30 results on '"Matthis Synofzik"'
Search Results
2. Consensus Paper: Ataxic Gait
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Pierre Cabaraux, Sunil K. Agrawal, Huaying Cai, Rocco Salvatore Calabro, Carlo Casali, Loic Damm, Sarah Doss, Christophe Habas, Anja K. E. Horn, Winfried Ilg, Elan D. Louis, Hiroshi Mitoma, Vito Monaco, Maria Petracca, Alberto Ranavolo, Ashwini K. Rao, Serena Ruggieri, Tommaso Schirinzi, Mariano Serrao, Susanna Summa, Michael Strupp, Olivia Surgent, Matthis Synofzik, Shuai Tao, Hiroo Terasi, Diego Torres-Russotto, Brittany Travers, Jaimie A. Roper, and Mario Manto
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Neurology ,Cerebellum ,Therapies ,Posture ,Rehabilitation ,Cerebellar ataxia ,Gait ,Neurology (clinical) - Abstract
The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.
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- 2022
3. French Translation and Cross-cultural Adaptation of the Scale for the Assessment and Rating of Ataxia
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Dax Bourcier, Nicolas Bélair, Élyse-Anne Pedneault-Tremblay, Isabelle Lessard, Thomas Klockgether, Matthis Synofzik, Caroline Rahn, Bernard Brais, Elise Duchesne, and Cynthia Gagnon
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Cross-cultural adaptation ,Psychometric properties ,Translation ,Neurology ,ISPOR guidelines ,Ataxia ,ddc:610 ,Neurology (clinical) - Abstract
The Scale for the Assessment and Rating of Ataxia (SARA) is a widely used scale for assessing the severity of ataxia in clinics, natural history studies, and treatment trials worldwide. However, no French translation with validated cross-cultural adaptation is available. This study aimed to translate and adapt the SARA into French. The translation process was conducted according to the ISPOR guidelines for the translation and cultural adaptation process for patient-reported outcomes. A total of five translators, an expert committee, and two physiotherapists took part in the process to assess and ensure comprehension and language equivalences of the final French version. A few misinterpretations were pointed out during the translation process and were changed accordingly by the translation team. The French version of the SARA is ready to be used in clinical and research settings with French-speaking populations living with ataxia.
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- 2022
4. A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype
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Friedemann Bender, Tobias B. Haack, Alejandra Leyva-Gutiérrez, Stefan Hauser, Selina Reich, Matthis Synofzik, Andreas Traschütz, and David Mengel
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Adult ,0301 basic medicine ,Spastic gait ,Ataxia ,Cerebellar Ataxia ,Ubiquitin-Protein Ligases ,Early-onset ataxia ,Disease ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,SCA48 ,medicine ,Humans ,Spinocerebellar Ataxias ,Dominant ,ddc:610 ,Index case ,Exome sequencing ,genetics [Ubiquitin-Protein Ligases] ,Genetics ,Sanger sequencing ,Original Communication ,CHIP ,genetics [Ataxia] ,medicine.disease ,Phenotype ,Pedigree ,Neurology ,symbols ,Neurology (clinical) ,medicine.symptom ,STUB1 ,Myoclonus ,030217 neurology & neurosurgery - Abstract
Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.
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- 2021
5. Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra
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Mahmoud Reza Ashrafi, Pouria Mohammadi, Ali Reza Tavasoli, Morteza Heidari, Sareh Hosseinpour, Maryam Rasulinejad, Mohammad Rohani, Masoud Ghahvechi Akbari, Reza Azizi Malamiri, Reza Shervin Badv, Davood Fathi, Ali Zare Dehnavi, Shahram Savad, Ali Rabbani, Matthis Synofzik, Nejat Mahdieh, and Zahra Rezaei
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Ataxia of Charlevoix Saguenay ,Neurology ,ARSACS ,Mutation ,Spastic ataxia ,ddc:610 ,Neurology (clinical) - Abstract
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
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- 2022
6. Effects of Levodopa on quality of sleep and nocturnal movements in Parkinson’s Disease
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Walter Maetzler, Jan-Hinrich Busch, Laura Zaunbrecher, Thomas Vaterrodt, Susanne Nussbaum, Clint Hansen, Benjamin Roeben, Matthis Synofzik, Eva Schaeffer, Morad Elshehabi, Kirsten Emmert, Inga Liepelt-Scarfone, Sara Becker, and Daniela Berg
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Sleep Wake Disorders ,medicine.medical_specialty ,Levodopa ,Neurology ,Parkinson's disease ,Movement ,etiology [Sleep Wake Disorders] ,therapeutic use [Levodopa] ,Hypokinesia ,Disease ,Nocturnal ,050105 experimental psychology ,drug therapy [Sleep Wake Disorders] ,Antiparkinson Agents ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Humans ,0501 psychology and cognitive sciences ,ddc:610 ,therapeutic use [Antiparkinson Agents] ,pharmacology [Antiparkinson Agents] ,Original Communication ,business.industry ,05 social sciences ,Parkinson Disease ,medicine.disease ,Sleep in non-human animals ,drug therapy [Parkinson Disease] ,nervous system diseases ,Cohort ,sense organs ,Neurology (clinical) ,complications [Parkinson Disease] ,medicine.symptom ,Sleep ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Sleep disturbances are common in Parkinson’s Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven. Methods We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson’s Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology. Results In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep. Conclusion Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.
