Monthly Archives: March 2022

Early data from landmark studyshows rapid whole genome sequencing (rWGS) provided diagnostic insights for more than half of newborns who received testing; one-third had no previously documented clinical suspicion of a genetic condition

GAITHERSBURG, Md., March 24, 2022 /PRNewswire/ -- GeneDx, LLC, a leader in genomic analysis, today announced new research in collaboration with the University of Washington, Seattle Children's and the Brotman-Baty Institute during the American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting which demonstrates the utility of rapid whole genome sequencing (rWGS) to diagnose critically ill infants in the neonatal intensive care unit.

The data is part of SeqFirst, a study at the University of Washington examining the impact on care of broad access to routine whole genome sequencing in critically ill infants at Seattle Children's Hospital. Results showed that rapid whole genome sequencing provided a potential, partial or full diagnosis for 53% of newborns tested. Moreover, of those infants who received a diagnosis through whole genome sequencing, 30% had no previously-documented suspicion of a genetic condition, highlighting the limitations of strategies that rely on family history or clinical indicators to qualify for genetic testing. The impact of the genetic information was profound, leading to a change of management for 93% of these patients.

In addition to improving diagnosis, the SeqFirst data also suggested that making whole genome sequencing routine for critically ill patients in the NICU could help overcomes disparities in access to testing. Notably, 67% of patients in whom a genetic condition was not considered prior to testing identified as non-White.

"Our study shows how impactful routine use of whole genome sequencing can be in the neonatal ICU," said Mike Bamshad, M.D., SeqFirst principal investigator and professor and chief of genetic medicine in the department of pediatrics at the University of Washington and Seattle Children's Hospital. "Whole genome sequencing is the most advanced type of genetic testing and our study offers clear insight on the benefit of using it early in the diagnostic process to help families of children with health conditions find a precise genetic diagnosis, better anticipate their child's needs and take advantage of new treatments."

The SeqFirst study was established at the University of Washington with the goal of making whole genome sequencing more accessible. SeqFirst is one of several projects focused on access to testing in the NICU and for use in diagnosing developmental delays in outpatient settings.

"The data is clear rapid whole genome sequencing can provide critical diagnostic insights and much-needed answers for infants in the NICU," said Paul Kruszka, M.D., chief medical officer at GeneDx. "Whole genome sequencing is vastly underutilized in the NICU, despite the clear support for its utility in getting to a diagnosis quickly. Genetic disorders are a leading cause of morbidity and mortality in infants and very often every minute counts. Our hope is that by understanding the benefits of sequencing, we may be able to intervene earlier and pursue clinical approaches that improve outcomes."

GeneDx performs exome sequencing for infants enrolled in the SeqFirst study. GeneDx has played a pivotal role in pediatric disease diagnosis for hundreds of thousands of patients. With a database of more than 300,000 clinical exomes and corresponding clinical information, GeneDx is a key driver in understanding gene-disease relationships.

About GeneDx

GeneDx, LLC, is a global leader in genomics, providing testing to patients and their families worldwide. Originally founded by scientists from the National Institutes of Health, GeneDx offers a world-renowned clinical genomics program with particular expertise in rare and ultra-rare genetic disorders. In addition to its market-leading exome sequencing service, GeneDx offers a suite of additional genetic testing services, including diagnostic testing for hereditary cancers, cardiac, mitochondrial, neurological disorders, prenatal diagnostics, and targeted variant testing. To learn more, please visit http://www.genedx.com.

CONTACT:Julie McKeough,JMcKeough@genedx.com

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New Research Illustrates the Benefits of Rapid Whole Genome Sequencing for Critically Ill Infants - Longview News-Journal

NEW YORK GeneMatcher has become instrumental in the discovery of new genes underlying hereditary diseases. Since its inception in 2015, the "matchmaking" service, which connects researchers, clinicians, and patients interested in the same genes, has been used to help identify at least 416 novel disease-related genes and has been cited in 562 publications.

As the service continues to grow, its developers at the Baylor-Hopkins Center for Mendelian Genomicsplan to make it easier for researchers to find information related to animal models and to add tools for patients as more of them start using the service to research their own conditions.

The growth in users is reflected in a huge uptick in publications referencing GeneMatcher, which increased from 20 publications in 2015 to 143 in 2021, with 58 already having been published this year.

"It's like 'Field of Dreams'," said Ada Hamosh, one of GeneMatcher's original developers and a professor of genetic medicine at Johns Hopkins University. "If you build it, they will come."

That said, both Hamosh and Nara Sobreira, the first author of the original GeneMatcher publication and an assistant professor of genetic medicine at Johns Hopkins, are quick to point out that initially building the service was no walk in the park.

"It took us years talking about GeneMatcher and convincing people to use it," Sobreira said. "Now it's all good and beautiful but at the beginning, we got a lot of pushback, with a lot of people thinking that it was not going to work."

GeneMatcher is part of the Matchmaker Exchange project, which also allows GeneMatcher submitters to query other connected databases through the Exchange's API. These include PhenomeCentral, Decipher, IRUD, MyGene2, and the newer ModelMatcher, which is geared toward researchers using animal models.

GeneMatcher allows individuals to submit genes of interest and automatically matches them with others submitting the same genes. Submitters may include other information along with the gene or genes, such as variants by base pair position, diagnoses from the OMIM database, and clinical/phenotypic features.

Submitters are currently limited to posting 10 candidate genes per submission, as a way to avoid unnecessary data dumping.

Most recently, GeneDx cited the service in a publication in Human Genetics, accrediting it with having helped the company and its collaborators discover over 200 new and expanded genetic conditions.

In its report, the company estimated that it accounts for some 20 percent of GeneMatcher submissions, an impressive quantity given the 11,883 total submitters from 98 countries that were recorded on the platform as of March 22.

GeneDx's GeneMatcher-mediated collaborations that have led to discoveries include a yet-unnamed neurological disorder caused by an autosomal dominant FAR1 variant, resulting in spastic paraparesis and bilateral cataracts.

Similarly, HudsonAlpha has cited GeneMatcher in having facilitated the research needed to identify a previously unknown rare variant of the EBF3 gene that causes intellectual disability, ataxia, and facial dysmorphism.

"This gene encodes an early B-cell factor, is a known developmental transcription factor, suspected to function in neuronal differentiation and maturation, and was a target ofARX, a known NDD gene," Michelle Thompson, a variant analyst with HudsonAlpha, said via email.

After submitting to GeneMatcher, the HudsonAlpha researchers were able to find a second patient within their own cohort and to connect with several other labs investigating EBF3 around the world.

Graduate students at HudsonAlpha performed functional analysis on the variants and helped establishEBF3as a new neurodevelopmental disease gene.

"We were able to provide two diagnoses within our own study, and eight other patients were provided an answer, many of which had been on a diagnostic odyssey,"Thompson added.

Thompson said that GeneMatcher has led to 23 publications from HudsonAlpha, with additional manuscripts in preparation.

More recently, a team of researchers from across the globe published the discovery of RECON (RECql ONe) syndrome, a rare disorder caused by mutations in the RECQL1 helicase gene, after researchers and clinicians studying that gene connected with each other through GeneMatcher and were able to share their findings.

In addition to genetics professionals, patients also increasingly turn to GeneMatcher as a means of seeking information on their own conditions.

"I get a lot of emails from patients asking me how to use it, what's the best way to use it, if GeneMatcher is the best tool to use," Sobreira said. While she thinks that the best tool for patients right now is probably MyGene2, "I completely support them using GeneMatcher," and the site includes a way for patients to identify themselves as such and say whether they're looking to connect with clinicians or researchers.

As of March 1, approximately 688 patients had submitted requests for information from GeneMatcher, according to Hamosh.

