral ALD (CERALD) type typically begins between ages four and eight and progresses rapidly to total disability within a few years. An adult form is non-inflammatory, progresses slowly and is far less disabling. Children who do not develop abnormalities as measured by magnetic resonance imaging (MRIs) by age seven or clinical symptoms by age 10, have greatly diminished risk of developing cerebral ALD.

In 1989, one of the authors of this study, Augusto Odone, pioneered a treatment (Lorenzo's oil), which was shown to normalize the levels of saturated very long-chain fatty acids within four weeks in most patients with ALD. "The striking effect of LO on plasma C26:0 [a saturated very long-chain fatty acid] levels engendered the hope that it would be of clinical benefit for patients with ALD," the authors write. However, previous clinical trials led to the conclusion that Lorenzo's oil did not alter the rate of progression of the disease in patients who already had neurological symptoms.

Hugo W. Moser, M.D., of the Kennedy Kreiger Institute, Baltimore, and colleagues treated 89 boys with ALD who had no neurological symptoms and normal brain MRIs with moderate dietary fat restriction and Lorenzo's oil between 1989 and 2002. Sixty-four of the patients were younger than seven years old when they began treatment and all were followed up for an average of approximately seven years. Because of the devastating nature of cerebral ALD, and the hope that the striking reduction of very long chain fatty acid levels would lead to clinical benefit, none of the boys were given placebo. Fatty acids blood levels were assessed every month for the first six months after enrollment in the study and every three to six months thereafter. Neurological examinations and MRIs were scheduled every six to 12 months.

Sixty-six patients (74 percent) were well at last follow-up. Twenty-one patients (24 percent) developed MRI abnormalities and 10 patients (11 percent) developed neurological abnormalities. The researchers found a significant association between the development of MRI abnormalities and an increase in the levels of the saturated very long chain fatty acid C26:0. "Patients who had a neurological abnormality had significantly higher weighted average C26:0 levels than those who did not have an abnormality, suggesting that an LO-induced decrease in the C26:0 level could protect against the inflammatory cerebral disease," the authors report.

"We recommend that LO therapy be offered to male patients with ALD who are neurologically asymptomatic, have normal brain MRI results, and are at risk of developing CERALD," the authors conclude. "This recommendation is based on strongly suggestive, albeit not fully definitive, evidence of a preventive effect combined with our awareness of the severe prognosis of the untreated patients with CERALD. ...The patients who are younger than seven years represent prime candidates for this therapy. We hypothesize that intensive LO therapy during the ages at which the risk for CERALD is greatest may protect against this phenotype until they reach the ages at which the risk for CERALD diminishes."

In an editorial accompanying the article, Raymond Ferri, M.D., Ph.D. and Phillip F. Chance, M.D., of the University of Washington, Seattle, write "In recent years, extraordinary progress has also been made in developing effective treatments, and ALD serves as an excellent model for the treatment of neurometabolic diseases. ...Current treatment includes hematopoietic stem cell transplantation (HSCT) to stabilize neurologic progression, steroid therapy for adrenal insufficiency, and symptomatic treatments. The article by Moser et al in this issue may establish new standards for the treatment of this degenerative disorder."

"Therefore, Moser and colleagues propose LO therapy for all asymptomatic patients with biochemical evidence of ALD to slow the progression of disease and to prevent symptoms until the child is past the age for the development of the childhood cerebral form of the disorder," the authors write. "Successful implementation of this practice requires early identification of at-risk patients. However, because almost 20 percent of the patients are either asymptomatic or have Addison disease only, at-risk children may not be identified. As also mentioned in the article, neonatal screening would identify more at-risk patients at a very early age. This would allow for further studies to examine very early treatment with LO for affected children, and dietary therapy can be studied in other ALD phenotypes [manifestations]. Also, this study can be extended to follow patients for an even greater duration to establish the full treatment effects of LO."

"X-linked ALD is a rare, progressive neurometabolic disorder, but coordinated, worldwide research efforts have made it a treatable disease," the authors conclude. "Dietary therapy started early in life and HSCT have markedly improved the longevity and quality of life for affected people, and new standards for treatment have been established."

Understanding the interaction of Fragile X mental retardation protein and kissing complex RNAs

Mon, 18 Apr 2005 04:56:38 PST

( from http://www.rxpgnews.com ) Fragile X syndrome is the most common inherited form of mental retardation, affecting approximately 1 in 3600 males and 1 in 4000-6000 females. Fragile X syndrome results from loss of expression of the Fragile X mental retardation protein (FMRP), the product of the FMR1 gene. Now, Drs. Robert and Jennifer Darnell and colleagues, from The Rockefeller University, report the uncovering of a new interaction between FMRP and messenger RNAs (mRNAs) containing a tertiary RNA structure termed a "kissing complex".

Their studies, published in the April 15th issue of Genes & Development, provide a new direction for efforts to understand how the loss of FMRP function leads to the complex behavioral and cognitive defects characteristic of Fragile X syndrome.

