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ICNA March 20, 2021

In the largest DNA sequencing study of Tourette Disorder (TD) to date, UC San Francisco researchers and their collaborators have unearthed new data suggesting a potential role for disruptions in cell polarity in the development of this condition.

The researchers focused on "de novo" mutations, or rare mutations that arise anew at conception, rather than being inherited from parents. They observed that these mutations tend to affect genes with a role in cell "polarity," which is the process by which cells differentiate "top" and "bottom." This is particularly important in the brain, where neurons must form with specialized information gathering and transmitting sides to function properly.

"You might expect that mutations in these cell polarity genes would affect things like neurons getting to the right place in the brain, or forming the right connections, with the appropriate directionality," said Jeremy Willsey, PhD, an expert on psychiatric genetics in the UCSF Weill Institute for Neurosciences and a senior author of the paper. "Our group has already started experiments modeling the effect of mutations in these cell polarity genes during early brain development."

Such disruptions to neuronal wiring may eventually explain the uncontrollable chronic vocal and motor tics that mark TD. Although as many as one percent of children worldwide develop TD, the condition has been relatively neglected in studies compared to other child-onset psychiatric disorders, such as autism, intellectual disability, and epilepsy.

Referring to the relatively small number of studies on TD genetics, Matthew State, MD, PhD, professor and chair of the UCSF Department of Psychiatry, said, "Tourette disorder has tended to be marginalized in psychiatric research, but with the promise of these genetic findings and a major recent investment by the National Institute of Mental Health, we can deepen our understanding of TD and potentially use the new insights to develop improved treatments."

State and Jay Tischfield, PhD, of Rutgers University, founded the Tourette International Collaborative Genetics (TIC Genetics) consortium in 2009 to collect, study and share genetic data from TD patients and their families across multiple U.S. and international sites. Willsey now serves alongside them, and several other authors of the new paper, on the executive board.

Collaboration was at the heart of the new study, too, with TIC Genetics joining forces with the Tourette Association of America International Consortium for Genetics (TAAICG), and the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE); the researchers also received samples from the Uppsala Tourette Cohort, based in Sweden.

This pooling of resources allowed researchers to amass genetic data from much larger samples of TD patients, and their unaffected parents, than would otherwise be possible. With this data in hand, the researchers conducted a powerful approach, known in genetics as trio analysis, in order to identify de novo mutations, by determining which mutations were present in patients but not in their parents. These are very rare events, occurring one or two times for every 100 million DNA base pairs sequenced.

De novo mutations arise spontaneously in a sperm or egg cell, or in a zygote soon after fertilization. Unlike inherited mutations, these de novo events are subject to natural selection over only a very short period of time, and mutations that have large effects are thus overrepresented or "enriched" among de novo mutations. De novo mutations have already been strongly linked to autism, epilepsy, and intellectual disability.

Last year, the TIC Genetics group found the same is true for TD, based on analysis of 511 trios (1,533 total samples). The new study, published online September 25 in Cell Reports, expands on the 2017 study with 291 more trios (873 new samples), for a total of 802 trios (2,406 samples).

First author Sheng Wang, a graduate student in both the State and Willsey labs, and colleagues set about sequencing the exome -- the protein-coding parts of the genome -- in DNA samples from each person with TD, plus each of their parents. By focusing on the coding parts of the genomes, the researchers can easily identify mutations that disrupt the corresponding proteins encoded by these sequences.

The researchers then compared the exome sequences between parents and their affected child. This painstaking process identified 309 new de novo sequence mutations, or accidental genetic "typos" that alter a few "letters" of the DNA code.

First and foremost, the new independent sample of 291 trios allowed the authors to independently confirm the 2017 results. Namely, that de novo mutations deemed to be damaging to protein function were present more often in individuals with TD than in unaffected control samples -- a suspicious enrichment that suggests these variants directly contribute to the disorder.

"It cannot be overstated that in psychiatric genetics it's critical for replication to happen. It should not be taken for granted," Willsey said, acknowledging that some results that have not been replicated have stymied the field for years.

But in addition to replicating their earlier findings, the researchers arrived at several key new insights. First, de novo variants tend to be enriched in families without any history of TD, suggesting, as expected, that future studies should match the types of genetic analyses conducted with the type of families recruited.

They also observed some evidence for an enrichment of de novo variants in females affected with TD, as compared to males affected with TD. This indicates that females may be more resilient to developing TD. Similar findings have been observed in autism. Understanding the basis of this biological difference in susceptibility holds promise for developing new treatments. Finally, they identified a new, high-confidence risk gene, CELSR3, adding to the first high-confidence gene they identified in 2017, WWC1.