Thanks to patients and researchers, use of GeneMatcher has grown steadily since its launch, and Sobreira now employs one lab technician whose job is to field emails concerning the platform, mainly from submitters, while she finds herself sometimes responding to emails from patients.

GeneDx also noted a rise in queries and matches made through GeneMatcher, particularly over the course of the pandemic.

"With stayathome orders," the company wrote in its recent article, "perhaps many clinicians and researchers suddenly had time they had lacked previously and decided to work on research projects."

As a result, the firm's response time to requests through GeneMatcher has increased, and it has found itself unable to respond to them in real time.

"We have a triage process to prioritize inquiries and work to respond to the most urgentwithin a week or so, while other inquiries can take longer," Julie McKeough, GeneDx's chief communications officer, explained via email.

Sobreira and Hamosh mentioned that as GeneMatcher's user base keeps growing, they plan to make improvements and add features to ensure that it remains useful for all stakeholders.

ModelMatcher, the most recent addition to the Matchmaker Exchange, has brought more queries from animal model researchers into GeneMatcher, as these scientists seek to link genes found in animals to their human counterparts.

Because of this, Sobreira and her team recently added model organism statistics to the platform and are planning to add a feature allowing users to identify themselves as model organism researchers, along with an option to connect with other animal model researchers.

She also plans to add a link for Publication and Researchers - Rare Disease Gene Mechanisms (PaR-RaDiGM), a feature aimed at connecting rare disease researchers to relevant publications, to the match email notification system.

More changes may yet come from further user feedback.

"It would be useful to be able to search for genes that have already been submitted to GeneMatcher," Thompson commented. "Currently, you submit a gene of interest and get a 'match report,'ranging from 'no matches'to a list of other researchers/clinicians with the same gene of interest. However, one potential downside would be that it may discourage submitters to continue submitting that gene through the portal, as it may later develop as a gene of interest."

As with any public database, the more people use it, the more useful it becomes, increasing the chances of finding clinically relevant rare variants in particular candidate genes.

It has already proven a valuable resource to GeneDx in the company's numerous collaborations.

"We hope that [our] article inspires others to participate in GeneMatcher so that, together, we can advance our understanding of human genetic disease and ultimately help more patients," McKeough said.

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GeneMatcher Team Plans Improvements for Researchers, Patients to Build on Recent Successes - GenomeWeb

LEXINGTON, Mass., March 23, 2022 /PRNewswire/ -- LogicBioTherapeutics, Inc.(Nasdaq: LOGC), a clinical-stage genetic medicine company, today announced that president and chief executive officer, Frederic Chereau, will present a company overview at the H.C. Wainwright Gene Therapy and Gene Editing Conference. The presentation will be available on demand beginning at 7:00 a.m. ET on March 30, 2022.

A webcast of the presentation will be made available on the Investors section of the Company's website at https://investor.logicbio.com. The webcast replay will be available for approximately 30 days.

AboutLogicBio Therapeutics

LogicBio Therapeutics is a clinical-stage genetic medicine company pioneering genome editing and gene delivery platforms to address rare and serious diseases from infancy through adulthood. The company's genome editing platform, GeneRide, is a new approach to precise gene insertion harnessing a cell's natural DNA repair process potentially leading to durable therapeutic protein expression levels. The company's gene delivery platform, sAAVy, is an adeno-associated virus (AAV) capsid engineering platform designed to optimize gene delivery for treatments in a broad range of indications and tissues. The company is based in Lexington, MA. For more information, visit http://www.logicbio.com, which does not form a part of this release.

Investor Contacts:

Stephen Jasper

Gilmartin Group

858-525-2047

stephen@gilmartinir.com

Media Contacts:

Adam Daley

Berry & Company Public Relations

W:212-253-8881

C: 614-580-2048

adaley@berrypr.com

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LogicBio Therapeutics to Present at H.C. Wainwright Gene Therapy and Gene Editing Conference - 69News WFMZ-TV

BETHESDA, Md., March 24, 2022 /PRNewswire/ -- The unprecedented, rapid advances in genetic and genomic knowledge and technologies have made it challenging for primary care and other nongenetics healthcare providers to stay current on recommendations and practices in clinical genetics. To address this education gap for nongenetics providers and to foster the effective integration of those advances into the broad clinical practice of primary care and specialty healthcare providers, the American College of Medical Genetics and Genomics (ACMG) announces the creation of a new online Continuing Medical Education (CME)* series, "Genetics101 for Healthcare Providers." The free educational series will be featured in the widely popular AMA Ed Hub, the online learning platform of the American Medical Association.

ACMG CEO Max Muenke, MD, MBA, FACMG said, "We're proud to collaborate with the AMA Ed Hub, an online platform bringing together high-quality education from the American Medical Association and other trusted sources, including ACMG. Designed to support the lifelong learning, licensure and certification needs of physicians and other health professionals, the AMA Ed Hub offers thousands of opportunities to earn CME, CEU and MOC."

This exciting new educational program addresses a key part of ACMG's Strategic Plan to develop customized education and resources for nongeneticists.

ACMG President Marc S. Williams, MD, FACMG said, "The ACMG's strategic plan states that we will take the lead in 'educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease.' This partnership with the AMA Ed Hub is a significant milestone is achieving this objective."

In each module of the "Genetics101 for Healthcare Providers" course, a board-certified medical genetics expert will provide a case-based presentation, along with supporting reading materials. Initially, there will be 10 modules, with some modules covering general topics and others specific to a particular medical specialty area. Topics included in this initial series:

1. Neurogenetics

2. Prenatal Genetics

3. Key Principles in Pharmacogenomics

4. Online Genetics Resources

5. Inherited Cancer Syndromes

6. Genetics for the Primary Care Provider (Adult)

7. Genetics for Endocrinologists

8. Genetics for Cardiologists

9. Genetics Workup for the Pediatrician

10. General Overview of Genetics (Coming soon)

This course is supported by an independent medical education grant from Illumina, Inc.

ACMG is the largest group of medical geneticists in the country and the only medical society that represents the full spectrum of medical genetics disciplines including clinical and laboratory geneticists as well as genetic counselors in a single organization. ACMG's mission is to improve health through the practice of medical genetics, as well as through education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health.

This activity has been approved for AMA PRA Category 1 Credit.

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics. The ACMG provides education, resources and a voice for more than 2,400 biochemical, clinical, cytogenetic, medical and molecular geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. The College's mission is to develop and sustain medical genetics-related initiatives in clinical and laboratory practice, education and advocacy. Four overarching strategies guide ACMG's work: 1) reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG peer-reviewed journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Contact:

Kathy Moran, MBA

kmoran@acmg.net

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SOURCE American College of Medical Genetics and Genomics

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New "Genetics101 for Healthcare Providers" Online Course Addresses Gap in Education for Nongenetics Healthcare Providers: Course will be...

Tennis legend Chris Evert known for her 18-time grand slam success in the sport has made recent headlines after revealing an early-stage ovarian cancer diagnosis and speaking out to help others by sharing her personal experience.

According to the American Cancer Society ovarian cancer is the fifth leading cause of cancer in women, accounting for more deaths than any other cancer of the female reproductive system. Impacting as many as 250,000 women each year, ovarian cancer is referred to as a silent disease because most women do not experience symptoms until its later stages. But when caught early and before the disease spreads, 90 percent of women can be cured. Late stage ovarian cancer, where the disease has spread beyond the ovaries, is more difficult to treat, and survival rates are low for patients.