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- 2021
7. Correction to: Consensus Paper: Ataxic Gait
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Pierre Cabaraux, Sunil K. Agrawal, Huaying Cai, Rocco Salvatore Calabro, Carlo Casali, Loic Damm, Sarah Doss, Christophe Habas, Anja K. E. Horn, Winfried Ilg, Elan D. Louis, Hiroshi Mitoma, Vito Monaco, Maria Petracca, Alberto Ranavolo, Ashwini K. Rao, Serena Ruggieri, Tommaso Schirinzi, ·Mariano Serrao, Susanna Summa, Michael Strupp, Olivia Surgent, Matthis Synofzik, Shuai Tao, Hiroo Terasi, Diego Torres‑Russotto, Brittany Travers, Jaimie A. Roper, and Mario Manto
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Neurology ,Neurology (clinical) - Published
- 2022
8. Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures
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Matthis Synofzik, Claire Didszun, Imis Dogan, Robin Schubert, Jörg B. Schulz, Thomas Klockgether, Kathrin Reetz, Ludger Schöls, Ralf Reilmann, Christian Hohenfeld, and Ilaria Giordano
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Adult ,medicine.medical_specialty ,Ataxia ,Neurology ,Adolescent ,physiopathology [Friedreich Ataxia] ,Disease ,physiology [Psychomotor Performance] ,050105 experimental psychology ,Generalized linear mixed model ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,diagnosis [Friedreich Ataxia] ,medicine ,Humans ,0501 psychology and cognitive sciences ,ddc:610 ,Cerebellar ataxia ,business.industry ,Lift (data mining) ,05 social sciences ,Linear model ,Middle Aged ,Friedreich Ataxia ,Motor Skills ,Finger tapping ,Linear Models ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Psychomotor Performance ,physiology [Motor Skills] ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Friedreich's ataxia (FRDA) is a rare autosomal-recessive slowly progressive neurodegenerative disorder. As common clinical measures for this devastating disease lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA.
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- 2019
9. Pattern of Cerebellar Atrophy in Friedreich’s Ataxia—Using the SUIT Template
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Klaus Scheffler, Benjamin Bender, Till-Karsten Hauser, Jennifer Just, Ulrike Ernemann, Vinod Kumar, Wolfgang Grodd, Tobias Lindig, Bettina Brendel, Matthis Synofzik, Uwe Klose, and Ludger Schöls
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Adult ,Male ,Cerebellum ,Ataxia ,pathology [Friedreich Ataxia] ,computer.software_genre ,050105 experimental psychology ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Voxel ,pathology [Cerebellum] ,Cerebellar Degeneration ,Humans ,Medicine ,0501 psychology and cognitive sciences ,ddc:610 ,pathology [Atrophy] ,business.industry ,05 social sciences ,Anatomy ,diagnostic imaging [Atrophy] ,Middle Aged ,diagnostic imaging [Cerebellum] ,medicine.disease ,Cross-Sectional Studies ,medicine.anatomical_structure ,Dentate nucleus ,nervous system ,Neurology ,Friedreich Ataxia ,Female ,diagnostic imaging [Friedreich Ataxia] ,Cerebellar atrophy ,Neurology (clinical) ,medicine.symptom ,business ,computer ,030217 neurology & neurosurgery - Abstract
Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich’s ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich’s ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.
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- 2019
10. Fall Risk in Relation to Individual Physical Activity Exposure in Patients with Different Neurodegenerative Diseases: a Pilot Study
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Karin Srulijes, Michael Schwenk, Cornelia Schatton, Lars Schwickert, Clemens Becker, Walter Maetzler, Kristin Teubner-Liepert, Srijana K C, Jochen Klenk, Miriam Meyer, and Matthis Synofzik
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Male ,medicine.medical_specialty ,Neurology ,Ataxia ,Parkinson's disease ,Physical activity ,Pilot Projects ,050105 experimental psychology ,Progressive supranuclear palsy ,Wearable Electronic Devices ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Accelerometry ,Humans ,Medicine ,0501 psychology and cognitive sciences ,In patient ,ddc:610 ,Risk factor ,Exercise ,Aged ,business.industry ,Incidence ,Incidence (epidemiology) ,05 social sciences ,Neurodegenerative Diseases ,Middle Aged ,medicine.disease ,complications [Neurodegenerative Diseases] ,Accidental Falls ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Falls in patients with neurodegenerative diseases (NDDs) have enormous detrimental consequences. A better understanding of the interplay between physical activity (PA) and fall risk might help to reduce fall frequency. We aimed to investigate the association between sensor-based PA and fall risk in NDDs, using 'falls per individual PA exposure time' as a novel measure. Eighty-eight subjects (n = 31 degenerative ataxia (DA), n = 14 Parkinson's disease (PD), n = 12 progressive supranuclear palsy (PSP) and 31 healthy controls) were included in this pilot study. PA was recorded in free-living environments with three-axial accelerometers (activPAL™) over 7 days. Falls were prospectively assessed over 12 months. Fall incidence was calculated by (i) absolute number of falls per person years (py) and (ii) falls per exposure to individual PA. Absolute fall incidence was high in all three NDDs, with differing levels (DA, 9 falls/py; PD, 14 falls/py; PSP, 29 falls/py). Providing a more fine-grained view on fall risk, correction for individual exposure to PA revealed that measures of low walking PA were associated with higher fall incidence in all three NDDs. Additionally, higher fall incidence was associated with more sit-to-stand transfers in PD and longer walking bouts in PSP. Our results suggest that low walking PA is a risk factor for falls in DA, PD and PSP, indicating the potential benefit of increasing individual PA in these NDDs to reduce fall risk. Moreover, they show that correction for individual exposure to PA yields a more differentiated view on fall risk within and across NDDs.