Both of the proteins these genes encode have known roles in cell polarity. This inspired the team to look at the rest of the genes with de novo mutations in TD patients. Consulting a database of gene function, the authors noted that 15 other cell polarity genes had damaging de novo mutations, almost three times as many as would be expected, which suggests that disruption of cell polarity during brain development may be a central biological mechanism in the development of TD.

When looking at all the genes hit by damaging de novo variants in TD, the researchers also found an overlap with genes implicated in obsessive-compulsive disorder (OCD), which suggests the biology of these conditions is intertwined. People with TD often also have OCD, yet when the researchers excluded these cases from their samples, the gene overlap remained. This suggests that the same genes can give rise to TD or OCD, and that pursuing the biology of these genes may offer insights on multiple disorders.

"While tics are the defining feature of TD, there are many other symptoms that tend to go along with the disorder, like attention problems, learning difficulties, OCD, depression, and anxiety," State said. "If we knew exactly what was going wrong and could target this more specifically, not only could we do a better job of decreasing tics, but we could potentially simultaneously address multiple symptoms that accompany TD, and that in many children are more debilitating than the tics themselves."

The researchers also detected, for the first time, a statistically significant enrichment of larger-scale de novo alterations, called copy number variants (CNVs), in TD. A role for CNVs, which are deletions or duplications of sections of DNA, in TD had been suspected from previous studies, but the enlarged sample in the new study allowed researchers to clearly establish the association for the first time.

The success of the TD collaboration spurred the National Institute of Mental Health to fund a $10 million dollar grant earlier this year to help the research team pursue their findings. The award will go to seven U.S. and 14 international sites to enroll more than 1,000 parent-child trios (3,000 samples), genetically characterize them, and identify new genes. The researchers expect this will generate new biological insights and potentially opportunities for new and improved treatments.


Authors: First author Sheng Wang is a visiting graduate scholar from China Agricultural University and National Institute of Biological Sciences, in Beijing; co-senior author Jay Tischfield, PhD, is MacMillan Distinguished Professor and chair of the Department of Genetics at Rutgers University; the paper's co-senior and co-corresponding authors are Willsey, assistant professor of psychiatry and member of UCSF's Institute for Neurodegenerative Diseases; State, the Oberndorf Family Distinguished Professor and chair of UCSF's Department of Psychiatry; and Peristera Paschou, PhD, associate professor of biological sciences at Purdue University. A complete list of authors, including members of the TAAICG and TSGENESEE, is available in the online version of the paper.

Funding: The study was supported by grants from the National Institute of Mental Health (R01MH092290; R01MH092291; R01MH092292; R01MH092293; R01MH092513; R01MH092516; R01MH092520; R01MH092289; and K08MH099424), from the Human Genetics Institute of New Jersey, and the New Jersey Center for Tourette Syndrome and Associated Disorders. The work was also supported by the UCSF Weill Institute for Neurosciences and the Overlook International Foundation. A complete list of international funders is available in the online version of the paper.

Disclosures: Co-author Donald L. Gilbert, MD, of the TIC Genetics Consortium, has received salary/travel/honoraria from the Tourette Association of America; the Child Neurology Society; the U.S. National Vaccine Injury Compensation Program; Ecopipam Pharmaceuticals; EryDel Pharmaceuticals; Elsevier; and Wolters Kluwer. Willsey is a paid consultant for Daiichi Sankyo.

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ICNA March 20, 2021

mitoResearchers at Children's Hospital of Philadelphia (CHOP) have demonstrated that autism spectrum disorder (ASD) may be caused by defects in the mitochondria of brain cells. The findings were published online by the Proceedings of the National Academy of Sciences.

Multiple studies have revealed hundreds of mutations associated with autism spectrum disorder, but there is no consensus as to how these genetic changes cause the condition. Biochemical and physiological analyses have suggested that deficiencies in mitochondria,  might be a possible cause. Recent studies have shown that variants of mitochondrial DNA (mtDNA) are associated with autism spectrum disorder.

The study team hypothesized that if defects in the mitochondria do predispose patients to ASD, then a mouse model in which relevant mtDNA mutations have been introduced should present with autism endophenotypes, measurable traits similar to those seen in patients. For this model, the traits related to autism included behavioral, neurophysiological, and biochemical features.

"Autism spectrum disorder is highly genetically heterogeneous, and many of the previously identified copy number and loss of function variants could have an impact on the mitochondria," said Douglas C. Wallace, PhD, Director of the Center for Mitochondrial and Epigenomic Medicine and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases at CHOP, co-senior author of the study, with Eric D. Marsh, MD, PhD, attending pediatric neurologist, Division of Child Neurology at CHOP.

