Category Archives: Genetic Medicine

The images show no hint of his life today: the seizures that leave him temporarily paralyzed, the weakness that makes him fall over, his labored speech, his scrambled thoughts.

Andrew, 28, can no longer feed himself or walk on his own. The past nine years have been a blur of doctor appointments, hospital visits and medical tests that have failed to produce answers.

"You name it, he doesn't have it," his mother said.

Andrew has never had a clear diagnosis. He and his family are in a torturous state of suspense, hanging their hopes on every new exam and evaluation.

Recently, they have sought help from the Undiagnosed Diseases Network, a federally funded coalition of universities, clinicians, hospitals and researchers dedicated to solving the toughest medical mysteries in the US. The doctors and scientists in the network harness advances in genetic science to identify rare, sometimes unknown, illnesses.

At UCLA, one of the network's sites, Andrew's medical team would later map his genetic makeup, then bring him in for a week of exams and consultations with specialists.

The Undiagnosed Diseases Network was founded in 2015 with a $43 million grant from the National Institutes of Health (NIH). Building on work already being done at NIH, the initiative expanded to include universities across the country: Duke, Columbia and Stanford are among the other sites. The goals are to provide answers for patients with mysterious diseases and to learn more about the disorders.

A proposal last month by President Donald Trump to cut the NIH budget by $5.8 billion could put the program in jeopardy.

Even with the best technology and the finest brains at work, progress is slow. Since its launch, the network has received nearly 1,400 applications on behalf of patients. It has accepted 545 for review so far. Just 74 of the cases have been diagnosed, including 11 at UCLA. Andrew Whittaker's case is among many in progress.

It's like battling "an unknown enemy," said Euan Ashley, one of the principal investigators of the network's Stanford University site. "That is a particular form of torment that other patients don't have."

A diagnosis can end families' painful odyssey while helping physicians and scientists better understand rare diseases and human physiology, said Rachel Ramoni, former executive director of the network, which is based at Harvard University.

Researchers throughout the network use advanced medical technology. For example, to study patients' gene expression and disease progression, they can make models using nearly transparent zebrafish, whose genetic structure is similar to that of humans. And scientists can conduct whole genome sequencing, which allows the medical team to read a patient's DNA and identify changes that can reveal what may be causing a disease.

"We have powerful techniques to look at every gene that is being expressed as well as every gene that is inherited," said Stanley Nelson, one of UCLA's principal investigators and the lead doctor on Andrew's case. "This is an example of true precision medicine."

Nelson said the network can examine all known genes not just the ones believed to have mutations that cause diseases. Doing that can lead to the discovery of new illnesses.

"Part of what we have to do is keep building that library, that encyclopedia of what gene and what gene mutations cause what symptoms," Nelson said. "It's just incomplete at this moment."

Already the work is helping patients and their families come to terms with their illnesses. In one case, at Stanford, a toddler was diagnosed with two rare diseases, including a connective tissue disorder called Marfan Syndrome, after doctors conducted a form of sequencing that looks for changes in coded genetic segments known as exons.

Sometimes answers come from something decidedly lower-tech: collaboration among clinicians and researchers who share experiences, data and expertise.

"A lot of times your ability to be diagnosed depends on who is in the room," Ramoni said. "And what we are doing with the network is we are expanding exponentially the number of people in the room."

Doctors at one institution might think their patient is a unique case, only to learn that colleagues elsewhere have a patient with a similar illness. But even when diseases are diagnosed or gene mutations are discovered, treatments may still not be available.

Andrew Whittaker's odyssey began one afternoon at age 19, when he started trembling and couldn't speak. Doctors suspected he was suffering from anxiety and prescribed medication to control it. But Andrew said he continued to have "episodes," during which everything just went blank.

"It's like there's not enough blood going to your brain," he said. "You can't think."

Andrew also started losing his balance and falling off his bicycle. The family visited several hospitals. Doctors discovered that the receptors in his brain were malfunctioning and that he lacked sufficient dopamine, a chemical compound in the body responsible for transmitting signals between nerve cells. As a result, Andrew has some symptoms similar to those of Parkinson's disease. Doctors also confirmed he was having seizures.

Still, Andrew's symptoms didn't add up to any known disease.