While the importance of identifying a function for FMRP has been clear for some time, what this function actually is has continued to evade researchers. FMRP is a protein characterized by the presence of three RNA binding domains: two tandem KH-type RNA binding domains and an RGG box. Scientists have focused on the identification of FMRP RNA ligands in an effort to understand FMRP function. This effort is particularly meaningful since FMRP is believed to regulate mRNA translation in the brain, and identifying the mRNA targets of this regulation would be a huge step in understanding how loss of this protein results in the varied and complex phenotypes of Fragile X syndrome.

In most Fragile X patients, loss of FMRP is due to silencing of FMR1 resulting from the unusual amplification of a CGG repeat (over 200 copies in affected patients versus less than 60 copies in unaffected individuals) that leads to hypermethylation of FMR1 and shut down of transcription of the gene. However, Fragile X patients expressing mutations or deletions within the FMR1 gene have also been described, including a severely affected patient harboring a missense mutation that resulted in a one amino acid change, isoleucine at position 304 for asparagine, in one of the KH domains of FMRP, KH2.

Dr. Darnell and colleagues focused on understanding how this specific mutation leads to loss of FMRP function. They first screened an RNA library to identify what RNA motif is recognized by the KH2 domain. They found that the KH2 domain of FMRP recognizes a loop-loop pseudoknot, or "kissing complex" structure in the RNA, and that this recognition is abrogated by the isoleucine to asparagine mutation. Notably, they show that the association of FMRP with the translation machinery (in brain polyribosomes) can be competed out with kissing complex RNA, an important finding since previous biochemical studies have reported altered polyribosome distribution of mRNAs in Fragile X patients.

These findings will redirect the search for the RNA targets of FMRP whose misregulation is responsible for the disease, to those containing kissing complex motifs.

Though much remains to be understood in the biology leading to Fragile X syndrome and the function of FMRP, Dr. Darnell is confident that "these findings may provide a crucial link between the association of FMRP in brain polyribosomes, its proposed role in regulation mRNA translation, and neurologic dysfunction in the Fragile X syndrome".

Roberts Gene ESCO2 Discovered to be behind "PSEUDOTHALIDOMIDE" Syndrome

Tue, 12 Apr 2005 13:01:38 PST

( from http://www.rxpgnews.com ) A team of scientists from Colombia, the United States and elsewhere has successfully completed a 15-year-plus search for the genetic problems behind the very rare Roberts syndrome, whose physical manifestations often include cleft lip and palate and shortened limbs that resemble those of babies whose mothers took thalidomide during pregnancy.

The discovery, which is reported in the April 10 advance online section of Nature Genetics, proves that genes behind very rare inherited diseases can now be found, offering excellent opportunities to strengthen understanding of craniofacial and limb development, health and disease beyond the rare disease itself, say the researchers.

Because of advances in technology and computer analysis, the researchers were able to find the Roberts gene, called ESCO2, by studying samples from just 15 Roberts syndrome families from Colombia, Turkey, Canada and Italy and to provide insight into its biological effect.

"For decades now, we've known that the appearance and number of chromosomes were abnormal in people with Roberts syndrome, but we hadn't been able to figure out why or how," says Ethylin Jabs, M.D., a professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "Just within the last few years have the genetic techniques, the genomic information, and the computer analysis become powerful enough to find the genetic mutations behind a disease as rare as Roberts."

Some of the techniques they used -- such as that to make many copies of DNA from a small sample -- have been around in some form for more than a decade. But others are much more recent developments. For example, the researchers found important genetic changes in part by comparing different species' genetic sequences, most of which were published only within the last four years.

"In 1989, we were collecting samples and characterizing the chromosome problem in cells from people with Roberts syndrome," Jabs remembers. "We knew it would be really important to find the gene, but it just wasn't practical at that time."

A few years later, in 1995, two Colombian geneticists started their quest to fully understand Roberts syndrome. Without their push, the gene for Roberts might still be unknown.

Colombian Hugo Vega had noticed an unusual number of patients with Roberts syndrome in the clinic at the University of Bogotá. Fairly quickly, he tracked down seven families with Roberts syndrome in two villages outside Bogotá. Four of the families share an 18th-century ancestor, he and Miriam Gordillo, then an undergraduate, discovered.

"The families have really collaborated with us, they've worked with us quite closely to help us uncover the gene behind the syndrome," says Gordillo. "Now we have about 10 affected families from outside Bogotá, and we can offer a genetic test to families at risk of Roberts syndrome."

Vega and Gordillo, a husband-and-wife team, criss-crossed the globe to continue their work and find better funding opportunities. In Japan, Vega tied the Colombian families' syndrome to a large region of chromosome 8. In The Netherlands, a post-9/11 detour, he added to his analysis samples from Turkish and Italian families with Roberts syndrome.

In 2004, Gordillo got a student visa to work with Jabs and to study for her doctorate in human genetics at Johns Hopkins. Over the past year, Gordillo analyzed the chromosome 8 region in samples from 15 families (consisting of 18 affected members and 33 unaffected members) and tied the condition to one of 6 genes.

