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1. The ESSTS (European Society for the Study of Tourette Syndrome) 2022 Criteria for Clinical Diagnosis of Functional Tic Like Behaviours (FTLBs): An international consensus from experts in tic disorders

Author

Pringsheim, T, Ganos, C, Nilles, C, Cavanna, A, Gilbert, D, Greenburg, E, Hartmann, A, Hedderly, T, Heyman, I, Liang, H, Malaty, I, Malik, O, Debes, N, Vahl, K, Munchau, A, Murphy, T, Nagy, P, Owen, T, Rizzo, R, Skov, L, Stern, J, Szejko, N, Worbe, Y, Martino, D, Pringsheim T, Ganos C, Nilles C, Cavanna A, Gilbert DL, Greenburg E, Hartmann A, Hedderly T, Heyman I, Liang H, Malaty I, Malik O, Debes NM, Vahl KM, Munchau A, Murphy T, Nagy P, Owen T, Rizzo R, Skov L, Stern J, Szejko N, Worbe Y, Martino D, Pringsheim, T, Ganos, C, Nilles, C, Cavanna, A, Gilbert, D, Greenburg, E, Hartmann, A, Hedderly, T, Heyman, I, Liang, H, Malaty, I, Malik, O, Debes, N, Vahl, K, Munchau, A, Murphy, T, Nagy, P, Owen, T, Rizzo, R, Skov, L, Stern, J, Szejko, N, Worbe, Y, Martino, D, Pringsheim T, Ganos C, Nilles C, Cavanna A, Gilbert DL, Greenburg E, Hartmann A, Hedderly T, Heyman I, Liang H, Malaty I, Malik O, Debes NM, Vahl KM, Munchau A, Murphy T, Nagy P, Owen T, Rizzo R, Skov L, Stern J, Szejko N, Worbe Y, and Martino D

Abstract

Background and purpose: In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic-like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic-like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition. Methods: We used a formal consensus development process, using a multiround, web-based Delphi survey. The survey was based on an in-person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting. Results: In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A clinically definite diagnosis of FTLBs can be confirmed by the presence of all three major criteria. A clinically probable diagnosis of FTLBs can be confirmed by the presence of two major criteria and one minor criterion. Conclusions: Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity.

Published
2023

4. European Clinical Guidelines for Tourette Syndrome and Other Tic Disorders – version 2.0. Part IV: Deep Brain Stimulation

Author

Szejko, N, Worbe, Y, Hartmann, A, Visser Vandewalle, V, Ackermans, L, Ganos, C, Porta, M, Leentjens, A, Mehrkens, J, Huys, D, Baldermann, J, Kuhn, J, Karachi, C, Delorme, C, Foltynie, T, Cavanna, A, Cath, D, Müller-Vahl, K, Szejko N, Worbe Y, Hartmann A, Visser Vandewalle V, Ackermans L, Ganos C, Porta M, Leentjens AFG, Mehrkens J-H, Huys D, Baldermann JC, Kuhn J, Karachi C, Delorme C, Foltynie T, Cavanna A, Cath D, Müller-Vahl K, Szejko, N, Worbe, Y, Hartmann, A, Visser Vandewalle, V, Ackermans, L, Ganos, C, Porta, M, Leentjens, A, Mehrkens, J, Huys, D, Baldermann, J, Kuhn, J, Karachi, C, Delorme, C, Foltynie, T, Cavanna, A, Cath, D, Müller-Vahl, K, Szejko N, Worbe Y, Hartmann A, Visser Vandewalle V, Ackermans L, Ganos C, Porta M, Leentjens AFG, Mehrkens J-H, Huys D, Baldermann JC, Kuhn J, Karachi C, Delorme C, Foltynie T, Cavanna A, Cath D, and Müller-Vahl K

Abstract

In 2011 the European Society for the Study of Tourette Syndrome (ESSTS) published its first European clinical guidelines for the treatment of Tourette Syndrome (TS) with part IV on deep brain stimulation (DBS). Here, we present a revised version of these guidelines with updated recommendations based on the current literature covering the last decade as well as a survey among ESSTS experts. Currently, data from the International Tourette DBS Registry and Database, two meta-analyses, and eight randomized controlled trials (RCTs) are available. Interpretation of outcomes is limited by small sample sizes and short follow-up periods. Compared to open uncontrolled case studies, RCTs report less favorable outcomes with conflicting results. This could be related to several different aspects including methodological issues, but also substantial placebo effects. These guidelines, therefore, not only present currently available data from open and controlled studies, but also include expert knowledge. Although the overall database has increased in size since 2011, definite conclusions regarding the efficacy and tolerability of DBS in TS are still open to debate. Therefore, we continue to consider DBS for TS as an experimental treatment that should be used only in carefully selected, severely affected and otherwise treatment-resistant patients.

Published
2022

5. European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: Pharmacological treatment

Author

Roessner, V, Eichele, H, Stern, J, Skov, L, Rizzo, R, Debes, N, Nagy, P, Cavanna, A, Termine, C, Ganos, C, Münchau, A, Szejko, N, Cath, D, Müller-Vahl, K, Verdellen, C, Hartmann, A, Rothenberger, A, Hoekstra, P, Plessen, K, Roessner V, Eichele H, Stern JS, Skov L, Rizzo R, Debes NM, Nagy P, Cavanna A, Termine C, Ganos C, Münchau A, Szejko N, Cath D, Müller-Vahl KR, Verdellen C, Hartmann A, Rothenberger A, Hoekstra PJ, Plessen KJ, Roessner, V, Eichele, H, Stern, J, Skov, L, Rizzo, R, Debes, N, Nagy, P, Cavanna, A, Termine, C, Ganos, C, Münchau, A, Szejko, N, Cath, D, Müller-Vahl, K, Verdellen, C, Hartmann, A, Rothenberger, A, Hoekstra, P, Plessen, K, Roessner V, Eichele H, Stern JS, Skov L, Rizzo R, Debes NM, Nagy P, Cavanna A, Termine C, Ganos C, Münchau A, Szejko N, Cath D, Müller-Vahl KR, Verdellen C, Hartmann A, Rothenberger A, Hoekstra PJ, and Plessen KJ

Abstract

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients’ self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient’s needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician’s preferences, experience, and local regulatory requirements.

Published
2022

6. Compulsive sexual behavior and paraphilic interests in adults with chronic tic disorders and Tourette syndrome: a survey-based study

Author

Kurvits, L, Tozdan, S, Mainka, T, Munchau, A, Muller-Vahl, K, Cavanna, A, Briken, P, Ganos, C, Muller-Vahl, KR, Cavanna, AE, Kurvits, L, Tozdan, S, Mainka, T, Munchau, A, Muller-Vahl, K, Cavanna, A, Briken, P, Ganos, C, Muller-Vahl, KR, and Cavanna, AE

Abstract

Early research suggested that compulsive sexual behavior (CSB) and paraphilic interests (PI) are more prevalent in adults with primary tic disorders compared to the general population. However, recent data on this topic remain scarce. We conducted an anonymous online survey capturing data on CSB and PI in adult patients with primary tic disorders. We also explored the role of antipsychotic tic medication and the impact of neuropsychiatric comorbidities like attention-deficit hyperactivity disorder and depression. In total, 62 participants (26 females/36 males) completed the survey. The prevalence of CSB and PI were 12.9% and 19.4%, respectively. There was no association with antipsychotic medication nor with symptoms of depression. However, the presence of attention-deficit hyperactivity disorder was associated with a higher prevalence of both CSB and PI. The current results contrast with earlier reports and show that in adults with primary tic disorders, the prevalence of CSB and PI is not overly prominent.

Published
2023

8. Nomenclature of Genetic Movement Disorders

Author

Lange, L.M., Gonzalez-Latapi, P., Rajalingam, R., Tijssen, Marina A. J., Ebrahimi-Fakhari, D., Gabbert, C., Ganos, C., Ghosh, R., Kumar, K.R., Lang, A.E., Rossi, M., Veen, S. ter, Warrenburg, B.P.C. van de, Warner, T., Lohmann, K., Klein, C., and Marras, C.

Subjects
Dystonia, Phenotype, Neurology, Parkinsonian Disorders, Dystonic Disorders, Humans, movement disorders, Parkinson Disease, genetics, nomenclature, Neurology (clinical), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract

Contains fulltext : 252096.pdf (Publisher’s version ) (Open Access) In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Published
2022
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12. Aggression Toward Others Misdiagnosed as Primary Tics

Author

Kurvits, L, Mainka, T, Cavanna, A, Kühn, A, Ganos, C, Kurvits L, Mainka T, Cavanna A, Kühn AA, Ganos C, Kurvits, L, Mainka, T, Cavanna, A, Kühn, A, Ganos, C, Kurvits L, Mainka T, Cavanna A, Kühn AA, and Ganos C

Abstract

Background: Tics describe a wide range of sudden and repetitive behaviors. Their multifaceted clinical features may resemble other explosive behaviors, including repetitive episodes of aggression toward others (allo-aggression) reported by subjects without tics. Here, we document 3 exemplary cases that help disentangle allo-aggressive behaviors from tics. Cases: We report 3 cases who presented with an array of complex repetitive behaviors, most notably allo-aggression (eg, sudden kicking, hitting, slapping and biting others, or pushing someone off a bike), which were misdiagnosed as primary tics. In all cases, additional symptoms, such as blackouts, feeling of being controlled by different personalities, or being empowered by repetitive behaviors, and examination pointed toward different neuropsychiatric diagnoses. Conclusions: Repetitive allo-aggressive behaviors are not part of the range of motor manifestations of tics. This observation not only has important medico-legal implications but is also relevant for the overall perception of Tourette syndrome and other primary tic disorders.

Published
2021

13. European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment

Author

Roessner, V., Eichele, H., Stern, J.S., Skov, L., Rizzo, R., Debes, N.M., Nagy, P., Cavanna, A.E., Termine, C., Ganos, C., Münchau, A., Szejko, N., Cath, D., Müller-Vahl, K.R., Verdellen, C., Hartmann, A., Rothenberger, A., Hoekstra, P.J., and Plessen, K.J.