Early detection of breast cancer is possible due in large part to screening methods including mammograms, self-breast exams, and annual visits with a doctor. The same holds true for colonoscopies for the prevention of colon cancer. While ovarian cancer is not as common as other womens cancers, a lack of early detection or prevention strategies is a major cause of poor outcomes for patients. For some, knowing family history and seeking out genetic testing to identify mutations in genes such as BRCA1 and BRCA2 is one way to detect risk for this cancer early. But most people with ovarian cancer do not have a family history or inherited genetic risk, so there is a pressing need for the development of earlier detection methods.

Catching cancer early often allows for more treatment options and provides patients the best chance for good outcomes. Some cancers have early signs and symptoms, but ovarian cancer does not. While patients undergo regular pelvic exams they may also get transvaginal ultrasounds and a specific blood test (which, while not accurate enough alone, measures the amount of the cancer antigen 125 protein in the blood).

However, there is no formal screening method for ovarian cancer that is equivalent to the pap smear for cervical cancer, which can detect early-stage cancer or even precancerous cells.

Those who know they have an elevated genetic risk due to family history are a step ahead, and can take action to learn about possible mutations or gene errors they may have, along with getting regular screenings. This knowledge can help inform a game plan towards earlier detection that offers an alternative to invasive and disruptive prevention surgery, or waiting for possible symptoms of late-stage disease.

Additional screening methods can help, and ongoing research here at Penn Medicine is looking to catch this cancer early by looking beyond the ovaries.

Penn Medicines Ovarian Cancer Research Center (OCRC) serves as a catalyst to promote comprehensive and interdisciplinary research on ovarian cancer. The center is focused on understanding how ovarian cancers begin, and translating those insights into potential approaches for early detection and ovarian cancer therapies. Whats more, the OCRC recently received a new $2.8 million grant from the Department of Defense (DoD) to further these efforts.

In the past, most doctors and scientists naturally assumed that ovarian cancer develops in the ovaries. However, about fifteen years ago, Penn researchers helped make an exciting discovery and found that the most common and deadly form of ovarian cancer, called high grade serous carcinoma (HGSC), actually often begins as tiny groups of abnormal cells in the fallopian tube. These precursor lesions, called serous tubal intraepithelial carcinomas (STICs), are so tiny that they can only be found by careful, microscopic examination of the fallopian tubes. Ever since this discovery, Penn has been dedicated to studying STICs and how these cells eventually spread to the ovaries where they can quickly form tumors that further spread to the rest of the body.

Learning about STICs lesions themselves is the beginning. Now, with support from the DoD grant, Penn experts are studying how STICs interact with surrounding tissues, and why they form in the first place. This includes building a shared, centralized bank of high-quality STIC specimens to perform studies of STICs and their surrounding tissues; leveraging tissue characterization technologies to examine DNA, RNA, and proteins of all cells located within and surrounding the STIC lesions; and identifying specific chemical changes (biomarkers) that occur that might be used to detect the lesions before they have a chance to progress. Collectively, this will help inform the creation of a test or tests to detect STICs using blood or Pap specimens from patients with lesions as a tool for physicians to help with early diagnosis of ovarian cancer.

For a long time experts studied the ovaries in the hopes of finding answers to assist with earlier diagnosis and detection of ovarian cancer, so knowing that these tumors start in the fallopian tubes opens up so many possibilities for prevention and detection, which can have a tremendous impact on standard of care for these patients, said Ronny Drapkin, MD, PhD, director of the OCRC, an associate professor of Pathology in Obstetrics and Gynecology, and a gynecologic cancer researcher with the Basser Center at Penn. Were even seeing this in the news today, with Chris Everts early ovarian cancer diagnosis, which was found in the fallopian tube after she was tested for a BRCA mutation.

Evert has shared that her family history of ovarian cancer is what led her to seek out genetic testing. Through the testing process, she was confirmed to have a BRCA genetic mutation, which led her to her preventive surgery where the cancer was found in her fallopian tube.

Both men and women have BRCA1 and BRCA2 genes, which play a role in controlling and preventing cancer. When there is an error, or mutation, in a BRCA1 or BRCA2 gene, an individual has increased risks for breast, ovarian, prostate, and pancreatic cancers. They can also pass the mutation on to their children who will then have increased cancer risks in adulthood.

Its important for individuals with a family history of cancer to get tested. While those who have mutations are considered high risk for developing breast cancer and ovarian cancer, not everyone who inherits these genes will get cancer. Furthermore, once they have this knowledge, patients can make plans to help lower their risk, saidSusan Domchek, MD, executive director the Basser Center for BRCA at Penn. Knowing that there is risk means you can choose different types of surveillance or prevention options to decrease your chances of developing and dying of cancer.

While these genetic mutations can increase risk, anyone with ovaries is at risk of ovarian cancer. However, some factors, such as afamily history, genetic predisposition, increasing age and use of hormone replacement therapycan put one at a higher risk. If you are concerned, learn more about your symptoms and talk to your doctor aboutovarian cancer prevention and screening.

And for those with a family history, like in Everts scenario, you can reach out to a genetic counselor who can help assess your history and criteria for testing.

No one can exactly predict whether or not a person will develop cancer. But, knowing the factors that increase risk may create an opportunity for prevention or more effective treatment.

For questions and assistance in finding a genetic counselor in your area, or general information about BRCA and risk assessment, contact the Basser Center at 215-662-2748 or visit basser.org.

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Key to Detecting Ovarian Cancer Early May Be in the Fallopian Tubes - Penn Medicine

Scientists are getting their first peek at the genes of nearly 100,000 Americans in whats considered a uniquely diverse genomic database part of a quest to reduce health disparities and end cookie-cutter care.

The National Institutes of Health released the data Thursday to help researchers start unraveling how peoples genes, environments and lifestyles interact to affect their health. And half of the studys participants are from racial and ethnic groups historically left out of medical research.

That diversity will add a kind of knowledge that just isnt out there, said Dr. Josh Denny, who heads the NIHs massive All of Us study that eventually aims to have such data from 1 million Americans.

Until now, more than 90% of people in the worlds large genome studies have been of European descent, a lack of diversity that hinders scientific progress, he said.

Researchers have been awaiting the genetic information to study some of the most perplexing health disparities.

For example, African Americans have a fourfold higher risk of kidney failure than their white counterparts, everything else being equal, said Dr. Akinlolu Ojo of the University of Kansas Medical Center.

We will for the first time be able to tease out what are the underlying genetic factors behind that difference, he said.

This is not just a snapshot in time, Ojo said, adding that he hopes to finally track how genes and other factors work together to explain why some people survive for years with damaged kidneys while others rapidly worsen.

Todays healthcare is pretty much one size fits all. Most treatments are based on what has worked best for the average person in short studies of a few hundred or thousand patients.

All of Us is part of a push toward precision medicine, a way to customize care based on the complex combinations of factors that determine health, including your genes, habits and where you live as well as age, gender and socioeconomics.

The study is recruiting volunteers from all walks of life both the sick and the healthy to share DNA samples, medical records, fitness tracking and answer health questions. Researchers also will cull environmental information about participants communities.

While the pandemic delayed enrollment, the NIH said more than 474,000 people have agreed to participate so far and more than 325,000 have provided blood or saliva samples for researchers to start analyzing.

The database that opened Thursday contains the whole genome sequences of nearly 100,000 of the first volunteers meaning information on all their genes rather than the more common practice of studying a subset.

As with other genomic programs, the NIH team protects study participants privacy by removing all identifying information from the data. U.S. scientists seeking to use the database for their research must meet strict requirements.

Individual participants can request to learn the results of their own genetic testing. Last year, the NIH program began releasing ancestral information to participants who asked. Plans are underway to also notify participants who bear certain well-known genetic variants that cause inherited diseases or trigger medication problems.