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- 2019
11. Correction to: A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome
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Steven Laurie, Teresinha Evangelista, Gulcin Gumus, Angela Lochmüller, Patrick F. Chinnery, Leigh C. Carmody, Gisèle Bonne, Hanns Lochmüller, Matthew J. Jennings, Thiloka Ratnaike, Rachel Thompson, Holm Graessner, Sergi Beltran, Leslie Matalonga, Carles Hernandez-Ferrer, Katherine Schon, Jean-François Desaphy, Peter N. Robinson, Virginie Bros-Facer, Carola Reinhard, Alberto Corvo, Rita Horvath, Matthis Synofzik, Bertrand Fontaine, Antonio Atalaia, David Gómez-Andrés, Davide Piscia, Katja Lohmann, Rabah Ben Yaou, Alfons Macaya, Olaf Riess, and Birte Zurek
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Computer science ,Writing ,lcsh:R ,Pharmacology toxicology ,lcsh:Medicine ,Correction ,General Medicine ,Data science ,Human genetics ,Rare Diseases ,Systematic review ,Research Design ,Humans ,Pharmacology (medical) ,ddc:610 ,Genetics (clinical) ,Data Management ,Systematic Reviews as Topic ,Rare disease - Abstract
Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families.This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD.Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence.This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data.
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- 2021
12. Validation of a German version of the Cerebellar Cognitive Affective/ Schmahmann Syndrome Scale: preliminary version and study protocol
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Matthis Synofzik, Kathrin Reetz, Saskia Elben, Elke Wondzinski, Ulrich Sure, Juergen Konczak, Jennifer Faber, Andreas Thieme, Oliver Mueller, Sandra Roeske, Dagmar Timmann, Patricia Sulzer, Jeremy D. Schmahmann, Mario Siebler, Thomas Klockgether, Miriam Barkhoff, Heike Jacobi, Imis Dogan, and Martina Minnerop
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medicine.medical_specialty ,Clinical Trial Protocol ,lcsh:RC346-429 ,lcsh:RC321-571 ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Physical medicine and rehabilitation ,Cerebellum ,medicine ,Cerebellar disorder ,ddc:610 ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,Bedside test ,Neuropsychology ,Construct validity ,Neuropsychological test ,Test (assessment) ,Affect ,Inter-rater reliability ,Psychology ,Motor learning ,030217 neurology & neurosurgery ,Human - Abstract
Background Traditionally, cerebellar disorders including ataxias have been associated with deficits in motor control and motor learning. Since the 1980’s growing evidence has emerged that cerebellar diseases also impede cognitive and affective processes such as executive and linguistic functions, visuospatial abilities and regulation of emotion and affect. This combination of non-motor symptoms has been named Cerebellar Cognitive Affective/ Schmahmann Syndrome (CCAS). To date, diagnosis relies on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. Recently, a short and easy applicable bedside test (CCAS Scale) has been developed to screen for CCAS. It has been validated in an US-American cohort of adults with cerebellar disorders and healthy controls. As yet, the CCAS Scale has only been available in American English. We present a German version of the scale and the study protocol of its ongoing validation in a German-speaking patient cohort. Methods A preliminary German version has been created from the original CCAS Scale using a standardized translation procedure. This version has been pre-tested in cerebellar patients and healthy controls including medical experts and laypersons to ensure that instructions are well understandable, and that no information has been lost or added during translation. This preliminary German version will be validated in a minimum of 65 patients with cerebellar disease and 65 matched healthy controls. We test whether selectivity and sensitivity of the German CCAS Scale is comparable to the original CCAS Scale using the same cut-off values for each of the test items, and the same pass/ fail criteria to determine the presence of CCAS. Furthermore, internal consistency, test-retest and interrater reliability will be evaluated. In addition, construct validity will be tested in a subset of patients and controls in whom detailed neuropsychological testing will be available. Secondary aims will be examination of possible correlations between clinical features (e.g. disease duration, clinical ataxia scores) and CCAS scores. Perspective The overall aim is to deliver a validated bedside test to screen for CCAS in German-speaking patients which can also be used in future natural history and therapeutic trials. Study registration The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854).
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- 2020
13. Genetische Architektur der amyotrophen Lateralsklerose und frontotemporalen Demenz
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Markus Otto, Jochen H. Weishaupt, Albert C. Ludolph, and Matthis Synofzik
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0301 basic medicine ,Gynecology ,medicine.medical_specialty ,business.industry ,General Medicine ,medicine.disease ,03 medical and health sciences ,Psychiatry and Mental health ,030104 developmental biology ,0302 clinical medicine ,Neurology ,medicine ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,business ,030217 neurology & neurosurgery ,Frontotemporal dementia - Abstract
Amyotrophe Lateralsklerose (ALS) und frontotemporale Demenz (FTD) uberlappen nicht nur klinisch, sondern auch neuropathologisch und genetisch. Gerade in den letzten Jahren ist eine grose Zahl neuer Gene identifiziert worden, die beiden Erkrankungen zugrunde liegen konnen, z. B. C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10 oder SQSTM1. Andere Gene wiederum finden sich nahezu ausschlieslich bei einer der beiden Erkrankungen, z. B. SOD1 bei ALS oder MAPT bei FTD. Dieses verweist auf eine grose Anzahl gemeinsamer Mechanismen, jedoch auch eine gewisse zellspezifische Vulnerabilitat. Die jungst identifizierten Gene sind nicht nur entscheidende Grundsteine fur die Erforschung der Pathophysiologie von ALS und FTD, sondern auch der erste Schritt fur die Entwicklung kausaler gen- oder Pathway-spezifischer molekularer Therapien. Mutationen in diesen Genen finden sich auch bei einer zunehmenden Anzahl scheinbar „sporadischer“ ALS- bzw. FTD-Patienten. Angesichts der zunehmenden genetischen Heterogenitat mit nunmehr >25 bekannten Genen fur ALS und FTD sollte die genetische Diagnostik bei familiaren und sporadischen Patienten nach Ausschluss einer C9orf72-Repeat-Expansion moglichst nicht mehr als Einzelgendiagnostik erfolgen, sondern gleich als Next-generation-sequencing-Diagnostik mittels Panel oder „whole exome sequencing“.