Subjects
Adult, Attention Deficit Disorder with Hyperactivity/drug therapy, Child, Female, Guanfacine/therapeutic use, Humans, Male, Risperidone/therapeutic use, Tic Disorders/complications, Tic Disorders/drug therapy, Tourette Syndrome/complications, Tourette Syndrome/drug therapy, Medication, Pharmacotherapy, Tics, Tourette syndrome, Treatment
Abstract

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Published
2022

14. Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An Update

Author

Lange, L.M., Gonzalez-Latapi, P., Rajalingam, R., Tijssen, Marina A. J., Ebrahimi-Fakhari, D., Gabbert, C., Ganos, C., Ghosh, R., Kumar, K.R., Lang, A.E., Rossi, M., Veen, S. ter, Warrenburg, B.P.C. van de, Warner, T., Lohmann, K., Klein, C., Marras, C., Lange, L.M., Gonzalez-Latapi, P., Rajalingam, R., Tijssen, Marina A. J., Ebrahimi-Fakhari, D., Gabbert, C., Ganos, C., Ghosh, R., Kumar, K.R., Lang, A.E., Rossi, M., Veen, S. ter, Warrenburg, B.P.C. van de, Warner, T., Lohmann, K., Klein, C., and Marras, C.

Abstract

Contains fulltext : 252096.pdf (Publisher’s version ) (Open Access), In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Published
2022

15. Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration

Author

Paschou, P., Jin, Y., Müller-Vahl, K., Möller, H.E., Rizzo, R., Hoekstra, P.J., Roessner, V., Debes, N. Mol, Worbe, Y., Hartmann, A., Mir, P., Cath, D., Neuner, I., Eichele, H., Zhang, C, Lewandowska, K., Munchau, A., Verrel, J., Musil, R., Silk, T.J., Hanlon, C.A., Bihun, E.D., Brandt, V., Dietrich, A., Forde, N., Ganos, C., Greene, D.J., Chu, C., Grothe, M.J., Hershey, T., Janik, P., Koller, J.M., Martin-Rodriguez, J.F., Müller, K., Palmucci, S., Prato, A., Ramkiran, S., Saia, F., Szejko, N., Torrecuso, R., Tumer, Z., Uhlmann, A., Veselinovic, T., Wolańczyk, T., Zouki, J.J., Jain, P., Topaloudi, A., Kaka, M., Yang, Z, Drineas, P., Thomopoulos, S.I., White, T., Veltman, D.J., Schmaal, L., Stein, D.J., Buitelaar, J.K., Franke, B., Heuvel, O. van den, Jahanshad, N., Thompson, P.M., Black, K.J., Paschou, P., Jin, Y., Müller-Vahl, K., Möller, H.E., Rizzo, R., Hoekstra, P.J., Roessner, V., Debes, N. Mol, Worbe, Y., Hartmann, A., Mir, P., Cath, D., Neuner, I., Eichele, H., Zhang, C, Lewandowska, K., Munchau, A., Verrel, J., Musil, R., Silk, T.J., Hanlon, C.A., Bihun, E.D., Brandt, V., Dietrich, A., Forde, N., Ganos, C., Greene, D.J., Chu, C., Grothe, M.J., Hershey, T., Janik, P., Koller, J.M., Martin-Rodriguez, J.F., Müller, K., Palmucci, S., Prato, A., Ramkiran, S., Saia, F., Szejko, N., Torrecuso, R., Tumer, Z., Uhlmann, A., Veselinovic, T., Wolańczyk, T., Zouki, J.J., Jain, P., Topaloudi, A., Kaka, M., Yang, Z, Drineas, P., Thomopoulos, S.I., White, T., Veltman, D.J., Schmaal, L., Stein, D.J., Buitelaar, J.K., Franke, B., Heuvel, O. van den, Jahanshad, N., Thompson, P.M., and Black, K.J.

Abstract

Contains fulltext : 281802.pdf (Publisher’s version ) (Open Access), Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Published
2022

16. Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration

Author

Paschou, P, Jin, Y, Mueller-Vahl, K, Moeller, HE, Rizzo, R, Hoekstra, PJ, Roessner, V, Debes, NM, Worbe, Y, Hartmann, A, Mir, P, Cath, D, Neuner, I, Eichele, H, Zhang, C, Lewandowska, K, Munchau, A, Verrel, J, Musil, R, Silk, TJ, Hanlon, CA, Bihun, ED, Brandt, V, Dietrich, A, Forde, N, Ganos, C, Greene, DJ, Chu, C, Grothe, MJ, Hershey, T, Janik, P, Koller, JM, Francisco Martin-Rodriguez, J, Mueller, K, Palmucci, S, Prato, A, Ramkiran, S, Saia, F, Szejko, N, Torrecuso, R, Tumer, Z, Uhlmann, A, Veselinovic, T, Wolanczyk, T, Zouki, J-J, Jain, P, Topaloudi, A, Kaka, M, Yang, Z, Drineas, P, Thomopoulos, S, White, T, Veltman, DJ, Schmaal, L, Stein, DJ, Buitelaar, J, Franke, B, van den Heuvel, O, Jahanshad, N, Thompson, PM, Black, KJ, Paschou, P, Jin, Y, Mueller-Vahl, K, Moeller, HE, Rizzo, R, Hoekstra, PJ, Roessner, V, Debes, NM, Worbe, Y, Hartmann, A, Mir, P, Cath, D, Neuner, I, Eichele, H, Zhang, C, Lewandowska, K, Munchau, A, Verrel, J, Musil, R, Silk, TJ, Hanlon, CA, Bihun, ED, Brandt, V, Dietrich, A, Forde, N, Ganos, C, Greene, DJ, Chu, C, Grothe, MJ, Hershey, T, Janik, P, Koller, JM, Francisco Martin-Rodriguez, J, Mueller, K, Palmucci, S, Prato, A, Ramkiran, S, Saia, F, Szejko, N, Torrecuso, R, Tumer, Z, Uhlmann, A, Veselinovic, T, Wolanczyk, T, Zouki, J-J, Jain, P, Topaloudi, A, Kaka, M, Yang, Z, Drineas, P, Thomopoulos, S, White, T, Veltman, DJ, Schmaal, L, Stein, DJ, Buitelaar, J, Franke, B, van den Heuvel, O, Jahanshad, N, Thompson, PM, and Black, KJ

Abstract

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Published
2022

18. The cognitive neuropsychiatry of Tourette syndrome

Author

Cavanna, A, Ganos, C, Hartmann, A, Martino, D, Pringsheim, T, Seri, S, Cavanna A, Ganos C, Hartmann A, Martino D, Pringsheim T, Seri S, Cavanna, A, Ganos, C, Hartmann, A, Martino, D, Pringsheim, T, Seri, S, Cavanna A, Ganos C, Hartmann A, Martino D, Pringsheim T, and Seri S

Abstract

Introduction: Converging evidence from both clinical and experimental studies has shown that Tourette syndrome (TS) is not a unitary condition, but a cluster of multiple phenotypes, which encompass both tics and specific behavioural and cognitive symptoms (mainly attention-deficit and hyperactivity disorder and obsessive-compulsive disorder). Methods: We conducted a narrative review of the recent literature on the cognitive neuropsychiatry of TS. Results: Although clinical research has shown that TS is not associated with cognitive deficits per se, the findings of recent studies have suggested the presence of subtle alterations in specific cognitive functions. A promising line of research on imitative behaviour could provide a common background for the alterations in executive control and social cognition observed in TS. Two different (but not mutually exclusive) neurocognitive theories have recently suggested that TS could originate from altered perception-action binding and social decision-making dysfunction, respectively. Conclusions: Since the presence of behavioural comorbidities influences individualised treatment approaches, it is likely that a more precise characterisation of TS phenotypes, including cognitive aspects, will result in improved levels of care for patients with tic disorders.

Published
2020

30. Parkinsonʼs disease in GTP cyclohydrolase-1 mutation carriers: 156

Author

Mencacci, N. E., Isaias, I. U., Reich, M. M., Ganos, C., Plagnol, V., Polke, J. M., Bras, J., Stamelou, M., Noyce, A. J., Opladen, T., Münchau, A., Hodecker, S., Volkmann, J., Lees, A., Alegria, P., Lesage, S., Cormier, F., Brice, A., Heutink, P., Gasser, T., Pittman, A., Lubbe, S., Morris, H. R., Singleton, A., Hardy, J., Klebe, S., Bhatia, K. P., and Wood, N. W.

Published
2014

31. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

Published
2019
Full Text
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32. Chemical profile and biological properties of the endemic Turkish species Phyllocara aucheri

Author

Varvouni, E.-F. Zengin, G. Graikou, K. Ganos, C. Mroczek, T. Chinou, I.

Abstract

The aim of the present study is the phytochemical analysis of the aerial parts of Phyllocara aucheri (Boraginaceae), which is an endemic plant of Turkey. The phytochemical profile of the studied species was determined through LC-MS method. Sixteen secondary metabolites were identified, among which thirteen phenolic constituents, such as quercetin and kaempferol glycosides and caffeic acid derivatives, as well as three pyrrolizidine alkaloids (PAs) in the form of bases and N-oxides (PANOs) (europine, heliotrine and heliotrine N-oxide). The methanol extract of the aerial parts was assayed for its antioxidant properties, using free radical scavenging (DPPH•, ABTS•+), reducing power (FRAP, CUPRAC), phosphomolybdenum and metal chelating assays, while it has been also evaluated for in vitro enzyme inhibition against cholinesterases, α-amylase and α-glucosidase, exhibiting an interesting biological profile. © 2020

Published
2021

33. Worldwide barriers to genetic testing for movement disorders

Author

Gatto, E. M., Walker, R. H., Gonzalez, C., Cesarini, M., Cossu, G., Stephen, C. D., Balint, B., Rodriguez-Violante, M., Jankovic, J., Morgante, F., Jinnah, H. A., Albanese, A., Amorin, I., Bhatia, K., Brandabur, M., Canals, F., Cardoso, F., Cardozo, A., Carvalho, V., Chade, A., Chana, P., Darling, A., Correia Guedes, L., De la Cerda, A., de Koning-Tijssen, M., Della Coletta, M. V., Duquette, A., Espay, A., Etcheverry, J., Ferreira, J., Friedman, J., Fung, V., Ganos, C., Ruiz, P. G., Gershanik, O., Gross, K. B. V., Han-Joon, K., Kaji, R., Kotschet, K., Rosa, A. L. D., Litvan, I., Lubarr, N., Marano, M., Josep Marti, M., Martinez Ramirez, D., Miyasaki, J., Munchau, A., Chesta, D. M., Pal, P., Peralta, M. C., Phielipp, N., Maria Riboldi, G., Oroz, M. C. R., Rodriguez-Porcel, F., Sarva, H., Schoels, L., Stamelou, M., and Uribe Roca, C.