One afternoon last fall at precisely noon, as Andrew sat propped up on the living room couch, Lynn's phone alarm sounded, signaling it was time for his medication. Lynn pried open Andrew's hand, which was clenched into a fist, and dropped in the pills.

To keep Andrew from falling, the family has lowered his bed and removed carpet from the house. They also bought him a wheelchair. Their precautions don't always work. One morning, Lynn was in the kitchen when she heard a crash. "I ran in there and he's laid flat on his back," she said.

Andrew is close to his mom. But he also gets frustrated. He can't shower or dress without her help. He's had to give up the things he loved to do: printing T-shirts. Skateboarding. Shooting short films. He's lost friends and can't imagine dating anymore.

"Girlfriends? Forget about it," he said, his face twitching as he talks. "They want a guy who can do stuff for them, not the other way around."

On a Monday morning in late January, Andrew and his parents were in an exam room at UCLA. Lynn teased her son, saying she was going to put him in a freezer until doctors figured out what was wrong.

"Then we'll pull you back out again," she said, smiling.

"I'll never get pulled out," Andrew responded.

"Yes, you will," she said. "You will."

Nelson, Andrew's main doctor, walked into the room. He told Andrew he'd read through the medical records. "We're going to try to figure you out."

The work Nelson does is personal. His teenage son, Dylan, has Duchenne muscular dystrophy, a genetic disorder that causes muscle degeneration and weakness. Nelson knows his son's disease will eventually take his life, but he said having a diagnosis makes all the difference.

"My heart very much goes out to the families that don't even get an adequate diagnosis," he said.

Nelson suspects that Andrew's disease is genetic as well.

He asked the Whittakers to describe their son's journey, then he conducted a short physical exam, asking Andrew to push against his hand and touch his own nose. Andrew trembled and his shoulders tensed, but he did it.

The rest of the week, Andrew underwent several other diagnostic tests, including a muscle biopsy, an EEG, MRI and a lumbar puncture. He remained upbeat, though running the medical gauntlet clearly wore him out. He also met with UCLA specialists in brain degeneration and muscle and nerve disorders.

At week's end, Nelson sat down with the family to explain what he'd found. He had reviewed Andrew's genome and compared it with that of both parents. Andrew had one copy of a defective gene that leads to Parkinson's but the genome sequencing didn't show a second copy, without which it could not be Parkinson's.

He explained that Andrew's illness was clearly progressive and that his brain was shrinking, making it harder for him to process language and information. Nelson said he still didn't have a diagnosis he believed it was a brand-new disease.

Nelson planned to continue poring over the test results, conducting additional exams and communicating with others in the network. He also is analyzing Andrew's muscle tissue, skin and blood to see whether any mutated gene is expressed abnormally.

Even in the absence of a clear diagnosis, Nelson said, rare diseases like Andrew's help educate scientists and may help other patients. "These are the people we as a society will owe a great debt of gratitude," he said. "They are effectively donating their lives to this process."

Lynn Whittaker was disappointed. "We are still left with just hope that they will come up with something," she lamented. "What else do we have?"

Andrew said his relatives have asked if he's scared the doctors will find something. "I'm more scared if they don't," he replied.

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Doctors battle 'torment' of rare undiagnosed illnesses - CNN

WRIC

In-depth: Hope for 16-year-old California boy fighting rare genetic disease WRIC It is about parents who are keeping up the fight to find a cure to a rare genetic disease that has gripped their son for 16 years. The McHale family in California has dramatic new hope Friday night because of a breakthrough in modern medicine. At 6 ...

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In-depth: Hope for 16-year-old California boy fighting rare genetic disease - WRIC

ScienceBlog.com (blog)

Understanding genetic variations in black women could improve ... ScienceBlog.com (blog) Although the odds of developing breast cancer are nearly identical for black and white women, black women are 42 percent more likely to die from the disease. Understanding genetic variations in black women could improve cancer outcomesUChicago News The surprising reason black women die more frequently from breast cancerCrain's Chicago Business all 37 news articles »

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Understanding genetic variations in black women could improve ... - ScienceBlog.com (blog)

An international team of scientists has identified a long-sought protein that causes liver fibrosis (scarring), paving the way for new treatments. The research was published in the journal Nature Genetics.

Stages of liver disease. Image credit: National Institute of Diabetes and Digestive and Kidney Diseases.