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Big U.S. gene database will add racial and ethnic diversity to medical research - Los Angeles Times

2022 Harrington Prize for Innovation in Medicine Recognizes Breakthrough Innovations in the Use ofHuman Antibodies to Treat COVID-19

CLEVELAND, March 24, 2022 /PRNewswire/ -- The ninth annual Harrington Prize for Innovation in Medicine has been jointly awarded to James E. Crowe, Jr., MD, Director, Vanderbilt Vaccine Center and Professor, Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt School of Medicine, and Michel C. Nussenzweig, MD, PhD, Investigator, HHMI, and Zanvil A. Cohn and Ralph M. Steinman Professor, The Rockefeller University. The award recognizes their groundbreaking work, which has elucidated fundamental principles of the human immune response and enabled the use of human antibodies to treat COVID-19.

The Harrington Prize for Innovation in Medicine, established in 2014 by the HarringtonDiscovery Institute at University Hospitals and the American Society for ClinicalInvestigation (ASCI), honors physician-scientists who have moved science forward withachievementsnotable forinnovation,creativityandpotentialforclinicalapplication.

Dr. Crowe has advanced the discovery of human monoclonal antibodies for many of the most pathogenic viruses that cause human disease. His team has discovered thousands of human monoclonal antibodies for SARS-CoV-2 (the virus that causes COVID-19) and facilitated their development, transferring clinical leads to multiple pharmaceutical partners including tixagevimab + cilgavimab, now in use in high risk patients. His work on the genetic and structural basis of virus neutralization has also revealed important principles that are being exploited in new vaccine and antibody development.

Dr. Nussenzweig addressed a critical issue in immunology the lack of a detailed understanding of the human antibody response by developing robust and scalable methods for cloning antibodies from single human B cells. Dr. Nussenzweig showed that antibodies cloned directly from humans can be a safe and effective treatment against viral infections when passively transferred to other humans. His work established a paradigm that made it possible for him and others to rapidly develop monoclonal antibody therapies against SARS-CoV-2.

A committee composed of members of the ASCI Council and the Harrington Discovery Institute Scientific Advisory Board reviewed nominations from leading academic medical centers from eight countries before selecting the 2022 Harrington Prize recipients.

"Drs. Crowe and Nussenzweig are extraordinary physician-scientists who took distinct and separate paths but arrived at the same endpoint. In doing so, they have taught us a great deal about the human immune response and have successfully translated those findings into therapies for patients. The creativity, innovation and clinical impact demonstrated by their work is precisely what The Harrington Prize seeks to recognize," said Hossein Ardehali, MD, PhD, Professor of Medicine in the Division of Cardiology at Northwestern Medicine and the 2021-2022 President of the ASCI.

"The translational implications of Dr. Crowe's and Dr. Nussenzweig's work are quite profound. Their antibody-based therapies have enabled the medical community to more effectively combat COVID, and will spare untold human suffering," said Jonathan S. Stamler, MD, President, Harrington Discovery Institute, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation and Professor of Medicine and of Biochemistry at University Hospitals and Case Western Reserve University.

Inaddition tosharingthe Prize's$20,000honorarium,co-recipientsDr.Croweand Dr. Nussenzweigwill deliver The Harrington Prize Lecture at the 2022 AAP/ASCI/APSA Joint Meeting on April 8, will be featured speakers at the 2022 Harrington Scientific Symposium May 25-26, and will co-publish anessayin theJournal of Clinical Investigation.

Sinceitsestablishment,TheHarringtonPrizehasrecognized outstanding and diverse innovation in medicine:

SOURCE Harrington Discovery Institute

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International Harrington Prize Jointly Awarded to Drs. James Crowe and Michel Nussenzweig - PR Newswire

HOUSTON A multicenter research team co-led by The University of Texas MD Anderson Cancer Center developed the first drug to treat the uncontrolled secretion of mucins in the airways, which causes potentially life-threatening symptoms in millions of Americans with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), as well as lung disease resulting from cancer and cancer treatment. The study was published today in Nature.

Mucus is a significant problem in pulmonary medicine, because in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function, said Burton Dickey, M.D., professor of Pulmonary Medicine and co-corresponding author of the study. Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.

Muco-obstructive lung diseases affect hundreds of millions of people worldwide. In the U.S., about 25 million people have asthma, 16 million adults have been diagnosed with COPD and CF is the most common life-threatening, genetic disease. Many cancer patients end up with lung disease because their cancer treatments or the cancer itself leaves them immunocompromised.

Normally, mucins are gradually released into the airways, where they absorb water and form a thin layer of protective mucus that traps pathogens and is easily cleared by cilia. In muco-obstructive lung diseases, high volumes of mucins are suddenly released and, unable to absorb enough water, result in a thick mucus that can plug airways and impair lung function.

Dickeys lab began studying mucin secretion two decades ago and previously identified the key genes and proteins involved, showing how synaptotagmin and a SNARE complex, similar to that found in neurons, contribute to the key process of Ca2+-triggered membrane fusion.

We built up a picture of what the secretory machinery looked like and we knew all of the major players, Dickey said. Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.

In this study, a collaborative effort between MD Anderson, Stanford Medicine and Ulm University, the researchers verified Syt2 as a viable therapeutic target protein in several types of preclinical models. Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of the Institute for Applied Cancer Science, designed a hydrocarbon-stapled peptide, SP9, to block Syt2, based on structures developed by the Stanford collaborators, including senior co-corresponding author Axel Brunger, Ph.D., professor of Molecular and Cellular Physiology.

Stapled peptides are a recent therapeutic development involving modified amino acids that form hydrocarbon crossbridges to hold their structure rigid so they can bind to a protein target and show enhanced stability. Stapled peptides have been used to treat other diseases, including cancer, but SP9 would represent the first stapled peptide to be used as an inhaled therapeutic.

In a reconstituted system model in Brungers Stanford laboratory, Ying Lai, Ph.D., used SP9 to successfully disrupt Ca2+-triggered membrane fusion. The Ulm laboratory of Manfred Frick, Ph.D., used SP9 conjugated to a cell penetrating peptide in cultured epithelial cells to inhibit rapid mucin secretion. The Dickey laboratory then used an aerosolized version in a mouse model to confirm the drug reduced mucin secretion and airway blockage by mucus. Importantly, SP9 did not affect the slow-release pathway for normal mucin secretion.

An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding production of thick mucus. You cant move air through an airway thats plugged, Dickey said. In asthma, COPD and CF, its been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if its shown to work in clinical trials.

The stapled peptide SP9 will be further refined before moving to human studies, as is typical for therapeutics at this stage of development, and may enter clinical trials in a couple of years.

Dickey and co-authors are inventors on a patent application related to SP9. The study was supported by the National Institutes of Health (R01 HL129795, R21 AI137319) and the Cystic Fibrosis Foundation. A full list of co-authors and their disclosures is available in the paper.

- 30 -

Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides

23-Mar-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease - EurekAlert

When Dr. Ming Guo says that she wants to reverse the aging process, shes not outlining a fantastical quest for the Fountain of Youth. Shes looking for ways to defeat incurable diseases.

If we could pause, delay or even reverse aging, we would make a significant impact against numerous diseases, said Guo, professor of neurology, molecular and medical pharmacology at theDavid Geffen School of Medicine at UCLA.I want to create a higher quality of life over a healthy life span, rather than just prolonging life.

Her particular approach to her research is inspired by her compassion for her patients who have Alzheimers and Parkinsons diseases and other brain degenerative disorders, and from the discoveries she has made in her research lab.

The percentage of people with Alzheimer's doubles every five years after the age of 65, so Guo believes that intervening in the aging process could be the path to reducing the diseases massive impact. Slowing aging could also help combat a range of other diseases and conditions, including Parkinsons disease, heart disease, cancer and osteoporosis, as well as the increased vulnerability to infection that occurs with aging.