Subjects
Asia, Movement disorders, Disease, Limited access, Middle East, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Genetic Testing, 030212 general & internal medicine, Public funding, Genetic testing, Dystonia, Movement Disorders, medicine.diagnostic_test, business.industry, Chorea, medicine.disease, Europe, Neurology, Neurology (clinical), medicine.symptom, business, chorea, dystonia, genetic and inherited disorders, genetic diagnosis, genetic testing, movement disorders, Parkinson's disease, whole exome sequencing, 030217 neurology & neurosurgery, Demography
Abstract

Author(s): Gatto, Emilia M; Walker, Ruth H; Gonzalez, Claudio; Cesarini, Martin; Cossu, Giovanni; Stephen, Christopher D; Balint, Bettina; Rodriguez-Violante, Mayela; Jankovic, Joseph; Morgante, Francesca; Jinnah, Hyder A; Rare Movement Disorders Study Group of the International Parkinson Disease, Movement Disorders Society | Abstract: Background and purposeDespite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization.MethodsThe Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members.ResultsSurvey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe.ConclusionsThis survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Published
2021

34. Volatiles from selected apiaceae species cultivated in poland-antimicrobial activities

Author

Widelski, J. Graikou, K. Ganos, C. Skalicka-Wozniak, K. Chinou, I.

Subjects
food and beverages
Abstract

As part of our ongoing research on phytoconstituents that can act as promising antimicrobial agents, the essential oils of nine selected Apiaceae plants, cultivated in Poland, were studied. The volatiles of the aerial parts with fruits (herba cum fructi) of Silaum silaus, Seseli devenyense, Seseli libanotis, Ferula assa-foetida, Glehnia littoralis and Heracleum dulce, in addition to the fruits (fructi) of Torilis japonica and Orlaya grandiflora as well as of the aerial parts (herba) of Peucedanum luxurians were investigated through Gas Chromatography-Mass Spectrometry to identify more than 60 different metabolites. The essential oils from S. devenyense, H. dulce, T. japonica and P. luxurians are reported for the first time. All examined species were also assayed for their antimicrobial activities against several human pathogenic Gram-positive and -negative bacteria and fungi. The species H. dulce, S. devenyense and S. libanotis exerted the strongest antimicrobial activity, mostly against Gram-positive bacteria strains (MIC values 0.90-1.20 mg/mL). To the best of our knowledge, this is the first attempt to determine the antimicrobial activity of the above Apiaceae species. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2021

35. Chemical profile and screening of bioactive metabolites of rindera graeca (A. dc.) bois. & heldr. (boraginaceae) in vitro cultures

Author

Graikou, K. Damianakos, H. Ganos, C. Sykłowska‐baranek, K. Jeziorek, M. Pietrosiuk, A. Roussakis, C. Chinou, I.

Abstract

Rindera graeca is a rare endemic plant where in vitro culture has been used in order to investigate bioactive metabolites. Phytochemical study of the in vitro shoots and hairy roots led to the isolation of seven phenolic derivatives and the unusual furano‐naphthoquinone rinderol. R. graeca was also analyzed for its pyrrolizidine alkaloids content by LC‐MS, and it was found to contain echinatine together with echinatine and rinderine N‐oxides. Rinderol, isolated only from in vitro hairy root culture for the first time in the genus, revealed promising bioactivities. It was evaluated in vitro against a panel of microorganisms, showing very strong activity specifically against Gram‐positive bacteria (MIC values 0.98 × 10−2–1.18 μg/mL) as well as very interesting antiproliferative effect against the human non‐small‐cell bronchopulmonary carcinoma cell line NSCLC‐N6‐L16 and the epidermoid lung cancer cell line A549. These findings were compared with the chemical profile of the plant from nature, while this study is the first to report on the effects of R. graeca extracts obtained from in vitro culture, providing a valuable contribution to the scientific community towards this sustainable method of production of potential bioactive molecules. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2021

37. Pimpinella anisum seeds essential oil from Lesvos island: Effect of hydrodistillation time, comparison of its aromatic profile with other samples of the Greek market. Safe use

Author

Anastasopoulou, E. Graikou, K. Ganos, C. Calapai, G. Chinou, I.

Abstract

The essential oil of Pimpinella anisum L. (Apiaceae) seeds from Lesvos Island (Greece), famous as flavor for the production of the aperitif “ouzo”, has been analyzed by GC-MS for the first time. Additionally, three samples of the Greek market originated from North and Central Greece (Thessaly, Viotia) and Turkey, were also analyzed and all of them were compared to the quality limits given in European Pharmacopoeia for medicinal purposes. The effect of hydrodistillation time found to be very important as the results showed differentiations of the oil yield and the chemical content. The most abundant identified metabolites were trans-anethole, γ-himachalene, estragole and pseudoisoeugenyl 2-methylbutyrate. It is noteworthy, that Lesvos anise oil showed the best quality according to European Pharmacopoeia's standards, while it had the highest yield and the richest chemical composition (28 identified compounds) among all studied samples, contributing to the well known quality of “ouzo” from Plomari. Furthermore, two major secondary metabolites from Lesvos' anise oil: trans-anethole and a mixture of himachalenes have been isolated and structurally determined. Moreover, the safe use of anise oil is discussed due to potential toxic effects of estragole. © 2019 Elsevier Ltd

Published
2020

38. Phytochemical analysis and biological evaluation of the aerial parts from Symphytum anatolicum Boiss. and Cynoglottis barrelieri (All.) Vural & Kit Tan (Boraginaceae)

Author

Varvouni, E.-F. Zengin, G. Graikou, K. Ganos, C. Mroczek, T. Chinou, I.

Subjects
food and beverages
Abstract

The present study is focused on the phytochemical analysis of the aerial parts of Symphytum anatolicum and Cynoglottis barrelieri (Boraginaceae). Their methanol extracts were subjected to qualitative LC-MS analysis, sixteen secondary metabolites have been identified from S. anatolicum and eighteen from C. barrelieri, respectively. Sixteen among all are phenolic derivatives (phenolic acids and flavonoids) and six belong to pyrrolizidine alkaloids (PAs) in the form of bases and/or N-oxides (PANOs). The observed chemical profiles are discussed chemotaxonomically as both species share the same tribe Boragineae. Caffeic acid and its derivatives together with quercetin- and kaempferol-glucosides were among the common metabolites, as they were identified in both studied plant species. Furthermore, their total phenolic and flavonoid contents were determined. Antioxidant capacity was evaluated by different chemical assays, together with their in vitro enzyme inhibitory properties towards cholinesterases (AChE and BChE), α-amylase and α-glucosidase. The results showed that C. barrelieri exhibited strong antioxidant activity, while S. anatolicum displayed good enzyme inhibitory effects contributing to a very interesting profile for further applications. © 2020 Elsevier Ltd

Published
2020

39. Rindera graeca (boraginaceae) phytochemical profile and biological activities

Author

Ganos, C. Aligiannis, N. Chinou, I. Naziris, N. Chountoulesi, M. Mroczek, T. Graikou, K.

Abstract

Rindera graeca is a Greek endemic plant of the Boraginaceae family which has never been studied before. Consequently, this study attempted to phytochemically examine the aerial parts of this species. Nine phenolic secondary metabolites were identified, consisting of seven caffeic acid derivatives and two flavonol glucosides, namely rutin and quercetin-3-rutinoside-7-rhamnoside. These flavonoids, together with rosmarinic acid, were isolated via column chromatography and structurally determined through spectral analysis. Quercetin-3-rutinoside-7-rhamnoside is an unusual triglycoside, which is identified for the first time in Rindera genus and among Boraginaceae plants. This metabolite was further examined with thermal analysis and its 3D structure was simulated, revealing some intriguing information on its interaction with biological membrane models, which might have potential applications in microcirculation-related conditions. R. graeca was also analyzed for its pyrrolizidine alkaloids content, and it was found to contain echinatine together with echinatine N-oxide and rinderine N-oxide. Additionally, the total phenolic and flavonoid contents of R. graeca methanol extract were determined, along with free radical inhibition assays. High total phenolic content and almost complete inhibition at experimental doses at the free radical assays indicate a potent antioxidant profile for this plant. Overall, through phytochemical analysis and biological activity assays, insight was gained on an endemic Greek species of the little-studied Rindera genus, while its potential for further applications has been assessed. © 2020 by the authors.

Published
2020

40. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, R.T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., Rootselaar, A.F. van, Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J.F., Delpu, Y., Avarello, M.D.M., Vijfhuizen, L.S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P.S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S.F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I.E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., LeGuern, E., Klein, K.M., Labauge, P., Bennett, M.F., Bahlo, M., Gecz, J., Corbett, M.A., Tijssen, M.A.J., Maagdenberg, A.M.J.M. van den, Depienne, C., and FAME Consortium

Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019

41. Identification of symbol digit modality test score extremes in Huntington's disease

Author

Braisch, U, Muche, R, Rothenbacher, D, Landwehrmeyer, GB, Long, JD, Bentivoglio, AR, Biunno, I, Bonelli, RM, Dunnett, SB, Illmann, T, Levey, J, Ramos-Arroyo, M, Nielsen, JE, Paivarinta, M, Sebastian, AR, Tabrizi, SJ, Vandenberghe, W, Uhrova, T, Come, A, Garde, MB, Betz, S, Capodarca, S, Wildson, SC, da Silva, V, Di Renzo, M, Finisterra, M, Genoves, C, Gilling, M, Handley, OJ, Hvalstedt, C, Koppers, K, Lamanna, C, Laura, M, Descals, AM, Monza, D, Mutze, L, Oehmen, M, Padieu, H, Paterski, L, Koivisto, SP, Rindal, B, Roren, N, Sasinkova, P, Seliverstov, Y, Timewell, E, Cubillo, PT, van Walsem, MR, Witjes-Ane, MN, Yudina, E, Zielonka, E, Zinzi, P, Braunwarth, EM, Brugger, F, Buratti, L, Hametner, EM, Hepperger, C, Holas, C, Hotter, A, Hussl, A, Larcher, B, Mahlknecht, P, Muller, C, Pinter, B, Poewe, W, Seppi, K, Sprenger, F, Wenning, G, Dupuis, M, Minet, C, Ribai, P, Van Paemel, D, Verellen-Dumoulin, C, Klempir, J, Majerova, V, Roth, J, Babiloni, B, Debruxelles, S, Duche, C, Goizet, C, Jameau, L, Lafoucriere, D, Spampinato, U, Bachoud-Levi, AC, Boisse, MF, de Langavant, LC, Lemoine, L, Morgado, G, Youssov, K, Annic, A, Barthelemy, R, De Bruycker, C, Cabaret, M, Carette, AS, Carriere, N, Decorte, E, Defebvre, L, Delliaux, M, Delval, A, Depelchin, A, Destee, A, Dewulf-Pasz, N, Dondaine, T, Dugauquier, F, Dujardin, K, Lemaire, MH, Manouvrier, S, Peter, M, Plomhause, L, Sablonniere, B, Simonin, C, Tard, C, Thibault-Tanchou, S, Vuillaume, I, Bellonet, M, Benoit, A, Blin, S, Courtin, F, Duru, C, Fasquel, V, Godefroy, O, Krystkowiak, P, Mantaux, B, Roussel, M, Tir, M, Schuler, B, Wannepain, S, Azulay, JP, Chabot, C, Delfini, M, Eusebio, A, Fluchere, F, Grosjean, H, Mundler, L, Nowak, M, Bioux, S, Bliaux, E, Girard, C, Guyant-Marechal, L, Hannequin, D, Hannier, V, Jourdain, S, Maltete, D, Pouliquen, D, Blondeau, L, Calvas, F, Cheriet, S, Delabaere, H, Demonet, JF, Pariente, J, Pierre, M, Beuth, M, Gelderblom, H, Priller, J, Pruss, H, Spruth, E, Thiel, S, Ellrichmannberlin, G, Herrmann, L, Hoffmann, R, Kaminski, B, Saft, C, Bosredon, C, Hunger, U, Lohle, M, Maass, A, Ossig, C, Schmidt, S, Storch, A, Wolz, A, Wolz, M, Kohl, Z, Kozay, C, Ullah, J, Winkler, J, Bergmann, U, Boringer, R, Capetian, P, Kammel, G, Lambeck, J, Meier, S, Rijntjes, M, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Heinicke, W, Hidding, U, Munchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Francis, F, Gayde-Stephan, S, Gorzolla, H, Kramer, B, Minschke, R, Schrader, C, Tacik, P, Longinus, B, Lusebrink, A, Muhlau, M, Peinemann, A, Stadtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bechtel, N, Beckmann, H, Bohlen, S, Gopfert, N, Holzner, E, Lange, H, Reilmann, R, Rohm, S, Rumpf, S, Sass, C, Schepers, S, Weber, N, Barth, K, Buck, A, Connemann, J, Ecker, D, Geitner, C, Held, C, Kesse, A, Landwehrmeyer, B, Lezius, F, Lewerenz, J, Nepper, S, Niess, A, Orth, M, Schneider, A, Schwenk, D, Sussmuth, S, Trautmann, S, Weydt, P, Klebe, S, Musacchio, T, Leypold, C, Noth, K, Cormio, C, de Tommaso, M, Franco, G, Sciruicchio, V, Serpino, C, Calandra-Buonaura, G, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Sambati, L, Scaglione, C, Maserati, MS, Agosti, C, Barlati, S, Compostella, S, Marchina, E, Padovani, A, Bertini, E, Ghelli, E, Ginestroni, A, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, AM, Sorbi, S, Abbruzzese, G, di Poggio, MB, Ferrandes, G, Mandich, P, Marchese, R, Tamburini, T, Baake, V, van den Bogaard, SJA, Bos, R, Dumas, EM, t'Hart, EP, Kampstra, A, Roos, RAC, Schoonderbeek, A, Aaserud, O, Bjorgo, K, Borgeod, N, Dramstad, E, Fannemel, M, Frich, JC, Gorvell, PF, Heiberg, A, Lorentzen, E, Retterstol, L, Rosby, O, Sikiric, A, Stokke, B, van Walsem, M, Wehus, R, Bjornevoll, I, Sando, SB, Haug, MG, Storseth, HH, Arntsen, V, Dziadkiewicz, A, Konkel, A, Narozanska, E, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Arkuszewski, M, Blaszczyk, M, Boczarska-Jedynak, M, Ciach-Wysocka, E, Gorzkowska, A, Nska-Myga, BJ, Kaczmarczyk, A, Klodowska-Duda, G, Opala, G, Stompel, D, Banaszkiewicz, K, Bocwinska, D, Bojakowska-Jaremek, K, Dec, M, Grabska, N, Krawczyk, GM, Kubowicz, E, Malec-Litwinowicz, M, Rudzinska, M, Stenwak, A, Szczudlik, A, Szczygiel, E, Wojcik, M, Wasielewska, A, Bryl, JAA, Ciesielska, A, Klimberg, A, Marcinkowski, J, Samara, H, Sempolowicz, J, Sniewski, BW, Zielonka, D, Gogol, A, Janik, P, Jamrozik, Z, Kaminska, A, Kwiecinski, H, Antczak, J, Jachinska, K, Krysa, W, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz-Jarosz, H, Stepniak, I, Sulek, A, Witkowski, G, Zaremba, J, Zdzienicka, E, Ziora-Jakutowicz, K, Januario, C, Julio, F, Guedes, LC, Coelho, M, Finisterra, AM, Ferreira, JJ, Mestre, T, Mendes, T, Rosa, MM, Valadas, A, Kopishinskaya, S, Korotysh, M, Herrera, CD, Moreno, PG, Bas, J, Busquets, N, Calopa, M, Classen, SJ, Dedicha, NR, Buongiorno, MT, Maria, ADS, Munoz, E, Santacruz, P, Barbera, MA, Pardo, SA, Guia, DB, Calzado, N, Hernanz, LC, Diaz-Zorita, JPT, Catena, JL, Ferrer, PQ, Carruesco, GT, Robert, MF, Viladrich, CM, Roca, E, Idiago, JMR, Riballo, AV, Campolongo, A, de Bobadilla, RF, Bojarsky, JK, Martinez-Horta, S, Pagonabarraga, J, Perez, JP, Ribosa, R, Villa, C, Gil, MAA, Corrales, KB, Esteban, JCG, Gonzalez, A, Merino, BT, Cubo, E, Polo, CG, Mariscal, N, Romero, SG, Arbelo, JM, de Molina, RM, Martin, I, Perianez, JM, Udaeta, B, Alonso-Frech, F, Frades, B, Villanueva, MA, Sevilla, MAZ, Frech, FA, Fenollar, MD, Garcia, RGR, Villanueva, C, Bascunana, M, Ventura, MF, Ribas, GG, de Yebenes, JG, Moreno, JLLS, Barral, VM, Ruiz, PJG, Garcia, A, Lopez, RG, Barcenas, AH, Martinez-Descals, A, Martin, VP, Martinez, NR, Artiga, MJS, Sanchez, V, Pueyo, A, Gonzalez, S, Guisasola, LM, Ribacoba, MPPR, Salvador, C, Lozano, PS, Caldentey, JG, Ramirez, IL, Arques, PN, Lopera, MR, Pastor, BV, Gaston, I, Garcia-Amigot, F, Martinez-Jaurrieta, MD, Ramos-Arroyo, MA, Carrillo, F, Redondo, MTC, Mir, P, Gonzalez, LV, Moreno, JMG, Lucena, CM, Pena, JC, Redondo, L, Sanchez, VS, Fernandez, CM, Mata, MP, Lemos, MDR, Bosca, M, Burguera, JA, Vilaplana, FCBCP, Solis, P, Figuerola, BJ, Palanca, PM, Berglund, P, Constantinescu, R, Fredlund, G, Hosterey-Ugander, U, Linnsand, P, Neleborn-Lingefjard, L, Wahlstrom, J, Palhagen, S, Svenningsson, P, Paucar, M, Wallden, T, Ekwall, C, Goller, ML, Sundblom, J, Stebler, Y, Kaelin, A, Romero, I, Schupbach, M, Zaugg, SW, Jung, H, Petersen, J, Auer, M, Mihaylova, V, Vernon, N, Akhtar, S, Crooks, J, Curtis, A, de Souza, J, Piedad, J, Rickards, H, Wright, J, Pallett, A, Coulthard, E, Gethin, L, Hayward, B, Sieradzan, K, Wright, A, Busse, M, Butcher, C, Dunnett, S, Clenaghan, C, Hunt, S, Jones, L, Jones, U, Khalil, H, Minster, S, Owen, M, Price, K, Townhill, J, Rosser, A, Edwards, M, Ho, C, McGill, M, Porteous, M, Pearson, P, Harrower, T, Irvine, S, Brockie, P, Foster, J, Johns, N, McKenzie, S, Rothery, J, Thomas, G, Yates, S, Deith, C, Ireland, J, Ritchie, S, Andrew, A, Frost, J, Noad, R, Cosgrove, J, Gallantree, D, Hamer, S, Hobson, E, Jamieson, S, Kraus, A, Longthorpe, M, Markova, I, Musgrave, H, Peacy, C, Raman, A, Rowett, L, Toscano, J, Wild, S, Yardumian, P, Clayton, C, Dipple, H, Freire-Patino, D, Hallam, C, Middleton, J, Alusi, S, Davies, R, Foy, K, Gerrans, E, Leggett, H, Pate, L, Anjum, U, Coebergh, J, Eddy, C, McEntagart, M, Patton, M, Peterson, M, Rose, S, Andrews, T, Brown, S, Bruno, S, Doherty, K, Golding, C, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Arran, N, Bek, J, Callaghan, J, Craufurd, D, Fullam, R, Howard, L, Huson, S, Johnson, L, Jones, M, Krishnamoorthy, A, Murphy, H, Oughton, E, Partington-Jones, L, Rogers, D, Sollom, A, Snowden, J, Stopford, C, Thompson, J, Tinkler, P, Trender-Gerhard, I, Verstraelen, N, Westmoreland, L, Cass, G, Davidson, L, Davison, J, Fullerton, N, Holmes, K, Komati, S, McDonnell, S, Mohammed, Z, Morgan, K, Savage, L, Singh, B, Wood, J, Chu, E, Knight, C, O'Neill, M, Das Purkayastha, D, Nemeth, AH, Siuda, G, Valentine, R, Dixon, K, Armstrong, R, Harrison, D, Hughes, M, Large, S, Donovan, JO, Palmer, A, Parkinson, A, Soltysiak, B, Timings, L, Williams, J, Burn, J, Weekes, R, Craven, J, Bailey, W, Coleman, C, Haig-Brown, D, Simpson, S, Hare, M, Majeed, T, Bandmann, O, Bradbury, A, Fairtlough, H, Fillingham, K, Foustanos, I, Gill, P, Kazoka, M, Nevitt, L, Peppa, N, Quarrell, O, Taylor, C, Tidswell, K, O'Donovan, K, Agarwal, V, Anderson, M, Gunner, K, Harris, K, Hayward, E, Heywood, M, Keys, L, Kipps, C, MacKinnon, L, Smalley, S, Gowers, L, Powell, K, Bethwaite, P, Edwards, R, Fuller, K, Phillips, M, Tan, L, Burgunder, JM, Lau, PN, Pica, E, Shoulson, I, Gusella, JG, Antonijevic, I, vankammen, D, Foroud, T, Warner, J, Giuliano, J, Vetter, L, Marshall, F, Marder, K, Frucht, S, Moskowitz, C, Clouse, R, Wasserman, P, Shannon, K, Jaglin, J, Jankovic, J, Palao, A, Harrison, M, Singer, C, Quesada, M, Hersch, S, Rosas, D, Tanev, K, Malarick, K, Colcher, A, Sanchez-Ramos, J, Kostyk, S, Paulsen, J, Perlmutter, J, Tabbal, S, Ross, C, Dorsey, R, Nucifora, F, Dubinsky, R, Dubinsky, H, Suchowersky, O, Klimek, ML, Jones, R, Morgan, J, Mohlo, E, Kang, U, Agarwal, P, Factor, S, Jennings, D, Higgins, D, Adams, J, Frank, S, Saint-Hilaire, M, Diggin, M, Furtado, S, Walker, F, O'Neill, C, Quaid, K, LeDoux, M, Raymond, L, Leavitt, B, Decolongon, J, Perlman, S, Peavy, G, Goldstein, J, Kumar, R, McCusker, E, Griffith, J, Loy, C, Wheelock, V, Tempkin, T, Martin, A, Nance, M, Mallonee, W, Suter, G, Revilla, F, Gartner, M, Drazinic, C, Fitzpatrick, MJ, Panisset, M, Duff, K, Scott, B, Weiner, W, Robottom, B, Chiu, E, Yastrubetskaya, O, Churchyard, A, Greenamyre, TJ, Oakes, D, Beck, C, Robertson, S, Eaton, K, Lindsay, P, Deuel, L, MacDonald, M, Hickey, C, Muratori, L, Leserman, A, Doucette, N, Uc, E, Rodnitzky, R, Vik, S, Davis, R, Dietrich, S, Segro, V, Erickson, D, Hunt, V, Lucarelli, N, Broyles, J, Delarosa, J, Louis, E, Panegyres, P, Schmidt, A, Barton, S, Sperin, E, Testa, C, Thiede, F, Zauber, SE, McInnis, R, Welsh, C, Wesson, M, Coleman, A, and European Commission