The researchers - including co-first authors Tal Yardeni, PhD and Ana G. Cristancho, MD, PhD - introduced a mild missense mutation in the mtDNA ND6 gene into a mouse strain. The resulting mouse exhibited impaired social interactions, increased repetitive behaviors and anxiety, all of which are common behavioral features associated with autism spectrum disorder. The researchers also noted aberrations in electroencephalograms (EEG), more seizures, and brain-region specific defects on mitochondrial function. Despite these observations, the researchers found no obvious change in the brain's anatomy. These findings suggest that mitochondrial energetic defects appear to be sufficient to cause autism.

"Our study shows that mild systemic mitochondrial defects can result in autism spectrum disorder without causing apparent neuroanatomical defects," Wallace said. "These mutations appear to cause tissue-specific brain defects. While our findings warrant further study, there is reason to believe that this could lead to better diagnosis of autism and potentially treatments directed toward mitochondrial function."


This work was supported by the Neurobehavior Testing Core at the University of Pennsylvania and the Intellectual and Developmental Disabilities Research Center at CHOP and Penn supported by grant U54HD086984. This work was also supported by National Institutes of Health grants MH108592, OD010944, and 5K12HD043245, U.S. Department of Defense grants W81XWH-16-1-0401 and PR202997, a grant from Accure, Inc., a CHOP K-readiness grant, and a CHOP Foerderer grant.

Yardeni et al, "An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes." Proc Natl Acad Sci U S A, online February 1, 2021. DOI: 10.1073/pnas.2021429118.

Additional resources

United Mitochondrial Disease Foundation
Mitochondrial Medicine Society

Siddiqui MF, Elwell C, Johnson MH (2016) Mitochondrial Dysfunction in Autism Spectrum Disorders. Autism Open Access 6 (5):. DOI: 10.4172/2165-7890.1000190 PMID: 27928515.

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Adelina Soares Updated November 07, 2020

Epilepsy is well recognised worldwide as a common, complex neurological disorder which places a significant burden on people and society. Uncontrolled seizures severely impact a person’s independence and quality of life and place enormous costs on the healthcare system. In recognition of this challenge the province of Ontario in Canada developed a network of comprehensive epilepsy centers where people can be assessed for available epilepsy treatments including potentially curative epilepsy surgery. They also created and disseminated evidence based clinical guidelines to improve epilepsy care throughout the province. Although this was a significant achievement, unfortunately it wasn’t enough. There was still a need to train frontline health care providers to diagnose and treat epilepsy and also to recognise when to refer patients to a comprehensive epilepsy center.

Project ECHO [Extensions for Community Healthcare Outcomes] has been shown to be a creative answer to this knowledge translation gap. Project ECHO was conceptualized and developed in 2003 by Dr Sanjeev Arora in Albuquerque New Mexico, to increase the capacity for management of patients with hepatitis C throughout that state ( Arora et al 2011). Project ECHO® is an innovative model for medical education that uses ZOOM video-conferencing to connect specialist multidisciplinary teams at academic health centres to community healthcare providers (CHCPs). Using didactic and case-based learning, each ECHO session fosters knowledge among CHCPs that can be translated to the care of their patients. In this way, ECHO creates a knowledge network to move knowledge, instead of patients and expedites the timely delivery of care, where it’s needed.

From 2013 to 2016 the Ontario regionalized system of comprehensive epilepsy care was organized and operationalized by the Ontario Ministry of Health [MOH] in a remarkable partnership with epilepsy care providers, hospital administrators, community epilepsy agencies, and epilepsy patients and their families. Once the system was up and running the MOH, working with the same partners, moved to create Project ECHO Epilepsy across the Lifespan in order to translate best practices of epilepsy care being delivered in the Regional and District Epilepsy Centres in Ontario to front line health care providers throughout the Province [see https://oen.echoontario.ca/ . The ECHO model was seen as an ideal solution to address the needs of people living with epilepsy in Ontario, now even more relevant in 2020, because of the disruptions in chronic disease health care networks by COVID 19.

Project ECHO Epilepsy across the Lifespan uses the same ECHO model as developed by Dr. Arora, described above. It is a virtual, technology based, collaborative partnership between community health care providers and epilepsy specialists that utilizes case-based and didactic learning to enhance care for people living with epilepsy. The adult and pediatric curricula are delivered to community partners [spokes] by hub teams in Pediatric and Adult District or Regional Epilepsy centres across Ontario. Each interprofessional hub is composed of an epileptologist, epilepsy nurse practitioner, social worker, neuropsychologist, community agency representative, and pharmacist connected to the local hub. This whole MOH-funded Project ECHO Ontario: Epilepsy Across the Lifespan system is administered by a central hub, The Hospital for Sick Children in Toronto.

