ARTICLE IN BRIEF
A federal initiative has invigorated research in precision medicine, including neurology programs in institutions nationwide.
While directing the Center for Humane Genome Variation at Duke University in 2013, David Goldstein, PhD, was called in on a puzzling case. A 15-month-old girl had come to Duke University Medical Center with a neurologic disease that absolutely stumped her clinical team. She had extreme upper body weakness, excessive drooling, difficulty holding her head upright and lifting her arms, and a variety of eye abnormalities and other conditions.
“Her condition was quite clearly highly progressive, and the clinical team had decided to treat first on the suspicion of an autoimmune condition since they needed to act quickly,” said Dr. Goldstein, now the director of the Institute for Genomic Medicine at Columbia University Medical Center. “But they also asked us to use an approach that we had recently used in a re-search study, more successfully than we had been expecting, using whole exome sequencing in the setting of undiagnosed diseases. We didn't expect to find anything that would result in a transformation of care, but we did think it was worth trying.”
When the sequencing was complete, Dr. Goldstein and his team were astonished. “We looked at the data and it was clear as day what she had — there was no ambiguity about it.” The little girl had Brown-Vialetto-Van Laere syndrome, a rare disorder of riboflavin transportation as-sociated with the SLC52A2 and SLC52A3 genes.
Even more surprising, the diagnosis indicated exactly what should be done therapeutically. “We almost immediately initiated her on supplementation with riboflavin, and she began improving quite dramatically. She began to regain use of her arms and regain head control. When we met her a few months ago, she ran around the room high-fiving every member of the genetics team. That really makes you wonder, how many other patients like that are there out there?”
The case, described in two papers published last year in the online journal, Cold Spring Harbor Molecular Case Studies, is a rare best-case scenario given the current state of the science, Dr. Goldstein emphasized. “We know thousands of Mendelian diseases already and the number that are treatable in this kind of way is tiny. Most of the time when we get such a diagnosis, it won't result in a transformational treatment. That said, this is not the only such condition that's treatable today, and this example really illustrates the importance of precision medicine.”
A WHITE HOUSE INITIATIVE
In fact, precision medicine has gotten the attention of the White House. In his 2015 State of the Union Address, President Obama announced the launch of a national Precision Medicine Initiative, with a $215 million investment in the federal budget for 2016. The initiative supports re-search aimed at tailored diagnostic and treatment approaches, such as exome sequencing, microbiome composition, and metabolomics, including the creation of a national research cohort of a million or more volunteers.
And in February, to commemorate the first year of the initiative, the White House hosted an all-day meeting, including panel discussions with researchers and patient advocacy groups involved in precision medicine efforts.
To date, the initiative's main impact has been in raising the profile of precision medicine. “I think eventually there will be more material effects of the initiative, in particular in greatly increasing the amounts of genomic information that's available and figuring out how we co-analyze large scale genomic and clinical data, which remains a real challenge for the field,” Dr. Goldstein said. “But right now, what it's done is gotten everyone's attention — researchers and clinicians, and critically the drug companies. It's focused them on the idea that there really is a fundamentally new way to optimize patient care and identify new leads for developing treat-ments, using genomic approaches to identify genomic contributions to disease and then using that information to develop and optimize new treatments.”
A major plank of the initiative invests $70 million in the investigation of genomic drivers in cancer, but Dr. Goldstein and other leading precision medicine experts say that neurology has the potential for some of the most immediate benefit from this new emphasis.
“There is no question that neurology is one of the areas that will see the most important and most rapid progress from precision approaches. Many neurologic conditions are very strongly genetic, and we are making real progress in characterizing the genetic basis of a lot of neurologic conditions. Also, in a number of cases — although certainly not all — we have at least a direction we know how to follow in order to characterize the functional consequences of the disease-causing mutations. That's exactly the foothold we're looking for,” he said.
TARGETED PROGRAMS NATIONWIDE
Institutions nationwide are developing targeted programs. The Institute for Precision Medicine at the University of California, Los Angeles (UCLA) Health System and David Geffen School of Medicine, for example, is charged with creating and running an integrated precision medicine diagnostic service, including genomics and other specialized testing services, associated bioin-formatics and biobanking.
“One huge thing we need to do is understand how genetics is acting to increase risk for disorders, and to change history of those disorders in a patient-specific way. To know that, we need large population-based data,” Daniel Geschwind, MD, PhD, UCLA's senior associate dean and associate vice chancellor of precision medicine, told Neurology Today.
Since 2013, the Clinical Genomics Center at UCLA, directed by Stanley Nelson, MD, vice chair of human genetics, and colleagues has been performing whole exome sequencing (the protein coding portion of the genome) as a clinical service, now for more than 1,000 cases throughout California. More than 100 neurologic patients have had this service, in which the diagnostic rate, even for those without a family history, is nearly 25 percent.
For example, in a study published in JAMA Neurology in August 2014, UCLA researchers used exome sequencing to obtain a definitive diagnosis in 21 percent of 76 consecutive patients presenting with chronic progressive cerebellar ataxia that was primary sporadic and adult-onset. In another 40 percent, they found useful genetic information that would direct further testing and could potentially lead to a clear diagnosis. These findings were particularly noteworthy given the heterogeneity of neurologic conditions associated with cerebellar ataxia.