The team, led by Professor Jacob George and Dr. Mohammed Eslam of the Westmead Institute for Medical Research in Sydney, Australia, has unequivocally shown that variations in the interferon lambda 3 (INLF3) protein are responsible for tissue damage in the liver.

The researchers had previously identified that the common genetic variations associated with liver fibrosis were located on chromosome 19 between the IFNL3 and IFNL4 genes.

In the new study, they analyzed liver samples from 2,000 patients with hepatitis C, using state-of-the art genetic and functional analysis, to determine the specific IFNL protein responsible for liver fibrosis.

They demonstrated that following injury there is increased migration of inflammatory cells from blood to the liver, increasing IFNL3 secretion and liver damage.

Notably, this response is determined to a great extent by an individuals inherited genetic makeup.

This was a significant outcome that will help to predict risk of liver disease for individuals, enabling early intervention and lifestyle changes, said Prof. George, who is the corresponding author of the study.

We have designed a diagnostic tool based on our discoveries, which is freely available for all doctors to use, to aid in predicting liver fibrosis risk.

This test will help to determine whether an individual is at high risk of developing liver fibrosis, or whether a patients liver disease will progress rapidly or slowly, based on their genetic makeup.

This important discovery will play a vital role in reducing the burden of liver disease into the future, he said.

This discovery holds great promise for the development of effective therapeutic treatments for liver disease, added co-lead author Dr. Eslam.

There is an urgent need for a safe pharmacologic therapy that can prevent of regress the progression of liver damage. There are currently no treatments available for patients with advanced fibrosis, and liver transplantation is the only treatment for liver failure, he said.

Now that weve identified IFNL3 as the cause of liver scarring, we can work towards developing novel treatments specifically targeting this gene.

This could be medicine targeting IFNL3 that is tailored to an individuals genetic makeup, but could also include modifying usual treatment depending on whether a patient has IFNL3 risk genes.

These outcomes fulfill several promises in the modern era of precision medicine, Dr. Eslam said.

Firstly, it brings us closer to the goal of personalized medicine. Secondly, we have a better understand of biology and the way the human body works. Finally, we are a step closer to developing novel potential treatments for liver disease.

The team will now extend their work to further understand the fundamental mechanisms of how IFNL3 contributes to liver disease progression and to translate these discoveries into new therapeutic treatments.

_____

Mohammed Eslam et al. 2017. IFN-3, not IFN-4, likely mediates IFNL3IFNL4 haplotypedependent hepatic inflammation and fibrosis. Nature Genetics 49: 795-800; doi: 10.1038/ng.3836

This article is based on text provided by the Westmead Institute for Medical Research.

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Researchers Identify Liver Fibrosis-Causing Protein - Sci-News.com

The federal government is already investing millions of dollars into precision medicine research, but the ability for consumers to access their genetic information without having to see a physician could be a launchpad for personalized medicine.

Allowing patients to understand their genetic makeup through 10 FDA-approved screening tests offered through 23andMe will be a turning point in the democratization of personalized medicine, two analysts with the Manhattan Institute wrote in the Wall Street Journal.

In fact, the right to know the risks contained in your genetic code will likely become the most fundamental medical right of the 21st century, Senior Fellows Peter Huber and Paul Howard wrote in an op-ed.

RELATED: SurveyPrecision medicine data will make the biggest splash in the next five years

Their argument revolves around the idea that direct-to-consumer genetic tests arm patients with more information about their health, which is likely to drive engagement. Companies like 23andMe are also providing more access to researchers studying genetic risk factor for diseases like Parkinsons and Alzheimers by allowing users to opt into research projects. Although it could further disease-specific research, data sharing within genetic tests have also been a concern for some who worry how companies could sell that information.

Genetic testing has garnered tremendous hypefor itsability to advance personalized treatment optionsbut some researchers have urged caution when it comes to interpreting those tests.

RELATED: Precision medicine will falter without a parallel focus on delivery, researchers say

Meanwhile, researchers at Brigham and Womens Hospital and the University of Pennsylvania argued that a concurrent focus on precision delivery is necessary to ensure genomic research reaches its full potential within the healthcare industry.

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Direct-to-consumer genetic tests are a 'turning point' for precision medicine, analysts say - FierceHealthcare

Although the odds of developing breast cancer are nearly identical for black and white women, black women are 42 percent more likely to die from the disease. This mortality gapdriven by social and environmental, as well as biological factorscontinues to persist.