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, COHORT, Cox hazard model, quantile regression, REGISTRY, symbol digit modalities test, Genotype, Neuropsychological Tests, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cognition, 0302 clinical medicine, Huntington's disease, Rating scale, mental disorders, medicine, Humans, Verbal fluency test, Longitudinal Studies, Genetics (clinical), Proportional Hazards Models, 030304 developmental biology, 0303 health sciences, Proportional hazards model, business.industry, Reproducibility of Results, Middle Aged, medicine.disease, nervous system diseases, Psychiatry and Mental health, Huntington Disease, Phenotype, Test score, Cohort, Disease Progression, Female, Observational study, business, 030217 neurology & neurosurgery, Stroop effect, Clinical psychology
Abstract

REGISTRY Investigators of the European Huntington's Disease Network and COHORT Investigators of the Huntington Study Group., Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers., This work was in part funded by a grant from the EuropeanCommission under the 7th framework programme (RD-Connect, grantagreement number 305444).

Published
2019
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42. Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Author

Traschütz, A., Schirinzi, T., Laugwitz, L., Murray, N.H., Bingman, C.A., Reich, S., Kern, J., Heinzmann, A., Vasco, G., Bertini, E., Zanni, G., Durr, A., Magri, S., Taroni, F., Malandrini, A., Baets, J., Jonghe, P. De, Ridder, W. De, Bereau, M., Demuth, S., Ganos, C., Basak, A.N., Hanagasi, H., Kurul, S.H., Bender, B., Schöls, L., Grasshoff, U., Klopstock, T., Horvath, R., Warrenburg, B.P.C. van de, Burglen, L., Rougeot, C., Ewenczyk, C., Koenig, M., Santorelli, F.M., Anheim, M., Munhoz, R.P., Haack, T., Distelmaier, F., Pagliarini, D.J., Puccio, H., Synofzik, M., Traschütz, A., Schirinzi, T., Laugwitz, L., Murray, N.H., Bingman, C.A., Reich, S., Kern, J., Heinzmann, A., Vasco, G., Bertini, E., Zanni, G., Durr, A., Magri, S., Taroni, F., Malandrini, A., Baets, J., Jonghe, P. De, Ridder, W. De, Bereau, M., Demuth, S., Ganos, C., Basak, A.N., Hanagasi, H., Kurul, S.H., Bender, B., Schöls, L., Grasshoff, U., Klopstock, T., Horvath, R., Warrenburg, B.P.C. van de, Burglen, L., Rougeot, C., Ewenczyk, C., Koenig, M., Santorelli, F.M., Anheim, M., Munhoz, R.P., Haack, T., Distelmaier, F., Pagliarini, D.J., Puccio, H., and Synofzik, M.

Abstract

Contains fulltext : 229734.pdf (Publisher’s version ) (Open Access), OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263.

Published
2020

43. Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

Author

Andelman-Gur, MM, Leventer, RJ, Hujirat, M, Ganos, C, Yosovich, K, Carmi, N, Lev, D, Nissenkorn, A, Dobyns, WB, Bhatia, K, Lerman-Sagie, T, Blumkin, L, Andelman-Gur, MM, Leventer, RJ, Hujirat, M, Ganos, C, Yosovich, K, Carmi, N, Lev, D, Nissenkorn, A, Dobyns, WB, Bhatia, K, Lerman-Sagie, T, and Blumkin, L

Abstract

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Published
2020

44. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, RT, Kraft, F, Leitao, E, Kaya, S, Klebe, S, Magnin, E, van Rootselaar, A-F, Buratti, J, Kuehnel, T, Schroeder, C, Giesselmann, S, Tschernoster, N, Altmueller, J, lamiral, A, Keren, B, Nava, C, Bouteiller, D, Forlani, S, Jornea, L, Kubica, R, Ye, T, Plassard, D, Jost, B, Meyer, V, Deleuze, J-F, Delpu, Y, Avarello, MDM, Vijfhuizen, LS, Rudolf, G, Hirsch, E, Kroes, T, Reif, PS, Rosenow, F, Ganos, C, Vidailhet, M, Thivard, L, Mathieu, A, Bourgeron, T, Kurth, I, Rafehi, H, Steenpass, L, Horsthemke, B, Berkovic, SF, Bisulli, F, Brancati, F, Canafoglia, L, Casari, G, Guerrini, R, Ishiura, H, Licchetta, L, Mei, D, Pippucci, T, Sadleir, L, Scheffer, IE, Striano, P, Tinuper, P, Tsuji, S, Zara, F, LeGuern, E, Klein, KM, Labauge, P, Bennett, MF, Bahlo, M, Gecz, J, Corbett, MA, Tijssen, MAJ, van den Maagdenberg, AMJM, Depienne, C, Florian, RT, Kraft, F, Leitao, E, Kaya, S, Klebe, S, Magnin, E, van Rootselaar, A-F, Buratti, J, Kuehnel, T, Schroeder, C, Giesselmann, S, Tschernoster, N, Altmueller, J, lamiral, A, Keren, B, Nava, C, Bouteiller, D, Forlani, S, Jornea, L, Kubica, R, Ye, T, Plassard, D, Jost, B, Meyer, V, Deleuze, J-F, Delpu, Y, Avarello, MDM, Vijfhuizen, LS, Rudolf, G, Hirsch, E, Kroes, T, Reif, PS, Rosenow, F, Ganos, C, Vidailhet, M, Thivard, L, Mathieu, A, Bourgeron, T, Kurth, I, Rafehi, H, Steenpass, L, Horsthemke, B, Berkovic, SF, Bisulli, F, Brancati, F, Canafoglia, L, Casari, G, Guerrini, R, Ishiura, H, Licchetta, L, Mei, D, Pippucci, T, Sadleir, L, Scheffer, IE, Striano, P, Tinuper, P, Tsuji, S, Zara, F, LeGuern, E, Klein, KM, Labauge, P, Bennett, MF, Bahlo, M, Gecz, J, Corbett, MA, Tijssen, MAJ, van den Maagdenberg, AMJM, and Depienne, C

Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019

45. Suicidal ideation in a European Huntington's disease population

Author

Hubers, Aa, van Duijn, E, Roos, Ra, Craufurd, D, Rickards, H, Bernhard Landwehrmeyer, G, van der Mast RC, Giltay, Ej, Bachoud Lévi AC, Bentivoglio, Ar, Biunno, I, Bonelli, Rm, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Llmann, Ti, Landwehrmeyer, Gb, Levey, J, Ramos Arroyo MA, Nielsen, Je, Prokoivisto, S, Päivärinta, M, Rojo Sebastián, A, Tabrizi, Sj, Vandenberghe, W, Verellen Dumoulin, C, Zaremba, J, Uhrova, T, Wahlström, J, Barth, K, Correia Guedes, L, Finisterra, Am, Garde, Mb, Bos, R, Betz, S, Callaghan, J, Fullam, R, Ecker, D, Nielsen, Mg, Hvalstedt, C, Held, C, Koppers, K, Laurà, M, Horta, Sm, Descals, Am, Mestre, T, Minster, S, Monza, D, Mütze, L, Oehmen, M, Townhill, J, Orth, M, Padieu, H, Paterski, L, Peppa, N, Pro Koivisto, S, Roedig, V, Rialland, A, Røren, N, Šašinková, P, Seliverstov, Y, Cubillo, Pt, Walsem, Mr, Wright, A, da Silva WV, Witjes Ané MN, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Herranhof, B, Holl, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinger, K, Scheibl, M, Hecht, K, Lilek, S, Müller, N, Schöggl, H, Ullah, J, Brugger, F, Hepperger, C, Hotter, A, Seppi, K, Wenning, G, Buratti, L, Hametner, Em, Holas, C, Hussl, A, Poewe, W, Braunwarth, Em, Sprenger, F, Müller, C, Sinadinosa, D, Walleczek, Am, Ladurner, G, Staffen, W, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempíř, J, Majerová, V, Roth, J, Hartikainen, P, Hiivola, H, Martikainen, K, Tuuha, K, Ignatius, J, Kärppä, M, Åman, J, Mustonen, A, Kajula, O, Santala, M, Allain, P, Guérid, Ma, Gohier, B, Olivier, A, Prundean, A, Scherer Gagou, C, Verny, C, Bost, M, Babiloni, B, Debruxelles, S, Duché, C, Goizet, C, Lafoucrière, D, Jameau, L, Spampinato, U, De Bruycker, C, Cabaret, M, Carette, As, Defebvre, L, Decorte, E, Delval, A, Delliaux, M, Destee, A, Dujardin, K, Peter, M, Plomhouse, L, Sablonnière, B, Simonin, C, Lemaire, Mh, Manouvrier, S, Thibault Tanchou, S, Vuillaume, I, Krystkowiak, P, Duru, C, Roussel, M, Wannepain, S, Berrissoul, H, Bellonet, M, Courtin, F, Mantaux, B, Fasquel, V, Godefroy, O, Azulay, Jp, Fluchère, F, Delfini, M, Eusebio, A, Mundler, L, Longato, N, Rudolf, G, Steinmetz, G, Tranchant, C, Wagner, C, Zimmermann, M, Marcel, C, Calvas, F, Pariente, J, Démonet, Jf, Cheriet, S, Kosinski, Cm, Milkereit, E, Probst, D, Reetz, K, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüß, H, Spruth, Ej, Andrich, J, Ellrichmann, G, Hoffmann, R, Kaminski, B, Saft, C, Stamm, C, Lange, H, Bosredon, C, Maass, A, Schmidt, S, Storch, A, Wolz, M, Kohl, Z, Winkler, J, Capetian, P, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Gorzolla, H, Schrader, C, Tacik, P, Heinicke, W, Longinus, B, Bürk, K, Möller, Jc, Rissling, I, Mühlau, M, Peinemann, A, Städtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bohlen, S, Hölzner, E, Reilmann, R, Dose, M, Leythaeuser, G, Marquard, R, Raab, T, Schrenk, C, Schuierer, M, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Schwenk, D, Süßmuth, S, Trautmann, S, Weydt, P, Cormio, C, Sciruicchio, V, Serpino, C, Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, di Poggio MB, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, De Michele, G, Di Maio, L, Salvatore, E, Rinaldi, C, Rossi, F, Massarelli, M, Roca, A, Ammendola, S, Russo, Cv, Squitieri, F, Elifani, F, Maglione, V, Di Pardo, A, Alberti, S, Griguoli, A, Amico, E, Martino, T, Petrollini, M, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Piano, C, Chiara, P, Quaranta, D, Romano, Silvia, Soleti, F, Spadaro, M, Romano, S, van Hout MS, van Vugt JP, Weert, A, Bolwijn, J, Dekker, M, Leenders, K, Kremer, Hp, Dumas, Em, van den Bogaard SJ, 't Hart EP, Økland, E, Hauge, E, Tyvoll, H, Frich, J, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Lorentzen, E, Koivisto, Sp, Retterstøl, L, Overland, T, Stokke, B, Sando, B, Dziadkiewicz, A, Nowak, M, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Blaszcyk, M, Boczarska Jedynak, M, Ciach Wysocka, E, Gorzkowska, A, Jasinska Myga, B, Opala, G, Kłodowska Duda, G, Stompel, D, Banaszkiewicz, K, Boćwińska, D, Szczudlik, A, Rudzińska, M, Wójcik, M, Dec, M, Krawczyk, M, Jaremek, Kb, Szczygieł, E, Stenwak, A, Ielewska, Aw, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempołowicz, J, Samara, H, Wiśniewski, B, Janik, P, Gogol, A, Kwiecinski, H, Jamrozik, Z, Kaminska, A, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz Jarosz, H, Stępniak, I, Witkowski, G, Zdzienicka, E, Sułek, A, Krysa, W, Zieora Jakutowicz, K, Júlio, F, Januário, C, Coelho, M, Mendes, T, Valadas, A, Timóteo, Â, Costa, C, Cavaco, S, Damásio, J, Loureiro, R, Magalhães, M, Andrade, C, Gago, M, Garrett, C, Guerra, Mr, Lima, J, Massano, J, Meireles, J, Herrera, Cd, Garcia, Pm, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Sánchez, J, Alonso Frech, F, Perez, Mr, Fenollar, M, García, Rg, Quiroga, Pp, Rivera, Sv, Villanueva, C, Alegre, J, Bascuñana, M, Caldentey, Jg, Ventura, Mf, Ribas, Gg, Yébenes, Jg, López Sendón Moreno JL, García Ruíz PJ, Martínez Descals, A, Artiga, Mj, Sánchez, V, Guerrero, R, Bárcenas, Ah, Noguera Perea MF, Fortuna, L, Martirio, M, Torres, A, Reinante, G, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Sebastián, Ar, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Elorza, Md, Díez AjaLópez, C, Terol, Sd, Robert, Mf, Ruíz, Bg, Casado, Ag, Martínez, Ih, Viladrich, Cm, Càrdenas, Rp, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, García, Ss, Riballo, Av, González, Sg, Guisasola, Lm, Salvador, C, San Martín ES, González, M, Gorospe, A, Legarda, I, Arques, Pn, Torres Rodríguez MJ, Vives, B, Gaston, I, Martinez Jaurrieta MD, Manuel, J, Moreno, G, Peña, Jc, Avarvarei, Ld, Bastida, Am, Recio, Mf, Vergé, Lr, Sánchez, Vs, Carrillo, F, Cáceres, Mt, Mir, P, Suarez, Mj, Bosca, M, Burguera, Ja, Garcia, Ac, Brugada, Fc, Martínez, Lm, Val, Jl, Loutfi, G, Olofsson, C, Stattin, El, Westman, L, Wikström, B, Lhagen, Se, Paucar, M, Svenningsson, P, Reza Soltani TW, Höglund, A, Sandström, B, Høsterey Ugander, U, Fredlund, G, Constantinescu, R, Neleborn Lingefjärd, L, Tedr off, J, Esmaeilzadeh, M, Winnberg, E, Pålhagen, S, Svennigsson, P, Riza Soltani TW, Sundblom, J, Johansson, A, Wiklund, L, Ekwall, C, Göller, Ml, Petersén, A, Reimer, J, Widner, H, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Weber, S, Miedzybrodzka, Z, Rae, D, Downie, L, Simpson, S, Summers, F, Ure, A, Jack, R, Matheson, K, Akhtar, S, Crooks, J, Curtis, A, Souza, J, Wright, J, Hayward, B, Sieradzan, K, Barker, Ra, O'Keefe, D, Di Pietro, A, Fisher, K, Hill, S, Mason, S, Swain, R, Valle, N, Guzman, Bisson, J, Busse, M, Butcher, C, Clenaghan, C, Dunnett, S, Handley, O, Hunt, S, Hughes, A, Johnstone, C, Jones, L, Jones, U, Khalil, H, Owen, M, Price, K, Rose, Le, Rosser, A, Porteous, M, Edwards, M, Ho, C, Mcgill, M, Pearson, P, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Rowett, L, Gallantrae, D, Longthorpe, M, Markova, I, Raman, A, Hamer, S, Wild, S, Yarduiman, P, Chu, C, Kraus, A, Yardumian, P, Musgrave, H, Toscano, J, Jamieson, S, Hobson, E, Clayton, C, Dipple, H, Middleton, J, Freire Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Laing, H, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Santhouse, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Howard, L, Sollom, A, Snowden, J, Thompson, J, Jones, M, Murphy, H, Trender Gerhard, I, Rogers, D, Bek, J, Oughton, E, Johnson, L, Hare, M, Arran, N, Verstraelen, N, Partington Jones, L, Huson, S, Stopford, C, Westmoreland, L, Davidson, J, Morgan, K, Savage, L, Singh, B, Komati, S, Nemeth, Ah, Armstrong, R, Valentine, R, Siuda, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Burn, J, Coleman, C, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, Kazoka, M, O'Donovan, K, Taylor, C, Tidswell, K, Quarrell, O., Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), A. A., M, E. v., Duijn, R. A., C, D., Craufurd, H., Rickard, G. B., Landwehrmeyer, R. C., Van, E. J., Giltay, R. E., G., Rinaldi, Carlo, Anna A.M. Huber, Erik van Duijn, Raymund A.C. Roo, David Craufurd, Hugh Rickard, G. Bernhard Landwehrmeyer, Rose C. van der Mast, Erik J. Giltay REGISTRY investigators of the European Huntington's Disease Network. Collaborators: Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, llmann TI, Landwehrmeyer GB, Levey J, Ramos-Arroyo MA, Nielsen JE, ProKoivisto S, Päivärinta M, Roos RA, Rojo Sebastián A, Tabrizi SJ, Vandenberghe W, Verellen- Dumoulin C, Zaremba J, Uhrova T, Wahlström J, Barth K, Correia-Guedes L, Finisterra AM, Garde MB, Bos R, Betz S, Callaghan J, Fullam R, Ecker D, Nielsen MG, Hvalstedt C, Held C, Koppers K, Laurà M, Horta SM, Descals AM, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Pro Koivisto S, Roedig V, Rialland A, Røren N, Šašinková P, Seliverstov Y, Cubillo PT, Walsem MR, Wright A, da Silva WV, Witjes-Ané MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H, Ullah J, Brugger F, Hepperger C, Hotter A, Seppi K, Wenning G, Buratti L, Hametner EM, Holas C, Hussl A, Poewe W, Braunwarth EM, Sprenger F, Müller C, Sinadinosa D, Walleczek AM, Ladurner G, Staffen W, Flamez A, Morez V, de Raedt S, Boogaerts A, van Reijen D, Klempíř J, Majerová V, Roth J, Hartikainen P, Hiivola H, Martikainen K, Tuuha K, Ignatius J, Kärppä M, Åman J, Mustonen A, Kajula O, Santala M, Allain P, Guérid MA, Gohier B, Olivier A, Prundean A, Scherer- Gagou C, Verny C, Bost M, Babiloni B, Debruxelles S, Duché C, Goizet C, Lafoucrière D, Jameau L, Spampinato U, De Bruycker C, Cabaret M, Carette AS, Defebvre L, Decorte E, Delval A, Delliaux M, Destee A, Dujardin K, Peter M, Plomhouse L, Sablonnière B, Simonin C, Lemaire MH, Manouvrier S, Thibault-Tanchou S, Vuillaume I, Krystkowiak P, Duru C, Roussel M, Wannepain S, Berrissoul H, Bellonet M, Courtin F, Mantaux B, Fasquel V, Godefroy O, Azulay JP, Fluchère F, Delfini M, Eusebio A, Mundler L, Longato N, Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann M, Marcel C, Calvas F, Pariente J, Démonet JF, Cheriet S, Kosinski CM, Milkereit E, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Gelderblom H, Priller J, Prüß H, Spruth EJ, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Lange H, Bosredon C, Maass A, Schmidt S, Storch A, Wolz M, Kohl Z, Winkler J, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Goerendt I, Hidding U, Lewerenz J, Münchau A, Schmalfeld J, Stubbe L, Zittel S, Diercks G, Dressler D, Gorzolla H, Schrader C, Tacik P, Heinicke W, Longinus B, Bürk K, Möller JC, Rissling I, Mühlau M, Peinemann A, Städtler M, Weindl A, Winkelmann J, Ziegler C, Bohlen S, Hölzner E, Reilmann R, Dose M, Leythaeuser G, Marquard R, Raab T, Schrenk C, Schuierer M, Buck A, Connemann J, Eschenbach C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Schwenk D, Süßmuth S, Trautmann S, Weydt P, Cormio C, Sciruicchio V, Serpino C, Tommaso M, Capellari S, Cortelli P, Gallassi R, Poda R, Rizzo G, Scaglione C, Bertini E, Ghelli E, Ginestroni A, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Paridi D, Soliveri P, Tomasello C, De Michele G, Di Maio L, Salvatore E, Rinaldi C, Rossi F, Massarelli M, Roca A, Ammendola S, Russo CV, Squitieri F, Elifani F, Maglione V, Di Pardo A, Alberti S, Griguoli A, Amico E, Martino T, Petrollini M, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro M, van Hout MS, van Vugt JP, Weert A, Bolwijn J, Dekker M, Leenders K, Kremer HP, Dumas EM, van den Bogaard SJ, 't Hart EP, van Duijn E, Økland E, Hauge E, Tyvoll H, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Koivisto SP, Retterstøl L, Overland T, Stokke B, Sando B, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszcyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Kłodowska-Duda G, Stompel D, Banaszkiewicz K, Boćwińska D, Szczudlik A, Rudzińska M, Wójcik M, Dec M, Krawczyk M, Jaremek KB, Szczygieł E, Stenwak A, ielewska AW, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Sempołowicz J, Samara H, Wiśniewski B, Janik P, Gogol A, Kwiecinski H, Jamrozik Z, Kaminska A, Antczak J, Jachinska K, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Stępniak I, Witkowski G, Zdzienicka E, Sułek A, Krysa W, Zieora-Jakutowicz K, Júlio F, Januário C, Coelho M, Mendes T, Valadas A, Timóteo Â, Costa C, Cavaco S, Damásio J, Loureiro R, Magalhães M, Andrade C, Gago M, Garrett C, Guerra MR, Lima J, Massano J, Meireles J, Herrera CD, Garcia PM, Barrero F, Morales B, Cubo E, Mariscal N, Sánchez J, Alonso-Frech F, Perez MR, Fenollar M, García RG, Quiroga PP, Rivera SV, Villanueva C, Alegre J, Bascuñana M, Caldentey JG, Ventura MF, Ribas GG, Yébenes JG, López-Sendón Moreno JL, García Ruíz PJ, Martínez-Descals A, Artiga MJ, Sánchez V, Guerrero R, Bárcenas AH, Noguera Perea MF, Fortuna L, Martirio M, Torres A, Reinante G, Moreau LV, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastián AR, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Elorza MD, Díez-AjaLópez C, Terol SD, Robert MF, Ruíz BG, Casado AG, Martínez IH, Viladrich CM, Càrdenas RP, Roca E, Llesoy JR, Idiago JM, Vergara MR, García SS, Riballo AV, González SG, Guisasola LM, Salvador C, San Martín ES, González M, Gorospe A, Legarda I, Arques PN, Torres Rodríguez MJ, Vives B, Gaston I, Martinez-Jaurrieta MD, Manuel J, Moreno G, Peña JC, Avarvarei LD, Bastida AM, Recio MF, Vergé LR, Sánchez VS, Carrillo F, Cáceres MT, Mir P, Suarez MJ, Bosca M, Burguera JA, Garcia AC, Brugada FC, Martínez LM, Val JL, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B, lhagen SE, Paucar M, Svenningsson P, Reza- Soltani TW, Höglund A, Sandström B, Høsterey-Ugander U, Fredlund G, Constantinescu R, Neleborn-Lingefjärd L, Tedr- off J, Esmaeilzadeh M, Winnberg E, Pålhagen S, Svennigsson P, Riza-Soltani TW, Sundblom J, Johansson A, Wiklund L, Ekwall C, Göller ML, Petersén A, Reimer J, Widner H, Stebler Y, Kaelin A, Romero I, Schüpbach M, Weber S, Miedzybrodzka Z, Rae D, Downie L, Simpson S, Summers F, Ure A, Jack R, Matheson K, Akhtar S, Crooks J, Curtis A, Souza J, Rickards H, Wright J, Hayward B, Sieradzan K, Barker RA, O'Keefe D, Di Pietro A, Fisher K, Hill S, Mason S, Swain R, Valle N, Guzman, Bisson J, Busse M, Butcher C, Clenaghan C, Dunnett S, Handley O, Hunt S, Hughes A, Johnstone C, Jones L, Jones U, Khalil H, Owen M, Price K, Rose LE, Rosser A, Porteous M, Edwards M, Ho C, McGill M, Pearson P, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Miller J, Ritchie S, Burrows L, Fletcher A, Harding A, Laver F, Silva M, Thomson A, Rowett L, Gallantrae D, Longthorpe M, Markova I, Raman A, Hamer S, Wild S, Yarduiman P, Chu C, Kraus A, Yardumian P, Musgrave H, Toscano J, Jamieson S, Hobson E, Clayton C, Dipple H, Middleton J, Freire-Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Patton M, Peterson M, Rose S, Bruno S, Chu E, Doherty K, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Robertson N, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Craufurd D, Howard L, Sollom A, Snowden J, Thompson J, Jones M, Murphy H, Trender-Gerhard I, Rogers D, Bek J, Oughton E, Johnson L, Hare M, Arran N, Verstraelen N, Partington-Jones L, Huson S, Stopford C, Westmoreland L, Davidson J, Morgan K, Savage L, Singh B, Komati S, Nemeth AH, Armstrong R, Valentine R, Siuda G, Harrison D, Hughes M, Parkinson A, Soltysiak B, Burn J, Coleman C, Bandmann O, Bradbury A, Gill P, Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O'Donovan K, Taylor C, Tidswell K, Quarrell O., Molecular Neuroscience and Ageing Research (MOLAR), Hubers, Aa, van Duijn, E, Roos, Ra, Craufurd, D, Rickards, H, Bernhard Landwehrmeyer, G, van der Mast, Rc, Giltay, Ej, CollaboratorsBachoud Lévi AC, REGISTRY investigators of the European Huntington's Disease N. e. t. w. o. r. k., Bentivoglio, Ar, Biunno, I, Bonelli, Rm, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Llmann, Ti, Landwehrmeyer, Gb, Levey, J, Ramos Arroyo, Ma, Nielsen, Je, Prokoivisto, S, Päivärinta, M, Rojo Sebastián, A, Tabrizi, Sj, Vandenberghe, W, Verellen Dumoulin, C, Zaremba, J, Uhrova, T, Wahlström, J, Barth, K, Correia Guedes, L, Finisterra, Am, Garde, Mb, Bos, R, Betz, S, Callaghan, J, Fullam, R, Ecker, D, Nielsen, Mg, Hvalstedt, C, Held, C, Koppers, K, Laurà, M, Horta, Sm, Descals, Am, Mestre, T, Minster, S, Monza, D, Mütze, L, Oehmen, M, Townhill, J, Orth, M, Padieu, H, Paterski, L, Peppa, N, Pro Koivisto, S, Roedig, V, Rialland, A, Røren, N, a??inková, P, Seliverstov, Y, Cubillo, Pt, Walsem, Mr, Wright, A, da Silva, Wv, Witjes Ané, Mn, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Herranhof, B, Holl, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinger, K, Scheibl, M, Hecht, K, Lilek, S, Müller, N, Schöggl, H, Ullah, J, Brugger, F, Hepperger, C, Hotter, A, Seppi, K, Wenning, G, Buratti, L, Hametner, Em, Holas, C, Hussl, A, Poewe, W, Braunwarth, Em, Sprenger, F, Müller, C, Sinadinosa, D, Walleczek, Am, Ladurner, G, Staffen, W, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempí??, J, Majerová, V, Roth, J, Hartikainen, P, Hiivola, H, Martikainen, K, Tuuha, K, Ignatius, J, Kärppä, M, Åman, J, Mustonen, A, Kajula, O, Santala, M, Allain, P, Guérid, Ma, Gohier, B, Olivier, A, Prundean, A, Scherer Gagou, C, Verny, C, Bost, M, Babiloni, B, Debruxelles, S, Duché, C, Goizet, C, Lafoucrière, D, Jameau, L, Spampinato, U, De Bruycker, C, Cabaret, M, Carette, A, Defebvre, L, Decorte, E, Delval, A, Delliaux, M, Destee, A, Dujardin, K, Peter, M, Plomhouse, L, Sablonnière, B, Simonin, C, Lemaire, Mh, Manouvrier, S, Thibault Tanchou, S, Vuillaume, I, Krystkowiak, P, Duru, C, Roussel, M, Wannepain, S, Berrissoul, H, Bellonet, M, Courtin, F, Mantaux, B, Fasquel, V, Godefroy, O, Azulay, Jp, Fluchère, F, Delfini, M, Eusebio, A, Mundler, L, Longato, N, Rudolf, G, Steinmetz, G, Tranchant, C, Wagner, C, Zimmermann, M, Marcel, C, Calvas, F, Pariente, J, Démonet, Jf, Cheriet, S, Kosinski, Cm, Milkereit, E, Probst, D, Reetz, K, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüß, H, Spruth, Ej, Andrich, J, Ellrichmann, G, Hoffmann, R, Kaminski, B, Saft, C, Stamm, C, Lange, H, Bosredon, C, Maass, A, Schmidt, S, Storch, A, Wolz, M, Kohl, Z, Winkler, J, Capetian, P, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Gorzolla, H, Schrader, C, Tacik, P, Heinicke, W, Longinus, B, Bürk, K, Möller, Jc, Rissling, I, Mühlau, M, Peinemann, A, Städtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bohlen, S, Hölzner, E, Reilmann, R, Dose, M, Leythaeuser, G, Marquard, R, Raab, T, Schrenk, C, Schuierer, M, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Schwenk, D, Süßmuth, S, Trautmann, S, Weydt, P, Cormio, C, Sciruicchio, V, Serpino, C, Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, di Poggio, Mb, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, DE MICHELE, Giuseppe, Di Maio, L, Salvatore, Elena, Rossi, F, Massarelli, Marco, Roca, Alessandro, Ammendola, S, Russo, Cinzia, Squitieri, F, Elifani, F, Maglione, V, Di Pardo, A, Alberti, S, Griguoli, A, Amico, E, Martino, T, Petrollini, M, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Piano, C, Chiara, P, Quaranta, D, Romano, S, Soleti, F, Spadaro, M, Rinaldi, C, Massarelli, M, Roca, A, Russo, Cv, van Hout, M, van Vugt, Jp, Weert, A, Bolwijn, J, Dekker, M, Leenders, K, Kremer, Hp, Dumas, Em, van den Bogaard, Sj, 't Hart, Ep, Økland, E, Hauge, E, Tyvoll, H, Frich, J, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Lorentzen, E, Koivisto, Sp, Retterstøl, L, Overland, T, Stokke, B, Sando, B, Dziadkiewicz, A, Nowak, M, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Blaszcyk, M, Boczarska Jedynak, M, Ciach Wysocka, E, Gorzkowska, A, Jasinska Myga, B, Opala, G, K??odowska Duda, G, Stompel, D, Banaszkiewicz, K, Bo??wi??ska, D, Szczudlik, A, Rudzi??ska, M, Wójcik, M, Dec, M, Krawczyk, M, Jaremek, Kb, Szczygie??, E, Stenwak, A, Ielewska, Aw, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempo??owicz, J, Samara, H, Wi??niewski, B, Janik, P, Gogol, A, Kwiecinski, H, Jamrozik, Z, Kaminska, A, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz Jarosz, H, St??pniak, I, Witkowski, G, Zdzienicka, E, Su??ek, A, Krysa, W, Zieora Jakutowicz, K, Júlio, F, Januário, C, Coelho, M, Mendes, T, Valadas, A, Timóteo, Â, Costa, C, Cavaco, S, Damásio, J, Loureiro, R, Magalhães, M, Andrade, C, Gago, M, Garrett, C, Guerra, Mr, Lima, J, Massano, J, Meireles, J, Herrera, Cd, Garcia, Pm, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Sánchez, J, Alonso Frech, F, Perez, Mr, Fenollar, M, García, Rg, Quiroga, Pp, Rivera, Sv, Villanueva, C, Alegre, J, Bascuñana, M, Caldentey, Jg, Ventura, Mf, Ribas, Gg, Yébenes, Jg, López Sendón Moreno, Jl, García Ruíz, Pj, Martínez Descals, A, Artiga, Mj, Sánchez, V, Guerrero, R, Bárcenas, Ah, Noguera Perea, Mf, Fortuna, L, Martirio, M, Torres, A, Reinante, G, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Sebastián, Ar, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Elorza, Md, Díez AjaLópez, C, Terol, Sd, Robert, Mf, Ruíz, Bg, Casado, Ag, Martínez, Ih, Viladrich, Cm, Càrdenas, Rp, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, García, S, Riballo, Av, González, Sg, Guisasola, Lm, Salvador, C, San Martín, E, González, M, Gorospe, A, Legarda, I, Arques, Pn, Torres Rodríguez, Mj, Vives, B, Gaston, I, Martinez Jaurrieta, Md, Manuel, J, Moreno, G, Peña, Jc, Avarvarei, Ld, Bastida, Am, Recio, Mf, Vergé, Lr, Carrillo, F, Cáceres, Mt, Mir, P, Suarez, Mj, Bosca, M, Burguera, Ja, Garcia, Ac, Brugada, Fc, Martínez, Lm, Val, Jl, Loutfi, G, Olofsson, C, Stattin, El, Westman, L, Wikström, B, Lhagen, Se, Paucar, M, Svenningsson, P, Reza Soltani, Tw, Höglund, A, Sandström, B, Høsterey Ugander, U, Fredlund, G, Constantinescu, R, Neleborn Lingefjärd, L, Tedr off, J, Esmaeilzadeh, M, Winnberg, E, Pålhagen, S, Svennigsson, P, Riza Soltani, Tw, Sundblom, J, Johansson, A, Wiklund, L, Ekwall, C, Göller, Ml, Petersén, A, Reimer, J, Widner, H, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Weber, S, Miedzybrodzka, Z, Rae, D, Downie, L, Simpson, S, Summers, F, Ure, A, Jack, R, Matheson, K, Akhtar, S, Crooks, J, Curtis, A, Souza, J, Wright, J, Hayward, B, Sieradzan, K, Barker, Ra, O'Keefe, D, Di Pietro, A, Fisher, K, Hill, S, Mason, S, Swain, R, Valle, N, Bisson, J, Busse, M, Butcher, C, Clenaghan, C, Dunnett, S, Handley, O, Hunt, S, Hughes, A, Johnstone, C, Jones, L, Jones, U, Khalil, H, Owen, M, Price, K, Rose, Le, Rosser, A, Porteous, M, Edwards, M, Ho, C, Mcgill, M, Pearson, P, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Rowett, L, Gallantrae, D, Longthorpe, M, Markova, I, Raman, A, Hamer, S, Wild, S, Yarduiman, P, Chu, C, Kraus, A, Yardumian, P, Musgrave, H, Toscano, J, Jamieson, S, Hobson, E, Clayton, C, Dipple, H, Middleton, J, Freire Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Laing, H, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Santhouse, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Howard, L, Sollom, A, Snowden, J, Thompson, J, Jones, M, Murphy, H, Trender Gerhard, I, Rogers, D, Bek, J, Oughton, E, Johnson, L, Hare, M, Arran, N, Verstraelen, N, Partington Jones, L, Huson, S, Stopford, C, Westmoreland, L, Davidson, J, Morgan, K, Savage, L, Singh, B, Komati, S, Nemeth, Ah, Armstrong, R, Valentine, R, Siuda, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Burn, J, Coleman, C, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, Kazoka, M, O'Donovan, K, Taylor, C, Tidswell, K, and Quarrell, O.