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- 2017
14. POLG-Associated Ataxia Presenting as a Fragile X Tremor/Ataxia Phenocopy Syndrome
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Martin Paucar, Emma Tham, Per Svenningsson, Martin Engvall, Lisa Gordon, and Matthis Synofzik
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Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Fragile x ,Ataxia ,Neurology ,DNA-Directed DNA Polymerase ,genetics [Fragile X Mental Retardation Protein] ,Diagnosis, Differential ,Fragile X Mental Retardation Protein ,03 medical and health sciences ,0302 clinical medicine ,medicine ,genetics [DNA-Directed DNA Polymerase] ,Humans ,ddc:610 ,diagnostic imaging [Brain] ,Phenocopy ,Genetics ,business.industry ,Brain ,diagnosis [Ataxia] ,genetics [Ataxia] ,FMR1 protein, human ,Middle Aged ,Hyperintensity ,DNA Polymerase gamma ,Fmr1 gene ,030104 developmental biology ,DNA polymerase gamma ,POLG protein, human ,Neurology (clinical) ,medicine.symptom ,Differential diagnosis ,business ,030217 neurology & neurosurgery - Abstract
Hyperintensities in the middle cerebellar peduncles (MCP), known as the MCP sign, and progressive late-onset ataxia constitute major characteristics of the fragile X tremor/ataxia syndrome (FXTAS). Here, we describe a 60-year-old male affected by ataxia due to biallelic mutations in the mitochondrial polymerase gamma (POLG) gene in which hyperintensities of the middle cerebellar peduncles (MCP) were found. The initial suspicion of FXTAS was however ruled out by a normal CGG expansion size in the FMR1 gene. We discuss the features of late-onset POLG-A as a phenocopy of FXTAS.
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- 2016
15. Atypical parkinsonism with severely reduced striatal dopamine uptake associated with a 16p11.2 duplication syndrome
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Benjamin Roeben, Heinz Gabriel, Matthis Synofzik, and Dominik Blum
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Male ,Striatal dopamine ,medicine.medical_specialty ,diagnostic imaging [Corpus Striatum] ,Neurology ,DNA Copy Number Variations ,genetics [Chromosome Duplication] ,Dopamine ,metabolism [Parkinsonian Disorders] ,Internal medicine ,Gene duplication ,medicine ,Humans ,ddc:610 ,metabolism [Dopamine] ,Aged ,Neuroradiology ,Tomography, Emission-Computed, Single-Photon ,business.industry ,metabolism [Corpus Striatum] ,Syndrome ,diagnostic imaging [Parkinsonian Disorders] ,genetics [Chromosomes, Human, Pair 16] ,Endocrinology ,genetics [Parkinsonian Disorders] ,Atypical Parkinsonism ,Neurology (clinical) ,business - Published
- 2019
16. Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
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Benjamin Bender, Alleene V. Strickland, Michael A. Gonzalez, Marina L. Kennerson, Hans Offenbacher, Rebecca Schüle, Michaela Auer-Grumbach, Stephan Züchner, Reinhard Windhager, Michaela Brunner-Krainz, Avencia Sanchez Mejias Garcia, Peter Young, Natalie Hauser, Maria Schabhüttl, Matthew B. Harms, Michael E. Shy, Steven A. Moore, Stephan Klebe, Ursula Gruber-Sedlmayr, and Matthis Synofzik
- Subjects
Cytoplasmic Dyneins ,DYNC1H1 protein, human ,pathology [Motor Neuron Disease] ,pathology [Motor Neurons] ,DNA Mutational Analysis ,Dynein ,genetics [Cytoplasmic Dyneins] ,Biology ,Article ,pathology [Muscle, Skeletal] ,Charcot-Marie-Tooth Disease ,Microtubule ,pathology [Charcot-Marie-Tooth Disease] ,Cytoplasmic dynein complex ,medicine ,Humans ,ddc:610 ,Motor Neuron Disease ,Muscle, Skeletal ,Gene ,Exome sequencing ,Dominance (genetics) ,Motor Neurons ,Genetics ,Spinal muscular atrophy ,medicine.disease ,Phenotype ,Neurology ,Mutation ,genetics [Motor Neuron Disease] ,Neurology (clinical) ,genetics [Charcot-Marie-Tooth Disease] - Abstract
Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
- Published
- 2015
17. Gelingendes Altern: Was können Neurologie und Geriatrie beitragen?
- Author
-
Walter Maetzler and Matthis Synofzik
- Subjects
Gynecology ,Psychiatry and Mental health ,medicine.medical_specialty ,Neurology ,business.industry ,medicine ,Neurology (clinical) ,General Medicine ,business - Abstract
Der relative Anteil an alteren Menschen in den westlichen Gesellschaften nimmt rasant zu und damit die relative Haufigkeit altersbezogener neurologischer Erkrankungen (wie z. B. Demenzen) und funktioneller Defizite (wie z. B. Immobilitat). Die vorliegende Arbeit argumentiert, dass diese Entwicklung eine Perspektiverweiterung notig macht. Die Grundfrage kann nicht mehr nur lauten: Wie konnen wir altersbezogene Erkrankungen besser behandeln?; sondern, zumindest gleichwertig wichtig: Wie konnen wir erreichen, dass altersbezogene Erkrankungen gar nicht erst – oder doch zumindest deutlich spater – auftreten? Oder noch grundsatzlicher: Wie konnen wir gelingendes Altern erreichen? Es ist also die Primarpravention des dysfunktionalen Alterns, die als zentrale gesellschaftliche, wissenschaftliche und klinische Aufgabe anerkannt und um den Denkhorizont des gelingenden Alterns erweitert werden muss. Der vorliegende Artikel stellt dysfunktionales Altern als gemeinsame Endstrecke multipler Systemprozesse und ihrer Interaktion dar, welchen jeweils durch primare Praventionsstrategien begegnet werden muss. Hochrangige Publikationen weisen darauf hin, dass Primarpravention verschiedener altersassoziierter Funktionsdefizite bis hin auf molekularer Ebene spezifisch und ursachlich erfolgen kann. Damit beginnt Geriatrie nicht erst bei alteren Menschen und bei speziellen geriatrischen Funktionsdefiziten, sondern vielmehr bereits bei 20- bis 30-jahrigen Menschen, die noch weitestgehend gesund voll im Alltag und Berufsleben stehen – eben in der Mitte der Neurologie und anderer Fachdisziplinen.