“To our knowledge, there are few clinical tests with yields this high, especially in such a diverse patient population where the underlying causes are rare, most of the diagnostic test results are negative, and the clinical workups can go on for years,” wrote the authors, led by Brent Fogel, MD, PhD, an assistant professor of neurology and Dr. Nelson. “Several very rare and unexpected diagnoses were made based on CES [clinical exome sequencing] in this initial cohort of only 76 patients, emphasizing clearly the power of this approach relative to any other.” (The paper was cited in “Best Neurology Advances of 2014” by Neurology Today's editorial advisory board.)
And when Dr. Nelson and his team sequenced the exomes of 814 children with unknown disorders, whose symptoms had baffled experts and eluded all previous diagnostic tests, they were able to obtain a definitive molecular diagnosis in 26 percent of the cases.
The yield was even higher in a study published in Science Translational Medicine in December 2014, in which investigators at Children's Mercy Hospital Kansas City used exome or genome sequencing to assess more than 100 families with children affected by a range of neurological and developmental disorders.
Forty-five percent of families received a diagnosis by exome or genome sequencing, and fifty percent of those diagnosed had a change in clinical impression or management. In older children, genome-based diagnosis could have cut the wait for a diagnosis by more than six years. The families in the study had spent, on average, nearly $20,000 on previous tests that did not yield a diagnosis.
UCLA is now hoping to develop a plan to perform exome sequencing on thousands of neurology patients every year for research purposes. “As the costs go down, I expect that within five years every patient who comes through UCLA Neurology will have their genome se-quenced,” Dr. Geschwind said.
While genomics is a key component of precision medicine, it isn't the whole story. Other applications of precision medicine in neurology might be as simple as using rapidly-advancing tech-nology involving monitoring devices and remote measurements.
“Right now, people with Parkinson's disease bring in a diary charting their symptoms,” said Dr. Geschwind. “But imagine devices that can measure tremor, movement, velocity, precisely from moment to moment. We would really be able to see how the patient is doing on therapy and change the dosing and schedule of their medication with much more precision, even just for symptomatic therapy.”
The Penn Center for Precision Medicine at the University of Pennsylvania has selected several projects as highly promising for using precision medicine to rapidly advance patient care. One of those is the Center for Autoimmune Neurology Precision Medicine Project, an ef-fort to isolate the synaptic protein antibodies identified with autoimmune synaptic encephalitis in order to better diagnose and treat the disease.
The Center, led by Josep Dalmau, MD, PhD, an adjunct professor of neurology at University of Pensylvania and a senior investigator at the Institut d'Investigacions Biomèdiques August Pi i Sunyer (referred to as IDIBAPS) at the University of Barcelona, had discovered a subset of patients with encephalitis who produced auto-antibodies that target the brain and neurons. The first to be identified — the most common — was anti-NMDA receptor encephalitis, which produces hallucinations, delusions, seizures, unstable blood pressure and heart rate, and progressive catatonia. But this just turned out to be the beginning of the story. Since that initial discovery in 2007, an entire family of diseases has been discovered that are defined by auto-antibodies to synaptic proteins, including LGI1, Caspr2, Gly1, GABA-A, and others.
Penn's clinical laboratory, like many hospitals, was only offering testing for one such an-tibody, the anti-NMDA receptor. “What's being done in the research laboratory had really been ahead of what we could do in clinical pathology,” said Eric Lancaster, MD, PhD, an assistant professor of neurology and an investigator in the Precision Medicine Project.
The Precision Medicine Project developed a high-end “boutique shop” for assessing difficult auto-antibody encephalitis cases, facilitated by a series of interlocking consent protocols and institutional review boards. Today, when a patient at Penn is suspected of having autoimmune encephalitis, a panel of six antibodies is reviewed within two days. Additional studies can then be done on a research basis.
“The patients who do best are the ones who are treated with appropriate, aggressive immunotherapy as soon as possible,” Dr. Lancaster said. “Every day that you accelerate the diagnosis and get them on the correct treatment is an equivalent day down the road, getting them out of the intensive care unit and out of the hospital.”
One of the clearest illustrations of the benefits of precision medicine in neurology is in epilepsy, said Dr. Goldstein. “We have many genes discovered, almost monthly, that cause serious early-onset epilepsies that result in a variety of very poorly controlled symptoms. We know that the epileptic encephalopathies in particular are incredibly genetic and in a relatively tractable way. I think it's now clear that all of these conditions really do need to be genetically investigated, as we frequently do find a very clear cause of disease in patient exomes. In the coming few years, we will see some very clear wins from this approach,” he predicts.
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•. Soden SE, Saunders CJ, Willig LK, et al. Effectiveness of exome and genome sequenc-ing guided by acuity of illness for diagnosis of neurodevelopmental disorders http://www.ncbi.nlm.nih.gov/pubmed/25473036
. Science Transl Med
2014; 6 (265): 265ra168.
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