Since Guo joined the UCLA faculty two decades ago, her research focus has broadened to include multiple brain diseases and aging. In a landmark publication in 2006, Guo and her team examined two genes, PINK1 and PARKIN, that are mutated in some people with Parkinsons disease.

They discovered that the two genes work together to control the quality of cellular structures known as mitochondria by culling and recycling damaged ones. (Mitochondria provide energy to almost all cells in every complex organism on the planet, and they play a vital role in metabolism.)

The finding opened up a new investigation into the importance of PINK1 and PARKIN on mitochondrial health, and it helped establish Guos scientific legacy. Guo was honored, in 2020, with election to the Association of American Physicians, which recognizes scientists for the highest caliber of physician-led science accomplishments and scientific leadership.

Theres now a body of research indicating that damaged mitochondria contribute to premature aging, and their implications for human health stretch beyond one illness.

Dysfunctional mitochondria are associated with not only Parkinsons disease, but also other neurodegenerative diseases, cancer, diabetes and heart disease, Guo said. So we asked, Is it possible for us to reverse this damaged mitochondrial signature?

Mitochondria have their own genetic materials distinct from those in the cells nucleus and exploring mitochondrial DNA has become a signature of Guos research. In one of her recent studies, a collaboration with Caltech researchers, Guo and her colleagues discovered how to reverse up to 95% of the damage to mitochondrial DNA in animals.

Among the most recent rewards for her success was an academic career leadership award from the National Institute on Aging that will enable UCLA to establish a new interdisciplinary center, led by Guo, that will focus on aging, mitochondrial health and dementia. The center, which will encompass teaching, research and outreach, will engage faculty members from the Geffen School of Medicine, the UCLA College, the UCLA Samueli School of Engineering, the UCLA Fielding School of Public Health and UCLA-affiliated hospitals.

The new center also will be aligned with theCalifornia NanoSystems Institute at UCLA,of which Guo is a member. The interdisciplinary nature of nanoscience, which concerns phenomena occurring on the scale of billionths of a meter, provides an opportunity to engage physicists, data scientists and engineers who can bring new perspectives to anti-aging research.

CNSI has a strong tradition of innovation and entrepreneurship, which is something I am passionate about, she said.

Indeed, in 2021, Guo was named a UCLA Faculty Innovation Fellow. The fellowship program, a collaboration among Startup UCLA, theUCLA Technology Development Groupand the Office of the Vice Chancellor of Research and Creative Activities, helps UCLA professors develop ideas for companies that are based on their research. Also in 2021, she received a Noble Family Innovation Fund grant from CNSI; the funds support a team of scientists including UCLAs Robert Damoiseaux and Jonathan Wanagat and Caltechs Bruce Hay working on aging research.

One of Guos newest areas of study is exploring PINK1 and PARKIN signaling in the gut. The subject is of interest because digestive issues often precede, by years, the neurological symptoms of Parkinsons. That work, which Guo is conducting with Dr. Elizabeth Videlock, a UCLA assistant clinical professor of digestive diseases, is funded by a 2021 grant from the Chan Zuckerberg Initiative.

Guo said her abilities and insights as a researcher are augmented by her role caring for people with neurodegenerative diseases. She invites some of her patients to speak in her lab, which has dual benefits: Patients see firsthand the scientists who are dedicated to tackling their disorders, and Guos trainees gain a deeper understanding from those who know the diseases inside out.

I love to be connected to patients, she said. They teach me a lot about resilience, about optimism and about life. It gives me an enormous amount of motivation to go back to my lab and identify fundamental causes of these diseases and find cures for these currently incurable diseases and to change the trajectory of aging.

See more here:
To fight diseases of aging, scientist makes aging itself the target - University of California

Introduction

Following a recent update of the definition and classification of inherited metabolic diseases (IMD), more than 1600 IMDs were described (http://www.iembase.org/).1 Although it is frequently presumed that IMDs are uncommon cause of epilepsy or seizures,2,3 timely diagnosis of these diseases is particularly important for several reasons: 1) As many as 600 (37%) IMDs out of 1616 currently described (as of 22.10.2021, accessed through http://www.iembase.org/) may involve epilepsy or seizures as the main or one of many symptoms (Box 1). Only a subset of these IMDs may be diagnosed through conventional metabolic testing, therefore, their true prevalence may have been underestimated in previous metabolic testing-based studies.4,5 Moreover, novel groups of IMDs have recently been defined (eg, congenital disorders of autophagy, disorders of the synaptic vesicle cycle) and many of these novel diseases may present with epilepsy or seizures;6,7 2) Specific etiological treatments are being developed for an increasing number of IMDs and it is imperative to diagnose these diseases and institute treatments in time.8,9 Conventional treatments of epilepsy can be ineffective in some IMDs, while specific etiological treatments (eg, in pyridoxine-dependent epilepsy10 may fundamentally improve patients prognosis and enable fulfilling life for the patient and his/her family. 3) Even in cases where specific treatments are not available, precise diagnosis of IMD may still be highly beneficial to patients and families as it allows halting diagnostic odyssey and avoidance of further, sometimes invasive testing.11 In some cases potentially detrimental treatments may be withheld as in the case of epilepsy due to some mitochondrial diseases where valproates may induce fatal hepatic failure.12 Besides, genetic diagnosis gives prognostic information, enables appropriate targeted long-term follow-up, informed reproductive choices for families, inclusion into clinical trials and engagement into patient organizations.4,13 In cases of refractory epilepsy, identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not.14 A subset of IMDs is highly amenable to ketogenic dietary treatment.15 Generally, diagnosis of IMD is more likely to change management of a patient compared to other genetic diagnoses: in a recent study of 59 patients with early-onset epilepsy who got the genetic diagnosis through whole exome sequencing (12 of them (20%) were diagnosed with IMD), clinical management following genetic diagnosis was changed in 5 patients with IMD (42% of patients with IMD) and 17 patients without IMD (36% of patients without IMD).16 Therefore, precise diagnosis of IMD is highly important for further multidisciplinary integrated care of patients.

Box 1 Genes Associated with Inherited Metabolic Diseases Involving Epilepsy or Seizures as a Symptom

The vast majority of IMDs that may present with epilepsy or seizures are multisystem, life-long disorders where epilepsy or seizures is just one among many other symptoms. Multidisciplinary care involves all stages of management: diagnostics, acute and chronic treatments, and long-term integrated care for patients with complex needs. Not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers must be taken into account.17,18 In this narrative review we investigate various aspects of multidisciplinary care and discuss about some key challenges, opportunities and suggestions for the organization of high-quality care services that meet expectations of patients and families and conform to current patient-centered and value-based care principles. Further research on the overall organization of multidisciplinary, integrated care and various aspects of service provision may enable optimization of complex care and, eventually, better outcomes for IMD patients with epilepsy or seizures and their caregivers.

We performed literature searches using PubMed and Medline electronic databases using the various combinations of the following search terms: epilepsy OR seizures AND inherited metabolic diseases OR inborn errors of metabolism OR multidisciplinary care OR care coordination OR transition of care OR self-management. Further searches were informed by references in the publications and related features in PubMed. Searches were limited to English language and included a period of 2010 to current (October 2021) period.