- Published
- 2015
18. Consensus Paper: Management of Degenerative Cerebellar Disorders
- Author
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Ludger Schöls, Wolfgang Nachbauer, Pablo Celnik, Roxana G. Burciu, Katharina Feil, Dagmar Timmann, I. Miyai, S Boesch, Julian Teufel, J. Claaßen, Michael Strupp, Roger Kalla, Winfried Ilg, Matthis Synofzik, and Amy J. Bastian
- Subjects
Adult ,medicine.medical_specialty ,Cerebellum ,Neurology ,Cerebellar Ataxia ,Adolescent ,drug therapy [Spinocerebellar Degenerations] ,medicine.medical_treatment ,therapeutic use [Anti-Dyskinesia Agents] ,Medizin ,Article ,therapy [Cerebellar Ataxia] ,drug therapy [Cerebellar Ataxia] ,Physical medicine and rehabilitation ,rehabilitation [Cerebellar Ataxia] ,medicine ,Cerebellar Degeneration ,Animals ,Humans ,Cerebellar disorder ,ddc:610 ,Child ,Spinocerebellar Degenerations ,Rehabilitation ,rehabilitation [Spinocerebellar Degenerations] ,Cerebellar ataxia ,Anti-Dyskinesia Agents ,business.industry ,Neurodegenerative Diseases ,therapy [Spinocerebellar Degenerations] ,medicine.anatomical_structure ,rehabilitation [Neurodegenerative Diseases] ,Brain stimulation ,Neurology (clinical) ,medicine.symptom ,Motor learning ,business ,Neuroscience ,drug therapy [Neurodegenerative Diseases] ,therapy [Neurodegenerative Diseases] - Abstract
Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.
- Published
- 2013
19. Routine Clinical Testing Underestimates Proprioceptive Deficits in Friedreich’s Ataxia
- Author
-
Svenja Borchers, Marc Himmelbach, Matthis Synofzik, and Elizabeth Kiely
- Subjects
Adult ,Male ,medicine.medical_specialty ,Ataxia ,Drug trial ,Neurology ,Adolescent ,Posture ,Degeneration (medical) ,Audiology ,Positive correlation ,etiology [Somatosensory Disorders] ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,physiology [Postural Balance] ,Outpatients ,medicine ,Humans ,ddc:610 ,Postural Balance ,Aged ,030304 developmental biology ,diagnosis [Somatosensory Disorders] ,Analysis of Variance ,0303 health sciences ,Proprioception ,Joint position sense ,Middle Aged ,complications [Friedreich Ataxia] ,3. Good health ,Friedreich Ataxia ,Case-Control Studies ,Vibration sense ,Disease Progression ,Somatosensory Disorders ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology ,physiology [Posture] ,030217 neurology & neurosurgery - Abstract
Friedreich's ataxia (FA) is the most common recessive ataxia in the Western world with degeneration of dorsal root ganglia neurons as its major neuropathological hallmark. The sensitivity of clinical tools commonly used for the assessment of the proprioceptive component of FA is currently unknown. We hypothesised that current clinical testing underestimates proprioceptive deficits in FA patients. Such an underestimation would hamper our understanding of the components of FA, the monitoring of disease progression, and the detection of deficits in the current advent of drug trials. We compared clinical tests for joint position sense (JPS) and vibration sense (VS) to a test of spatial position sense (SPS) that examines localisation of both hands across a horizontal 2D space. We tested 22 healthy controls to derive a cut-off for the SPS. Eleven patients with genetically confirmed FA participated in this study. All 11 FA patients were impaired in the SPS test. Two patients showed unimpaired JPS and VS. Two additional patients showed unimpaired JPS, while two other patients unimpaired VS. The SPS test was more sensitive and revealed deficits potentially earlier than clinical screening tests. Only the SPS showed a positive correlation with ataxia severity. The SPS was more sensitive than the commonly used JPS and VS. Thus, our results indicate that proprioceptive deficits in FA start earlier and are more severe than indicated by routine standard clinical testing. The contribution of proprioceptive deficits to the impairment of FA patients might therefore indeed be underestimated today.