Then, the international team compared the human sequence of the genes to those from chimpanzee, mouse, rat, chicken and zebrafish, and to the gene sequences of the affected family members. One segment of a gene called ESCO2 that was identical in all the animals contained changes that disrupted the gene's protein-making instructions in people with the syndrome. Knocking out the equivalent gene in yeast and fruit flies led to the same chromosome problems, says Gordillo.

"Comparative genomics didn't really exist even five years ago," says Jabs. "Techniques to genetically engineer yeast, fruit flies and even mice have dramatically improved in the last 15 years. And we were also able to look at when and where the gene is expressed during human development. Without these techniques, and without the powerful computer programs, we wouldn't have been able to identify this gene and confirm its role in Roberts syndrome."

The physical similarities of people with Roberts syndrome and those whose mothers took thalidomide suggest similar underlying biology, Jabs notes. Although there's some evidence that thalidomide prevents blood vessel growth, it's not clear why. If the underlying biology is related somehow, then thalidomide might affect chromosomes and cell division like ESCO2 in Roberts syndrome, Jabs speculates.

During normal cell division, every chromosome is copied, and each of the "original" chromosomes is attached to its "new" copy. While there are attachment points along the entire chromosome, the bulk of the connection is at the centromere, a chromosome's functional hub.

The chromosomes' connection allows the cell to move them together, ensuring that the two copies are lined up together at the center of the dividing cell. Once lined up, tiny molecular "motors" attach to the centromere of each copy and pull the original and the new copy away from each another as division proceeds.

However, in cells from people with Roberts syndrome, the chromosome copies are frequently not attached to each other at their centromeres and the chromosomes don't get lined up properly. As a result, the cell doesn't divide or divides very slowly, and the new cells can end up with too many or too few chromosomes (a problem also seen in cancer cells). In Roberts syndrome, the cells tend to stop growing or die, precluding proper development of the limbs, palate and other structures.

Potential therapeutic target for Huntington's disease

Thu, 07 Apr 2005 18:13:38 PST

( from http://www.rxpgnews.com ) Researchers studying yeast cells have identified a metabolic enzyme as a potential therapeutic target for treating Huntington's disease, a fatal inherited neurodegenerative disorder for which there is currently no effective treatment.

The group performed a genetic experiment known as a loss-of-function suppressor screen, which searches for genes that, when switched off, reduce the toxic effects of the mutant protein associated with Huntington's. One of the genes they identified encodes an enzyme, called KMO, that has been previously implicated in the disease. The enzyme functions in a metabolic pathway that is activated at early stages of the disease in people with Huntington's, as well as in animal models of the disease.

"The nice thing about this finding is that there is a chemical compound available that inhibits KMO activity," said Dr. Paul Muchowski, assistant professor of pharmacology at the UW, who led the study. "We're in the midst of testing that compound in a mouse model of Huntington's disease."

Further support for KMO as a therapeutic target for Huntington's disease comes from a recent study led by Dr. Aleksey G. Kazantsev of Harvard Medical School. In this study, researchers used cell-based experiments to screen about 20,000 chemical compounds, and identified one that suppresses neurodegeneration in a fly model of the disease. That compound has a very similar chemical structure as the drug that inhibits the target identified by Muchowski's group. The results appeared in the Jan. 18, 2005, issue of the Proceedings of the National Academy of Sciences.

In addition to finding a potential drug target for future Huntington's treatment, the study by Muchowski and his colleagues could take research on the disease in a new direction: towards microglial cells, which are immune cells in the brain. Previous research has focused exclusively on neuronal cells, but the enzyme KMO is found predominantly in microglial cells. Since inhibiting KMO activity has a direct effect on toxicity of the mutant protein associated with Huntington's, that could mean microgial cells are home to an important step in progression of the disease.

Huntington's affects an estimated 30,000 people in the United States. It is characterized by loss of motor control and cognitive functions, as well as by depression or other psychiatric problems.

Putting a finger on shortened digits

Sun, 03 Apr 2005 13:43:38 PST

( from http://www.rxpgnews.com ) Brachydactyly is a group of inherited disorders of the hands that are characterized by shortened fingers and abnormal joint formation.

In a paper appearing in the April 1 issue of The Journal of Clinical Investigation, Stefan Mundlos and colleagues from the Max Planck Institute for Molecular Genetics describe the analysis of a mouse model with limb mutations called short digits (Dsh).

The mice have disrupted Shh expression a factor that helps skeletal formation. The result is that the mice have symptoms similar to human brachydactyly type A1. This is because the misexpression of Shh disrupts other factors with normally regulate joint development as well as the growth and patterning of the digits

Luis de la Fuente and Jill Helms write, in an accompanying commentary, that this study shows "that removal or expansion of one of the factors that contributes to the establishment of a boundary can cause a multitude of processes, including those that shape and control development of the skeleton, then go awry." The developmental pathology associated with Shh misexpression extends our understanding of the developmental pathology of digit development and thus of human brachydactyly.