A large, multi-institutional study, published May 4 in JAMA Oncology, was designed to understand this gap by beginning to unravel the germline genetic variations and tumor biological differences between black and white women with breast cancer. This is the first ancestry-based comprehensive analysis of multiple platforms of genomic and proteomic data of its kind, the authors note.

Findings from this study could lead to more personalized risk assessment for women of African heritage and hasten the development of novel approaches designed to diagnose specific subtypes of aggressive breast cancers early and treat them effectively.

One new finding is that black women with hormone receptor positive, HER2-negative breast cancer had a higher risk-of-recurrence score than white women. The study also confirmed that black patients were typically diagnosed at a younger age and were more likely to develop aggressive breast-cancer subtypes, including basal-like or triple-negative cancerstumors lacking estrogen receptors, progesterone receptors and HER2as well as other aggressive tumor subtypes.

People have long associated breast cancer mortality in black women with poverty, or stress, or lack of access to care, but our results show that much of the increased risk for black women can be attributed to tumor biological differences, which are probably genetically determined, said study author Olufunmilayo Olopade,the Walter L. Palmer Distinguished Service Professor in Medicine and Human Genetics at the University of Chicago.

The good news, she said, is that as we learn more about these genetic variations, we can combine that information with clinical data to stratify risk and better predict recurrencesespecially for highly treatable cancersand develop interventions to improve treatment outcomes.

This is a great example of how team science and investments in science can accelerate progress in identifying the best therapies for the most aggressive breast cancers, said co-author Charles Perou, a member of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine.

In the largest dataset to date that has good representation of tumors from black women, we did not find much difference between the somatic mutations driving tumors in black and white women, he added. Yet black women were more likely to develop aggressive molecular subtypes of breast cancer. Now we provide data showing that differences in germline genetics may be responsible for up to 40 percent of the likelihood of developing one tumor subtype versus another.

The study used DNA data collected from 930 women154 of predominantly African ancestry and 776 of European ancestryavailable through The Cancer Genome Atlas, established by the National Cancer Institute and the National Human Genome Research Institute. The researchers combed through the data methodically, looking for racial differences in germline variations, somatic mutations, subtypes of breast cancers, survival time, as well as gene expression, protein expression and DNA methylation patterns.

Most significantly, explained first author Dezheng Huo, associate professor of public health sciences at the University of Chicago, we observed a higher genetic contribution to estrogen-receptor negative breast cancer in blacks.

Black women were more likely to get these highly aggressive cancers. This is one of the first studies to connect genetics to this racial difference in tumor subtype frequencies.

The study also revealed 142 genes that showed differences in expression levels according to race. One gene, CRYBB2, was consistently higher in tumors from black patients within each breast cancer subtype, as well as in normal tissues, suggesting it may be a race-specific gene.

The researchers also found somatic mutations in 13 genes or DNA segments that differed in frequency in tumors from black and white women. One of them, a mutated gene called TP53, was more common in black women than white women and was a strong predictor of disease recurrence.

Despite the relatively short follow-up time in the TCGA dataset, we were able to detect a significant racial disparity in patient survival using breast cancer-free interval as the endpoint between patients of African and European ancestries, said co-first author Hai Hu, vice president for research at the Chan Soon-Shiong Institute of Molecular Medicine at Windber. Most of the worst outcomes came from basal-like subtype breast cancer patients of African Ancestry.

Black women in all categories, including the most common breast cancers, were likely to have a worse prognosis, Olopade said.

Understanding the basic, underlying genetic differences between black and white women, the higher risk scores and the increased risk of recurrence should lead us to alternative treatment strategies, said Perou.

The crucial long-term benefit of this study, according to Olopade, is that it is a step toward the development of polygenic biomarkers, tools that can help us better understand each patients prognosis and, as we learn more, play a role in choosing the best treatment.

Genes matter, she added. This is a foot in the door for precision medicine, for scientifically targeted treatment.

This study now outlines a path for us to personalize breast cancer risk assessment and develop better strategies to empower all women, especially black women, to know their genetics and be more proactive in managing their risk, Perou said.

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Understanding genetic variations in black women could improve cancer outcomes - UChicago News