- Published
- 2013
20. C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers
- Author
-
Cornelis Blauwendraat, Javier Simón-Sánchez, Melissa Castillo-Lizardo, Emily M. Lynes, Ashutosh Dhingra, Elwira Pyz, Sasja Heetveld, Markus A. Hobert, Peter Heutink, Patrizia Rizzu, Margherita Francescatto, and Matthis Synofzik
- Subjects
Central Nervous System ,0301 basic medicine ,Myeloid ,Databases, Factual ,Lipopolysaccharide Receptors ,C9orf72 risk haplotype ,Progranulins ,C9orf72 ,Myeloid Cells ,Genetics ,Regulation of gene expression ,standards [Databases, Factual] ,genetics [Intercellular Signaling Peptides and Proteins] ,metabolism [Proteins] ,medicine.anatomical_structure ,Frontotemporal Dementia ,metabolism [Frontotemporal Dementia] ,metabolism [Central Nervous System] ,Intercellular Signaling Peptides and Proteins ,Haploinsufficiency ,statistics & numerical data [Databases, Factual] ,CD14 ,genetics [Mutation] ,MAPT protein, human ,tau Proteins ,Locus (genetics) ,Biology ,metabolism [Lipopolysaccharide Receptors] ,metabolism [Myeloid Cells] ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Humans ,ddc:610 ,Neurodegeneration ,C9orf72 Protein ,metabolism [Amyotrophic Lateral Sclerosis] ,Research ,Amyotrophic Lateral Sclerosis ,Proteins ,Hexanucleotide repeat expansion ,genetics [Proteins] ,Molecular biology ,Cap analysis gene expression ,genetics [tau Proteins] ,030104 developmental biology ,Gene Expression Regulation ,Mutation ,GRN protein, human ,Neurology (clinical) ,C9orf72 protein, human ,Trinucleotide repeat expansion - Abstract
A non-coding hexanucleotide repeat expansion (HRE) in C9orf72 is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) acting through a loss of function mechanism due to haploinsufficiency of C9orf72 or a gain of function mediated by aggregates of bidirectionally transcribed HRE-RNAs translated into di-peptide repeat (DPR) proteins. To fully understand regulation of C9orf72 expression we surveyed the C9orf72 locus using Cap Analysis of Gene Expression sequence data (CAGEseq). We observed C9orf72 was generally lowly expressed with the exception of a subset of myeloid cells, particularly CD14+ monocytes that showed up to seven fold higher expression as compared to central nervous system (CNS) and other tissues. The expression profile at the C9orf72 locus showed a complex architecture with differential expression of the transcription start sites (TSSs) for the annotated C9orf72 transcripts between myeloid and CNS tissues suggesting cell and/or tissue specific functions. We further detected novel TSSs in both the sense and antisense strand at the C9orf72 locus and confirmed their existence in brain tissues and CD14+ monocytes. Interestingly, our experiments showed a consistent decrease of C9orf72 coding transcripts not only in brain tissue and monocytes from C9orf72-HRE patients, but also in brains from MAPT and GRN mutation carriers together with an increase in antisense transcripts suggesting these could play a role in regulation of C9orf72. We found that the non-HRE related expression changes cannot be explained by promoter methylation but by the presence of the C9orf72-HRE risk haplotype and unknown functional interactions between C9orf72, MAPT and GRN. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0306-7) contains supplementary material, which is available to authorized users.
- Published
- 2016
21. Restless Legs and Substantia Nigra Hypoechogenicity are Common Features in Friedreich’s Ataxia
- Author
-
Daniela Berg, Tobias Lindig, Matthis Synofzik, Jana Godau, and Ludger Schöls
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neurology ,Ataxia ,Adolescent ,Ultrasonography, Doppler, Transcranial ,Population ,etiology [Restless Legs Syndrome] ,Substantia nigra ,Gastroenterology ,Young Adult ,Degenerative disease ,Restless Legs Syndrome ,Internal medicine ,mental disorders ,diagnostic imaging [Substantia Nigra] ,medicine ,Humans ,ddc:610 ,Restless legs syndrome ,Age of Onset ,education ,Aged ,education.field_of_study ,business.industry ,Echogenicity ,Middle Aged ,medicine.disease ,complications [Friedreich Ataxia] ,Substantia Nigra ,Peripheral neuropathy ,Friedreich Ataxia ,Physical therapy ,diagnostic imaging [Friedreich Ataxia] ,Female ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Friedreich's ataxia (FA) is a multisystemic degenerative disease, but the prevalence of restless legs syndrome (RLS) is unknown. FA patients might be particularly susceptible to develop RLS as FA presents with features commonly associated with RLS, e.g. multisystemic network dysfunction, peripheral neuropathy and disturbances in subcellular brain iron homeostasis. In this work, we assessed the following: (1) the prevalence of RLS; (2) the prevalence of sonographic hypoechogenicity of the substantia nigra (SN), which is known to be associated with idiopathic RLS; and (3) the relation between both in 28 FA patients. Thirty-two percent of the patients suffered from RLS, thus clearly exceeding the prevalence rate in the general population. SN hypoechogenicity was more frequent in FA patients (61%) compared to healthy controls (7%) and was significantly associated with RLS. However, as SN echogenicity also correlated inversely with disease severity, it seems to be related not only to RLS, but also to the neurodegenerative process in FA itself. The high prevalence of RLS in FA patients warrants specific assessment by neurologists involved in the care of FA patients as treatments are readily available. Similar to patients with idiopathic RLS, reduced SN echogenicity is a frequent finding in FA, possibly indicating regional changes in subcellular brain iron regulation in FA.
- Published
- 2010
22. Evidence for altered transport of insulin across the blood–brain barrier in insulin-resistant humans
- Author
-
Walter Maetzler, Andreas Peter, Hans-Ulrich Häring, Anita M. Hennige, Tina Sartorius, Martin Heni, Patricia Schöpfer, Andreas Fritsche, and Matthis Synofzik
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Central nervous system ,Carbohydrate metabolism ,Blood–brain barrier ,metabolism [Cerebrospinal Fluid] ,Endocrinology ,Cerebrospinal fluid ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Insulin ,ddc:610 ,Aged ,Cerebrospinal Fluid ,metabolism [Blood Glucose] ,Glucose tolerance test ,medicine.diagnostic_test ,business.industry ,Brain ,Biological Transport ,General Medicine ,Glucose Tolerance Test ,Middle Aged ,medicine.disease ,metabolism [Insulin] ,medicine.anatomical_structure ,metabolism [Brain] ,Blood-Brain Barrier ,Female ,Insulin Resistance ,metabolism [Blood-Brain Barrier] ,business - Abstract
Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.