ECHO sessions are interactive, safe learning environments, where participants present patient cases, ask questions and share best practices. Attending ECHO enables health care providers to gain the skills necessary to manage epilepsy effectively and safely. ECHO sessions usually happen during lunch hour, once a week with access via smart device or laptop. They are open, free of charge to health providers in Ontario.

The goal of the project is to build capacity in the community to diagnose and manage epilepsy appropriately, as early as possible. This is in order to reduce unnecessary emergency visits or hospital referrals and life threatening events due to status epilepticus. Benefits of the program include caring for patients closer to home, improved outcomes, patient satisfaction and quality of life. Health care providers have the opportunity to learn about best practices in epilepsy care, including the curative option of epilepsy surgery.

The program has been now been running for 3 years and has received a high level of interest from community neurologists, pediatricians and family physicians. Two thirds of the participants were from these disciplines with the balance consisting of registered nurses, nurse practitioners, pharmacists, social workers, epilepsy educators and psychologists and other allied health professionals. Feedback has been encouraging, as there has been a significant positive change in knowledge, self-efficacy, comfort level, and practice with respect to epilepsy care amongst learners. Providers who presented cases also commented that there was an improvement in the severity or impact of their patient’s illness after implementing recommendations made during an ECHO session. Various types of epilepsy are increasingly recognized as genetic conditions with a significant proportion caused by pathogenic variants in single genes. These are detectable using next generation sequencing gene panels in 15-30% of people living with epilepsy. The Ontario MOH, continuing its partnership with epilepsy care providers throughout Ontario has just announced a new Ontario Epilepsy Genetics Testing Program (OEGTP). All epilepsy genetic testing, which until now has been sent out of country, will be repatriated and performed in the Division of Molecular Diagnostics at the London Health Science Centre in Ontario. In this way, evidence based epilepsy gene panels will be provided for carefully selected epilepsy patients in Ontario.   Physicians who are approved to order these genetic tests for epilepsy include epilepsy specialists and neurologists affiliated with the District and Regional Epilepsy Centres throughout Ontario, Neurologists in the Province with at least six months of training in epilepsy and EEG and geneticists. As well, Project ECHO Epilepsy across the lifespan will inform and educate additional care providers by providing a Continuing Medical Education (CME) certified epilepsy genetics curriculum to Family Doctors, Paediatricians and Community Neurologists . On completion of the course these CHCPs also will be approved by the MOH to order genetic testing for their epilepsy patients. The development and evolution of Project ECHO: Epilepsy across the lifespan in Ontario is illustrative of the breadth, depth, compelling nature, and flexibility of the Project ECHO model as applied to epilepsy knowledge translation. The ECHO model has demonstrated effectiveness in expanding knowledge, self-efficacy and practice change in the delivery of adult and pediatric epilepsy care in Ontario. ECHO shows great promise as a tool to demonopolize epilepsy knowledge and enhance the care of all patients with epilepsy in their own communities. Finally Ontario continues to advance its world leadership in epilepsy care, first with the development and funding of a provincial comprehensive care system, then the creation of Project ECHO: Epilepsy across the lifespan, and most recently the development of OEGTP and our new Project ECHO epilepsy genetics curriculum.


Kevin Jones and Carter Snead

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ICNA Updated March 28, 2021

Collaborative projects between ICNA and CNS continue to expand. These programs focus on improving infrastructure in different countries in Africa, the Caribbean and Latin America, and include donations of EEG machines, creation of safe EEG laboratories, long-term training of EEG technologies and creation of epilepsy surgery programs (El Salvador, Central America). These programs improved availability of neurodiagnostic tests and specialized surgeries, such as hemispherectomies, temporal lobectomies of implantation of VNS systems for children living in poor resource areas. The key to such initiatives is the ongoing development, support and sustainability through continued interaction with the centres. In collaboration with the CNS the ICNA intends to strengthen these programs to ensure that they become independent and ideally can widen their capacity to other local centres.

If you would like to help the ICNA in its mission and support its activities, you can make a donation to the activity/project of you choice Your contributions will help us change many lives.

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Adelina Soares Updated September 23, 2020

Pratibha SinghiWe are pleased to inform our ICNA members that, following our recent election, Prof. Pratibha Singhi has been elected as the next President Elect of ICNA.

Her 4-year term as ICNA President will be from the ICNA Congress in Oct. 2022 to 2026. We wish her our sincerest congratulations and strong support.

There were more votes cast in this election than in any prior ICNA election and both candidates received more votes than any previous presidential candidate.

Please join me in thanking both Prof. Pratibha Singhi and Prof. Charles Newton for running and congratulate them on their excellent showing internationally, reflecting the high esteem in which they are both held.

Ingrid Tein MD
Chair, Nominating Committee
The International Child Neurology Association