Subjects
Male, medicine.medical_specialty, Heterozygote, Psychopharmacology, Population, Poison control, psychology/statistics /&/ numerical data, Suicide, Attempted, Suicide prevention, Suicidal Ideation, [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, medicine, Prevalence, Humans, epidemiology, Europe, Psychiatry, education, Suicidal ideation, ComputingMilieux_MISCELLANEOUS, Proportional Hazards Models, Attempted, Psychiatric Status Rating Scales, education.field_of_study, Psychological Tests, Suicide attempt, Psychopathology, Depression, Hazard ratio, Huntington's disease, Odds ratio, Middle Aged, 3. Good health, 030227 psychiatry, Europe, psychology, Male, Middle Aged, Prevalence, Proportional Hazards Models, Psychiatric Status Rating Scales, Psychological Tests, Suicidal Ideation, Suicide, Clinical Psychology, Psychiatry and Mental health, Suicide, Huntington Disease, epidemiology, Female, Heterozygote, Humans, Huntington Disease, Cohort studies, Female, medicine.symptom, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BACKGROUND: Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD.METHODS: The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis.RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive.LIMITATIONS: As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated.CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.

Published
2013
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47. 'Atypical' atypical parkinsonism: Critical appraisal of a cohort

Author

Hirschbichler, S.T. Erro, R. Ganos, C. Stamelou, M. Batla, A. Balint, B. Bhatia, K.P.

Abstract

Background Atypical parkinsonian conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and Dementia with Lewy bodies (DLB) comprise 10–15% of parkinsonian syndromes. Misdiagnosis with Parkinson disease (PD) and within the entities is common, given the absence of reliable biomarkers. However a correct diagnosis is not only important in clinical practice, but also crucial for any trial attempting to identify biomarkers or new treatments. Methods Consecutive patients, who were referred to our tertiary center with a diagnosis of a particular AP were included and the medical records were reviewed retrospectively. We applied each set of current diagnostic research criteria to the respective cohort to see which features fit in and if there are any additional atypical features “outside” the classic definition. Results Sixty-nine patients were recruited between January 2013 and May 2015 clinically presenting with one of the following phenotypes: 14 MSA, 24 PSP, 19 CBS and 12 DLB. Up to 49% showed additional “atypical” features and approximately 10% eventually received an alternative diagnosis, in half of whom this being based on genetic testing. Conclusions In a subset of our patients, despite the final diagnosis of an AP being maintained, there were additional “atypical” features. It remains to be seen if these reflect the clinical heterogeneity of APs, or should prompt a search for an alternative diagnosis. The search for biomarkers is more likely to be successful in homogenous groups of “typical” patients, hence the importance of recognizing “atypical” features. © 2016

Published
2017

48. Functional tics and echophenomena

Author

Ganos, C, Erro, R, Cavanna, A, Bhatia, K, Ganos C, Erro R, Cavanna A, Bhatia K, Ganos, C, Erro, R, Cavanna, A, Bhatia, K, Ganos C, Erro R, Cavanna A, and Bhatia K

Published
2014

50. The clinical syndrome of dystonia with anarthria/aphonia

Author

Ganos, C. Crowe, B. Stamelou, M. Kresojević, N. Lukić, M.J. Bras, J. Guerreiro, R. Taiwo, F. Balint, B. Batla, A. Schneider, S.A. Erro, R. Svetel, M. Kostić, V. Kurian, M.A. Bhatia, K.P.

Abstract

Objectives: In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies. We here describe the rare association of dystonia with anarthria/aphonia, by examining a large cohort of patients, to provide a narrow field of underlying conditions and a practical algorithmic approach to reach diagnosis. Methods: We retrospectively reviewed cases, which were evaluated between 2005 and 2014, to identify those with dystonia combined with marked anarthria and/or aphonia. We reviewed demographic information, clinical characteristics, as well as clinico-genetic investigations. We evaluated video material where available. Results: From 860 cases with dystonia as the predominant motor feature, we identified 32 cases (3.7%) with anarthria/aphonia. Age at neurological symptom onset was variable, but the majority of cases (n = 20) developed symptoms within their first eight years of life. A conclusive diagnosis was reached in 27 cases. Monoamine neurotransmitter disorders, neurodegeneration with brain iron accumulation syndromes, hypomyelination with atrophy of the basal ganglia and cerebellum, and syndromes with inborn errors of metabolism were the most common diagnoses. Brain MRI was crucial for reaching a diagnosis by examining the structural integrity of the basal ganglia, the cerebral cortex, brain myelination and whether there was abnormal metal deposition. Pathophysiological mechanisms underlying anarthria/aphonia included dystonia, corticobulbar involvement, apraxia and abnormalities of brain development. Conclusions: The spectrum of conditions that may present with the syndrome of dystonia with anarthria/aphonia is broad. Various causes may account for the profound speech disturbance. A practical brain MRI-based algorithm is provided to aid the diagnostic procedure. © 2016 Elsevier Ltd.

Published
2016

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