IMD was defined as any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical and/or pathophysiological features.1

Multidisciplinary care was defined as a care when professionals from a range of disciplines work together to deliver comprehensive care that addresses as many of the patients needs as possible.19

Care coordination involves deliberately organizing patient care activities and sharing information among all of the participants concerned with a patients care to achieve safer and more effective care.20

Care pathways were defined as a complex intervention for the mutual decision-making and organization of care processes for a well-defined group of patients during a well-defined period. Defining characteristics of care pathways include: a) an explicit statement of the goals and key elements of care based on evidence, best practice, and patients expectations and their characteristics; b) the facilitation of the communication among the team members and with patients and families; c) the coordination of the care process by coordinating the roles and sequencing the activities of the multidisciplinary care team, the patients and their relatives; d) the documentation, monitoring, and evaluation of variances and outcomes, and e) the identification of the appropriate resources.21

Patient empowerment was defined as patient engagement through which individuals and communities are able to express their needs, are involved in decision-making, take action to meet those needs.22

Self-management was defined as the interaction of health behaviors and related processes that patients and families engage in to care for a chronic condition.23

Transitional care was defined as the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems.24

Palliative care was defined as the active total care of body, mind and spirit, (as well as) giving support to the family. It begins at diagnosis, and continues regardless of whether or not a patient receives treatment directed at the disease.25

Ultra-rare disease was defined as a disease with a prevalence of <1 per 50,000 persons.26

Seizures were defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.27

Epilepsy was defined as a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.28

Epilepsy syndromes were defined as syndromes that have a typical age of seizure onset, specific seizure types and EEG characteristics and often other features which when taken together allow the specific epilepsy syndrome diagnosis.29

More than 1600 IMDs are currently on the list of IMD classification http://www.icimd.org/; http://www.iembase.org/,1 600 of them (37% of all described IMDs) may present with epilepsy or seizures (Box 1). All these IMDs are rare or ultra-rare diseases, and various stages of their management require highly-specialized services and expert knowledge that goes beyond those available at primary or secondary healthcare level. IMDs presenting with epilepsy or seizures are highly heterogeneous: although involvement of central nervous system (CNS) leads to the most disabling and life-threatening symptoms, any other body system or tissue may also be affected with frequently multisystem presentation.30,31

CNS involvement in these diseases results in a wide spectrum of symptoms including global developmental delay, autism, behavioral problems and intellectual disability,9 other more common neurological presentations include neurodegenerative and movement disorders.32,33 Epilepsy may be a dominating symptom (eg, pyridoxine-dependent epilepsy10 and other developmental and epileptic encephalopathies (DEE) due to IMD),34 or a more variable symptom in a subset of all patients with a given disorder (eg, succinic semialdehyde dehydrogenase deficiency).35 In other cases, symptomatic seizures occur only during acute metabolic decompensation or develop as a consequence of brain damage during metabolic crises (eg, organic acidurias).36 Seizures can be amenable to conventional anti-seizure drugs (ASD), although a substantial number of IMDs are associated with severe and treatment-resistant forms of epilepsy, including DEE34 or status epilepticus.37,38 Presentations of IMDs may be highly diverse, but metabolic etiologies should be considered in unexplained neonatal or infantile seizures, refractory seizures, seizures related to catabolic stress (eg, due to fasting, intercurrent illness or surgeries), multisystem presentation, family history or parental consanguinity.39 The first symptoms of IMDs usually develop in children, however, adolescent or adult-onset presentations are being increasingly identified. Treatments of many IMDs have been optimized leading to an increasing number of patients who survive well into adulthood and, on the other hand, with the improvement of genetic diagnostics IMDs adult persons for whom diagnostics was previously not available, can now be studied.4042 Currently, almost 50% of approximately 33,000 patients in the European Reference Network for IMDs MetabERN are adults.43

Conventional methods for the diagnosis of epilepsy (as seizure semiology, electrophysiological or neuroradiological investigations) may sometimes provide diagnostic clues to IMDs, however, most frequently findings are non-specific.13 Importantly, IMDs may present with any seizure and epilepsy type and any epilepsy syndrome, while some epilepsy-related brain lesions as neuronal migration defects may be due to IMD.44 Precise diagnosis of IMD may be achieved only through metabolic and/or molecular genetic testing that is usually available in specialized laboratories only.4,45

Many IMDs are amenable to specific etiological treatments,9,46 and many new potential personalized therapies are currently at various stages of clinical research and will be presumably translated into clinical practice in coming years.8 Specific treatments include nutritional or vitamin/ cofactor supplementation therapies, relatively inexpensive and frequently highly effective treatment modalities.47 Enzyme replacement and small molecule therapies, stem cell and solid organ transplantations, and cell or gene therapies may also provide opportunities of highly effective specific treatments. It is imperative for clinicians to have a sufficient index of suspicion for these diseases in order to identify and diagnose them in time, as early diagnosis and treatments may prevent major neurological sequelae and enable favorable outcomes.13

Although, to the best of our knowledge, there are no studies that specifically investigate care experiences of patients with IMDs that involve epilepsy or seizures and their families, studies of related patient groups (eg, patients with IMDs, early refractory epilepsy or epilepsy associated with intellectual disability) suggest, that both the overall organization of multidisciplinary, integrated care and various aspects of this care (eg, transition of care or care coordination) are insufficient.18,48,49 Fragmented health and social care systems do not meet expectations and needs of patients and families, there is a lack of support in navigating complex care pathways and insufficient communication among professionals and sectors, especially at transition of care points. Due to the scarcity of knowledge and awareness about these rare diseases, patients and families may be insufficiently provided with the necessary information about the disease, its presumed course, prognosis, possible comorbidities, as well as available services and supports, including psychological support and peer support groups. Patient education, empowerment and inclusion into common decision-making is also lacking.18,50 In some cases developed informational materials do not meet patients and caregivers needs in terms of content and form (eg, preferences of web-based information versus written).51 Importantly, patients and families needs change along the clinical path of the disease, therefore, they have to be assessed repeatedly and addressed accordingly.18 Caregivers of children with IMDs relate that these deficiencies are especially burdensome outside the highly-specialized settings, when encountering professionals unfamiliar with the childs disease.52 A distinctive feature of rare diseases with metabolic and epileptic emergencies is their unpredictability and often associated uncertainty, that evokes even higher anxiety, depression and other psychological and emotional issues of caregivers. These facts associated with difficulties in decision-making demand a close communication with professionals which is sometimes felt by patients as very difficult.17,49,50 Finally, care organization and quality of services is highly unequal across and sometimes within countries.36,53

Due to their multisystem, frequently life-long nature, IMDs that involve epilepsy or seizures usually induce complex long-term needs of patients and their families. The goals of integrated, multidisciplinary care are to place patients and their families at the center of care services planning in order to fully respond to their needs, to address holistically not only health-related but also other (psychological, social, educational, vocational) issues, and to ensure high-quality, accessible and effective services.54 Summarized goals of integrated, multidisciplinary care for patients with IMDs that involve epilepsy or seizures are presented in Box 2.

Box 2 The Goals of Multidisciplinary Care in IMD Patients with Epilepsy or Seizures

Care pathways for these diseases are highly complex and diverse (Figure 1) due to several reasons: 1) Heterogeneity of IMDs that may present with epilepsy or seizures; 2) Diversity in health systems organization and available expertise; 3) Patient and family-related factors (eg, rural vs urban living place or willingness to engage into self-management). Healthcare pathway of any rare disease consists of highly-specialized and less specialized services that may variably involve diagnostics, specific and symptomatic treatments, surveillance, rehabilitation, palliative care, cross-border care, patient empowerment, social and community services. Highly-specialized care services for rare diseases are usually provided in the Centers of Excellence (CoE) with sufficient expertise and infrastructural resources (as equipment and multidisciplinary teams of experts). These services are usually expensive, centralized and provided far away from patients home, therefore, it is highly important to find the right balance between highly-specialized and local services: in all cases where services may be safely provided locally or require continuous provision (eg, psychological and social support), they have to be provided closer to patients home, while ensuring appropriate specialized support when needed, empowerment of local care providers, patients and their families, and effective communication among all care providers.53

Figure 1 Care pathways for IMD patients with epilepsy or seizures.