- Published
- 2013
23. Ethically Justified, Clinically Applicable Criteria for Physician Decision-Making in Psychopharmacological Enhancement
- Author
-
Matthis Synofzik
- Subjects
Psychotherapist ,Health Policy ,media_common.quotation_subject ,Beneficence ,Context (language use) ,Neuroenhancement ,Bioethics ,Voluntariness ,Psychiatry and Mental health ,Philosophy ,Neurology ,Psychology ,Distributive justice ,Social psychology ,Neurocognitive ,Autonomy ,media_common - Abstract
Advances in psychopharmacology raise the prospects of enhancing neurocognitive functions of humans by improving attention, memory, or mood. While general ethical reflections on psychopharmacological enhancement have been increasingly published in the last years, ethical criteria characterizing physicians’ role in neurocognitive enhancement and guiding their decision-making still remain highly unclear. Here it will be argued that also in the medical domain the use of cognition-enhancing drugs is not intrinsically unethical and that, in fact, physicians should assume an important role in gating their usage. For finding normative orientation, concepts of disease, normality or medicine will not be helpful since—due to their cryptonormative nature—they rather hamper than allow targeted discussion and decision-making. As an alternative, the common and widely accepted bioethical criteria of beneficence, non-maleficence, autonomy and distributive justice allow a clinically applicable, highly differentiated context- and case-sensitive approach. By embedding decision-making in a participative physician–patient relationship extrinsic objections against neurocognitive enhancement (e.g. invalid perceptions about efficacy, benefit or risk; questionable voluntariness; restrained decision-making capacity) can be curtailed.
- Published
- 2009
24. Wie sollen wir Patienten mit Demenz behandeln? Die ethisch problematische Funktion der Antidementiva
- Author
-
Walter Maetzler and Matthis Synofzik
- Subjects
Gynecology ,Philosophy ,Issues, ethics and legal aspects ,medicine.medical_specialty ,Health (social science) ,Health Policy ,Political science ,Medicine public health ,medicine - Abstract
Angesichts begrenzter anderweitiger Behandlungsmoglichkeiten wird der Gabe von Antidementiva in der gegenwartigen medizinischen Demenz-Behandlung eine besondere Bedeutung zugeordnet. Eine evidenzbasierte ethische Analyse unter den Kriterien des Wohlergehens, des Nicht-Schadens, der Autonomie und der Gerechtigkeit zeigt jedoch, dass die Bedeutung von Antidementiva oftmals uberschatzt wird und die Erwartungen zu hoch sind: Die Wirksamkeit von Antidementiva ist rein symptomatisch, sie fallt bei einer grosen Anzahl an Patienten nur gering aus und bleibt fur manche Patienten ohne Nutzen. Zudem sind Antidementiva mit Schadensrisiken behaftet und verbrauchen finanzielle Ressourcen, deren Verteilung auf verschiedenen Ebenen zur Diskussion steht. Angesichts dieser Schwierigkeiten tritt eine bislang nur unzureichend beantwortete Grundfrage des Umgangs mit Demenz-Patienten in den Vordergrund: An welchen Zielen soll sich die Behandlung orientieren? Der folgende Artikel analysiert diese Frage vor dem Hintergrund der Grundstrukturen der derzeitigen Demenz-Behandlung und fordert hier zu einem grundlegenden Umdenken auf.
- Published
- 2007
25. PEG-Ernährung bei fortgeschrittener Demenz
- Author
-
Matthis Synofzik
- Subjects
medicine.medical_specialty ,Withholding Treatment ,Psychotherapist ,media_common.quotation_subject ,Beneficence ,Psychosomatic medicine ,General Medicine ,medicine.disease ,Clinical routine ,Psychiatry and Mental health ,Harm ,Neurology ,medicine ,Dementia ,Neurology (clinical) ,Psychology ,Empirical evidence ,Autonomy ,media_common - Abstract
Lacking clear empirical evidence and ethical obligations, decision-making about tube-feeding in patients with advanced dementia often presents as a difficult problem in clinical routine. Based on the principles of beneficence, non-maleficence and autonomy, an ethical analysis of the empirical evidence shows that tube-feeding should be avoided in many patients with advanced dementia: Recent studies demonstrate (1) that there is no proof of any benefit, (2) that tube-feeding often results in further harm to the dementia patient and (3) that the patient's will is not sufficiently taken into consideration. A practical model for interdisciplinary decision-making can account for these various difficulties and might improve the empirically and ethically highly complex process of decision-making about tube feeding in patients with advanced dementia.
- Published
- 2007
26. Wolfram Höfling (Hrsg.) (2005) Das sog. Wachkoma. Rechtliche, medizinische und ethische Aspekte. (Reihe Recht-Ethik-Gesundheit, Band 1)
- Author
-
Matthis Synofzik
- Subjects
Philosophy ,Issues, ethics and legal aspects ,Health (social science) ,Health Policy ,Theology - Published
- 2006
27. Wirksam, indiziert - und dennoch ohne Nutzen?
- Author
-
Matthis Synofzik
- Subjects
Gynecology ,Issues, ethics and legal aspects ,medicine.medical_specialty ,Health (social science) ,Geriatrics gerontology ,Political science ,medicine ,Geriatrics and Gerontology ,Gerontology - Abstract
Bei der Behandlung von Patienten mit Alzheimer- Demenz besteht oft eine Unsicherheit daruber, an welchen Zielen sich die Behandlung orientieren sollte und welche Masnahmen dem Patienten tatsachlich einen Nutzen bringen konnten. Die vorliegende Arbeit entwickelt drei Kriterien, um den Nutzen einer Behandlungsmasnahme zu prufen: Eine Masnahme (1) muss physiologisch oder psychologisch wirksam sein und (2) ein klinisch relevantes Behandlungsziel erreichen, das (3) fur den jeweiligen Patienten erstrebenswert ist. Am Beispiel der Antidementiva-Behandlung wird gezeigt, dass der Nutzen einer Masnahme fur einen Patienten selbst dann fragwurdig sein kann, wenn sie die ublicherweise angestrebten Ziele der Alzheimerbehandlung erreicht. Beispielsweise konnte selbst eine Verbesserung der kognitiven Leistungen oder eine Verzogerung des kognitiven Abbaus einen Schaden fur den Patienten bedeuten. Aus diesem Grunde sollte im Rahmen einer individuellen Alzheimer-Behandlung nicht nur darauf geachtet werden, dass ein Medikament wirksam ist und ein sinnvolles Behandlungsziel erreicht wird. Notwendig ist daruber hinaus eine explizite Reflexion, inwieweit die erreichbaren Behandlungsziele tatsachlich dem Wohl und dem mutmaslichen oder erklarten Willen des Patienten entsprechen. Mehrere Beispiele zeigen, wie dadurch koharente, patientenorientierte Behandlungsentscheidungen getroffen werden konnen.