Comprehensive patient care includes not only healthcare services at different levels of the health system, but also other services to meet the complex needs of patients and their families, including psychological, social, educational and vocational issues, all of which pose significant challenges for care coordination.55 While general practitioners usually lack time, knowledge and resources to ensure multipronged care coordination for patients with rare diseases, (specialist) nurse coordinators or case managers at the CoE and/ or at the primary care level are uniquely positioned to provide appropriate care coordination and management of transitions of care.56 Trusting patient-provider relationship between nurses and patients/ families supports active communication and allows identification of priorities and barriers for integrated care and self-management, enables holistic, proactive management, continuity of care and improved patient outcomes.56,57

Patients with IMDs involving epilepsy or seizures are highly active healthcare users with complex trajectories across care systems and multiple transitions of care across life and disease stages (eg, transition from pediatric to adult services or transition to palliative care). Patients and families face particular challenges at these transition points.43,58 Hence, these transitions have to be anticipated, planned, proactively prepared and discussed with the family and care providers.

IMDs involving epilepsy or seizures frequently present with epilepsy or metabolic decompensation-related emergencies, where timely treatments may determine patients outcomes.36,37 Management of these emergencies evoke particular challenges for families and needs particular consideration from the side of professionals: patients and their families must be able to recognize the first signs of an imminent or occurring emergency, have predefined plans for immediate action (eg, oral emergency regimens for nutritional therapies, emergency seizure protocols) and knowledge on how to monitor the patients condition, when and where to go for emergency care. These plans must also include 24h/7 days contacts for emergency specialist assistance. In some cases, the patient first goes to the nearest hospital; in such cases, it is necessary to ensure proper communication between healthcare providers and transfer of samples or patients to highly-specialized institutions when required.36,50 Widespread availability of evidence-based emergency protocols is highly important; through international collaboration involving MetabERN, generic emergency protocols for patients with fasting intolerance in eight languages and an on-line tool for generating protocols for individual patients were developed (https://www.emergencyprotocol.net/).59

The greatest burden of care for IMDs that involve epilepsy or seizures always falls on the shoulders of patients and/or families, therefore, each care pathway must include empowerment that must be family-centered.60 A lack of consideration of familys needs, including not only direct caregivers but also other family members (eg, siblings) harms their ability to provide effective care and may have detrimental effects on patients outcomes and wellbeing of the whole family.61 Depending on disease, organization of care in a given country and patient/ family-related factors, empowerment includes provision of required information, involvement into common decision-making, patients and familys education, support for self-management, liaison with peer support groups and emotional/ psychological support.18,48,52,62 Self-management is critical for individuals with epilepsy and their caregivers in order to maintain optimal physical, cognitive, and emotional health, especially in cases of refractory epilepsy or handling such challenging treatments as ketogenic diets.63 Although high benefits of these interventions were demonstrated,6466 their implementation is still insufficient and requires considering many factors at the person, program, and systems levels.67

International collaboration is indispensable in addressing various aspects of highly-specialized care for rare diseases, therefore, 24 European Rare Diseases Networks (ERNs) for rare and complex diseases were launched in 2017.68 These ERNs provide virtual and physical cross-border services not available in patients country of origin, moreover, they develop highly required resources for multidisciplinary, integrated care including clinical practice guidelines, educational programmes, recommendations and tools for integrated multidisciplinary care.43,53 Patients with IMDs that involve epilepsy or seizures may require services of several ERNs: MetabERN was developed for patients with IMDs, EpiCARE is for rare epilepsies, ERN-RND is for rare neurological disorders, and TransplantChild may be required in cases where there is a need for liver, stem cell or other transplantations. The accessibility of ERNs must be ensured through the proper organization of care pathways and referral systems towards ERNs.53

Digital technologies have paved the ways for innovative eHealth services, including teleconsultations for patients and professionals, electronic tools for patient monitoring, self-management and education, and more. Although these services are particularly important for patients with rare diseases and can significantly increase the availability of highly-specialized services and expertise, they are often not properly organized, regulated and reimbursed. The pandemic significantly increased the deployment and use of these services across all healthcare areas, including epilepsy care.69 These achievements are expected to be sustained and exploited for the benefit of patients and their families in the post-pandemic period. Besides, recent explosive spread of digital communication technologies enables liaison among rare disease patients and families dispersed across countries and continents and formation of peer support groups that may provide highly required emotional and practical support and advices, empowerment, advocacy and decrease the feelings of abandonment and isolation.60 Therefore, impact of digital technologies on service provision and outcomes should be evaluated and exploitation of these technologies along the entire care pathway where required should be encouraged.

Many IMDs involving epilepsy or seizures are included into neonatal screening programs when they have specific treatments that can improve significantly the prognosis. According to global standards, patients diagnosed through neonatal screening are usually provided with the full range of services that have a big impact on prognosis and quality of life, from screening to diagnosis, institution of treatment, monitoring, and long-term, multidisciplinary management.70 However, some newborns may develop acute symptoms before the results of neonatal screening are obtained, lists of screened IMDs differ among countries, and only a subset of all IMDs presenting with epilepsy or seizures are suitable for neonatal screening.71,72 It is therefore essential for neonatologists to know what diseases are being screened for in their country and where to get the information on IMD screening, diagnostics and expert advice on emergency treatment.

In some infantile-onset epilepsy syndromes, a considerable subset of patients is diagnosed with IMDs: eg, IMDs have been found in 3% to 22% of infants with West syndrome.34 Precise genetic diagnosis in these patients may not only enable specific etiological treatments, but also provide prognostic information and guidance for antiseizure treatment. Impact on psychomotor development and cognitive function may vary between some milder developmental encephalopathies to severe epileptic encephalopathies. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with developmental encephalopathies are unlikely to gain from aggressive antiseizure medication whilst those with epileptic encephalopathies will gain.73

Transition to adult care represents a vulnerable time in the life of a patient and his/her family.17,48,49,61 Transition as a purposeful and planned process should address manifold medical, psychosocial, educational, and vocational needs of adolescent and young adult patients as they move from a pediatric to an adult model of care. At the very least, it involves coordination of care between care providers to ensure that the adult providers have sufficient medical and other related information about the patient and his/her family and competence to provide optimal disease management. As much as it is possible, patients should acquire knowledge and skills in the domains of self-care, healthcare decision-making, and self-advocacy in such a way that will prepare them to increase their agency surrounding their healthcare needs.74 In children with IMDs that involve epilepsy or seizures the primary care provider is usually either pediatric neurologist or metabolic pediatrician. While in transition from pediatric to adult neurologist the largest problem may be excessive anxiety of patients and/or families that is completely resolved with the proper organization of transition,75 transition among the specialists of metabolic medicine is frequently complicated due to the lack of specialists for adult IMDs.76 According to the survey of the ERN for IMDs MetabERN, in most European countries transition of pediatric patients and services for adults with IMDs are insufficiently organized.43 Expertise in adult metabolic medicine is lacking worldwide, because education on IMDs in adolescents and adults is inadequate and the specialty is mostly not formally recognized.71 Due to the inherent phenotypic variability of adult IMDs dependent not only from genotype, but also due to the effect of environmental factors, ontogenetic changes and aging and lack of knowledge on many aspects of IMDs associated with prolonged survival and novel treatments (eg, late adverse effects of interventions and definition of new natural histories), the field of adult IMDs is still developing.77,78

An increasing number of females with IMDs that may present with epilepsy or seizures enter reproductive age. Pregnancy and perinatal care-related issues in this group of women are dual and involve: 1) IMD-related issues, eg disease effects on fertility, teratogenic effects of a disease (as phenylketonuria) or medicines, challenges of nutritional treatments and metabolic control, worsening of an underlying maternal IMD due to pregnancy, special recommendations for breastfeeding and IMD effects on labour (as skeletal dysplasia in mucopolysaccharidoses).79 Some IMDs of intermediary metabolism may present for the first time or exacerbate during the perinatal period (eg, urea cycle defects).40 2) epilepsy and ASD treatment-related issues, including teratogenic effects of some ASD, seizure control during the pregnancy and in the perinatal period and other associated issues.80 Therefore, obstetricians gynecologists have to be involved into multidisciplinary teams for the management of females with IMDs.