- Published
- 2006
28. Die neuen Möglichkeiten der Neurowissenschaften und ihre ethischen Implikationen
- Author
-
Matthis Synofzik
- Subjects
Gynecology ,Philosophy ,Issues, ethics and legal aspects ,medicine.medical_specialty ,Health (social science) ,Health Policy ,medicine - Abstract
Durch den rasanten Fortschritt in den Neurowissenschaften ergibt sich ein bidirektionales Implikationsverhaltnis zwischen Ethik und Neurowissenschaften: Einerseits haben neurowissenschaftliche Erkenntnisse epistemische Implikationen fur anthropologisch-ethische Grundkonzepte, andererseits haben ethische Kriterien normative Implikationen fur neurowissenschaftliche Interventionen. Die Neuroethik untersucht diese normativen Implikationen systematisch auf der metaethischen, der theoretischen und der praktischen Ebene. Um eine spezifische und differenzierte ethische Analyse der einzelnen neurowissenschaftlichen Interventionen zu ermoglichen, soll hier eine bereichsspezifische, neuroethische Kriteriologie vorgestellt werden. Durch exemplarische Anwendung ihrer einzelnen Kriterien auf gegenwartige und zukunftige neurowissenschaftliche Forschungs- und Interventionsmoglichkeiten soll gezeigt werden, dass sie eine systematische und zugleich praktisch anwendbare Moglichkeit bietet, einen normativen Orientierungsrahmen fur Neurowissenschaften und Neurologie zu gewinnen. Insofern sie auf weitgehend konsensfahigen ethischen Prinzipien basiert, kann sie zudem als ethische Grundlage fur einen breiten klinischen und wissenschaftlichen Diskurs dienen.
- Published
- 2005
29. Videogame-based coordinative training can improve advanced, multisystemic early-onset ataxia
- Author
-
Martin A. Giese, Cornelia Schatton, Julia Wolf, Winfried Ilg, Ludger Schöls, and Matthis Synofzik
- Subjects
Male ,medicine.medical_specialty ,Neurology ,Ataxia ,Severity of Illness Index ,physiology [Psychomotor Performance] ,physiopathology [Ataxia] ,Disability Evaluation ,Severity of illness ,Humans ,Medicine ,In patient ,ddc:610 ,Young adult ,Child ,rehabilitation [Ataxia] ,Balance (ability) ,business.industry ,diagnosis [Ataxia] ,Natural history ,Video Games ,Physical therapy ,Neurology (clinical) ,medicine.symptom ,Early onset ataxia ,business - Abstract
Dear Sirs,Treatment options are rare in neurodegenerative childhood-onset ataxias, especially if presenting in advanced diseasestages and with multisystemic disease load. Moreover,wheelchair-bound children and young adults with ataxiaare commonly excluded from current drug treatment trials[1, 2], thus leaving them without prospects of access tonovel treatments. Using a rater-blinded intraindividualcontrol design, we here provide first proof-of-principleevidence that videogame-based coordinative training mightserve as an effective treatment even for advanced, multi-systemic degenerative ataxia.A 10-year-old boy suffering from genetically confirmedAtaxia Telangiectasia (compound heterozygous ATMp.Glu2596Aspfs*4 and p.Asp1625_Ala2626delinsGluPro)since 3 years of age and wheelchair-bound with onlyresidual standing and walking capacities since 7 years ofage (clinical details, Supplement 1) was recruited for asequentially structured 12-week coordinative training pro-gram based on specifically selected, commercially avail-able Nintendo Wii games (for details, see Fig. 1a). Thesubject was examined four times: 5 weeks before theintervention (E1), immediately before the first trainingphase (E2), after the first home training phase (E3) andafter the second home training phase (E4). Delta E1–E2was taken as an intraindividual control period to control forchanges associated with a monthly intravenous applicationof 750 mg methylprednisolone per day for 3 days whichhad been initiated by the patient’s local physicians [8 months before the study. Dosis and interval were keptconstant before and throughout the study. The outcomemeasures were: (1) clinical degree of clinical ataxiaseverity, rated by means of videotaped Scale for theAssessment and Rating of Ataxia (SARA) [3] scores pre-sented in a random order to an ataxia specialist (J.W.)blinded to the number of the specific examination (E1–E4);(2) quantitative movement analysis of balance capacities insitting (methodological details, [4, 5] and Supplement 3);and (3) achievements in patient self-selected individuallyimportant goals with respect to standing and sitting,assessed by the goal attainment score (GAS) [6] (Supple-ment 4). This study has been approved by the appropriateethics committee and has been performed in accordancewith the ethical standards laid down in the 1964 Declara-tion of Helsinki and its later amendments.The SARA score of 26.5/40 points, indicating anadvanced disease stage, remained unchanged before train-ing (E1–E2), thus demonstrating no major effect of corti-costeroids or substantial fluctuations in the natural history
- Published
- 2013
30. Boudewijn Chabot, Christian Walther (2010) Ausweg am Lebensende. Selbstbestimmtes Sterben durch freiwilligen Verzicht auf Essen und Trinken
- Author
-
Matthis Synofzik
- Subjects
Philosophy ,Issues, ethics and legal aspects ,Health (social science) ,Health Policy ,Theology - Published
- 2010
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