Patients with life-limiting or life-threatening conditions require timely and family-centered palliative care, especially in a pediatric setting.81 In medical terms, palliative care aims to achieve pain and symptom management, enhanced dignity and quality of life for the patients. Though comfort is often the most common goal identified, symptom identification and treatment remains challenging in nonverbal children with neurological impairments.58 Besides, in IMDs symptom burden is usually high with neurologic, respiratory and gastrointestinal symptoms being the most frequent and most of those being difficult to treat or even intractable.82 Another issue in IMDs, pertinent to any rare disease, is a lack of knowledge and inherent uncertainty about prognosis and medical interventions that may complicate decision-making process.83 Noteworthy, a high number of children with metabolic diseases die in intensive care units. In these cases, an integrated model of care that combines pediatric intensive care and primary pediatric palliative care depending on the disease trajectory might be a fundamental component of the best available standard of care.81

Not only medical, but also ever changing social, psychological, emotional and spiritual needs of the family beyond what the primary care team can provide should be addressed.84,85 Therefore, palliative care should be planned in advance, ideally from the moment of diagnosis, and is best delivered in a team committed to family centered care and open and reflective practice throughout the journey of a childs illness and death, including bereavement period. Quality of relationship and inclusion of a patient and his/her family into a common decision-making are the core elements of palliative care.84,85 Families and professionals should also acknowledge the unique experiences and needs of siblings, include siblings in medical conversations and care plans when appropriate, and connect siblings to resources for informational and emotional support.61

In some cases, diagnosis of an IMD is only achieved post-mortem. Without a clear diagnosis the families find themselves in a very precarious situation, not least regarding end-of-life decisions. For both caregivers and health care professionals, it may be difficult to even consider palliative care because the course of the disease is not predictable Additionally, the lack of a diagnosis raises uncertainty about family planning and the risk of recurrence in future children. In spite of these uncertainties, patients and families have the same rights to receive optimized and symptom-adapted palliative care.83

Due to the complexity and rarity of IMDs, general practitioners (GPs) are usually unable to provide all the necessary information, services, and support, therefore, it is highly important for patients and families to have a named physician supervising them in a highly-specialized setting and a multidisciplinary team that encompass both local/regional and highly-specialized settings (Table 1).45 The specialty of this physician depends on the nature of the disease: where epilepsy or seizures is just the one of many other symptoms or occur only during acute metabolic decompensation, a supervising physician is usually a metabolic pediatrician or a specialist of adult IMDs. In some countries, specialty of metabolic pediatrician is not formalized, while in most countries specialists of adult IMDs are not available or lacking; in these cases functions of supervising highly-specialized physician may be assumed by geneticists or physicians of other specialties.76 When the predominant symptom of IMD is epilepsy, the supervising highly-specialized physician is usually a pediatric or adult neurologist or epileptologist. These specialists - A metabolic pediatrician or other specialist in metabolic diseases, a pediatric or adult neurologist (epileptologist) - usually lead a whole multidisciplinary team that is ideally based in a dedicated CoE. The multidisciplinary team consists of core members providing the main services to patients and families: in the IMD department, these may include laboratory specialists from biochemical genetic and molecular genetics laboratory, geneticists, dietician, specialized nurse or other care coordinator, neonatologist and intensive care specialist, rehabilitation specialists, psychologists, social workers and play specialist/therapist. In the epilepsy department, the multidisciplinary core team usually consists of laboratory specialists, neuroradiologist, neurophysiologist, neurosurgeon. If necessary, the core team is complemented by other extended team specialists, eg obstetrician-gynecologist, physicians of other specialties, pharmacist, etc. The CoE for rare diseases usually carry out not only provision of highly-specialized healthcare services but also education and research and these additional functions also determine the composition of the multidisciplinary team. There is a need for staff to manage rare disease registries and biobanks, to administer research projects, to conduct clinical trials, to provide education and training and to collaborate with various research and educational institutions.

Table 1 Multidisciplinary Teams for Care of IMD Patients with Epilepsy or Seizures

All multidisciplinary team members follow the same clinical practice guidelines (CPGs) or other evidence-based resources, develop and implement individual patient care plans, therefore, it is highly important to ensure proper communication and collaboration among the entire team. In addition, appropriate teams communication with GPs, other care providers across various levels of health and social care systems and appropriate involvement of patients and families are essential, hence, the role of a specialist nurse coordinator or other care coordinator is indispensable.

Multidisciplinary care should also involve primary care and community level: many long-term mental health, physical therapy and rehabilitation, social services for patients and families, services to address educational and vocational issues are inevitably provided at a primary or community level.86

Due to the heterogeneity, multisystem nature and complexity of IMDs, the need for highly-specialized services and expertise, and complex care pathways that cross various health system levels, sectoral and sometimes even national borders, the organization of services for patients with IMDs involving epilepsy or seizures and their families is a challenging task. Although these patients are highly active users of care services and their expectations and needs often remain unmet, very little data for evidence-based governance and principles of care organization are available.53,78 While diagnostic and treatment services are frequently provided simultaneously, precise genetic diagnosis usually establish a crucial landmark for the management of these patients.

Diagnosis of IMDs requires sufficient knowledge and experience and is almost invariably obtained through the highly-specialized laboratory testing. GPs and local healthcare providers typically have neither the expertise nor the resources to diagnose IMD. Unfortunately, the primary healthcare level, which is often the first medical contact point for any patient, often lacks sufficient awareness and index of suspicion for rare diseases and health system literacy on where to refer the patient for specialized services.8789 IMDs are implicated with an additional diagnostic urgency due to the fact that many of them have specific etiological treatments. In order to ensure timely diagnosis and treatment and to reduce diagnostic odyssey, it is necessary to properly organize care pathways and referrals systems towards CoE and ERNs in health systems and to increase IMD awareness and education among care providers.53

Once a precise diagnosis has been established, individual patients care plan must be developed that is not only evidence-based but also meets the individual needs of the patient and his or her family. Unfortunately, CPGs for rare diseases are very scarce,90 while the awareness of and implementation of existing guidelines is clearly deficient and highly unequal across countries.91 Fortunately, ERNs are currently intensively working on the development of novel CPGs for rare diseases and implementation of existing ones.

Depending on the nature of the disease and other factors (such as health system organization, available expertise and resources at primary and local level, patient and family empowerment, etc.), the individual care plans should include initial and follow-up examinations (laboratory and instrumental testing, consultations of specialists), disease monitoring, management of emergencies, family support, genetic counseling and testing, and expected transition points across illness and life stages.

Due to the heterogeneity, multisystem nature and complexity of IMDs, the need for highly-specialized services and expertise, and complex care pathways that cross various health system levels, sectoral and sometimes even national borders, the organization of services for patients with IMDs involving epilepsy or seizures and their families is a challenging task. Multidisciplinary care should place patients and their families at the center of care services planning and to respond to their complex needs, including not only health-related but also other (psychological, social, educational, vocational) issues.

This work was supported (not financially) by the European Reference Networks: European Reference Network on hereditary metabolic disorders (MetabERN). This ERN is co-funded by the European Union within the framework of the Third Health Program ERN-2016Framework Partnership Agreement 20172021.

The authors report no conflicts of interest in this work.

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