Research Outputs

Permanent URI for this communityhttps://hdl.handle.net/20.500.14288/2

Browse

Filters

2020 - 20225

Advanced Search

Filter by

Settings

Sponsors: search.filters.sponsors.EUSubject: search.filters.subject.Clinical neurology

Search Results

Now showing 1 - 5 of 5
  • Thumbnail Image
    PublicationOpen Access
    Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
    (Oxford University Press (OUP), 2021) Sanderson, L.E.; Lanko, K.; Alsagob, M.; Almass, R.; Al-Ahmadi, N.; Najafi, M.; Al-Muhaizea, M.A.; Alzaidan, H.; AlDhalaan, H.; Perenthaler, E.; van der Linde, H.C.; Nikoncuk, A.; Kühn, N. A.; Antony, D.; Owaidah, T.M.; Raskin, S.; Vieira, L. G. D. R.; Mombach, R.; Ahangari, N.; Silveira, T. R. D.; Ameziane, N.; Rolfs, A.; Alharbi, A.; Sabbagh, R. M.; AlAhmadi, K.; Alawam, B.; Ghebeh, H.; AlHargan, A.; Albader, A. A.; Binhumaid, F. S.; Goljan, E.; Monies, D.; Mustafa, O. M.; Aldosary, M.; AlBakheet, A.; Alyounes, B.; Almutairi, F.; Al-Odaib, A; Aksoy, D. B.; Trabzuni, D.; Rosenfeld, J. A.; Karimiani, E. G.; Meyer, B. F.; Karakaş, B.; Al-Mohanna, F.; Arold, S. T.; Çolak, D.; Maroofian, R.; Houlden, H.; Bertoli-Avella, A. M.; Schmidts, M.; Barakat, T. S.; van Ham, T. J.; Kaya, N.; Başak, Ayşe Nazlı; Palvadeau, Robin Jerome; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512; N/A
    Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.
  • Thumbnail Image
    PublicationOpen Access
    Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients
    (Wiley, 2020) Traschuetz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Hanagasi, Hasmet; Kurul, Semra Hız; Bender, Benjamin; Schoels, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Helene; Synofzik, Matthis; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    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.
  • Thumbnail Image
    PublicationOpen Access
    Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks
    (Wiley, 2022) Myren-Svelstad, Sverre; Jamali, Ahmed; Ophus, Sunniva S.; D'gama, Percival P.; Ostenrath, Anna M.; Mutlu, Aytac Kadir; Hoffshagen, Helene Homme; Hotz, Adriana L.; Neuhauss, Stephan C. F.; Jurisch-Yaksi, Nathalie; Yakşi, Emre; Other; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine
    Objective: the switch between nonseizure and seizure states involves profound alterations in network excitability and synchrony. In this study, we aimed to identify and compare features of neural excitability and dynamics across multiple zebrafish seizure and epilepsy models. Methods: inspired by video-electroencephalographic recordings in patients, we developed a framework to study spontaneous and photically evoked neural and locomotor activity in zebrafish larvae, by combining high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging. Results: our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that spontaneous locomotor and neural activity exhibit great diversity across models. Nonetheless, during photic stimulation, hyperexcitability and rapid response dynamics were well conserved across multiple models, highlighting the reliability of photically evoked activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by rapid decay of neural activity and a prominent depressed state. Elevated photic response and following depressed state in seizure-prone networks are significantly reduced by the antiseizure medication valproic acid. Finally, rapid decay and depression of neural activity following photic stimulation temporally overlap with slow recruitment of astroglial calcium signals that are enhanced in seizure-prone networks. Significance We argue that fast decay of neural activity and depressed states following photic response are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies.
  • Thumbnail Image
    PublicationOpen Access
    The ARCA Registry: a collaborative global platform for advancing trial readiness in autosomal recessive cerebellar ataxias
    (Frontiers, 2021) Traschuetz, Andreas; Reich, Selina; Adarmes, Astrid D.; Anheim, Mathieu; Ashrafi, Mahmoud Reza; Baets, Jonathan; Bertini, Enrico; Brais, Bernard; Gagnon, Cynthia; Gburek-Augustat, Janina; Hanagasi, Hasmet A.; Heinzmann, Anna; Horvath, Rita; de Jonghe, Peter; Kamm, Christoph; Klivenyi, Peter; Klopstock, Thomas; Minnerop, Martina; Muenchau, Alexander; Renaud, Mathilde; Roxburgh, Richard H.; Santorelli, Filippo M.; Schirinzi, Tommaso; Sival, Deborah A.; Timmann, Dagmar; Vielhaber, Stefan; Wallner, Michael; van de Warrenburg, Bart P.; Zanni, Ginevra; Zuchner, Stephan; Klockgether, Thomas; Schuele, Rebecca; Schols, Ludger; Synofzik, Matthis; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.
  • Thumbnail Image
    PublicationOpen Access
    The effect of SMN gene dosage on ALS risk and disease severity
    (Wiley, 2021) Moisse, Matthieu; Zwamborn, Ramona A. J.; van Vugt, Joke; van Der Spek, Rick; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel; Kenna, Kevin; Corcia, Philippe; Couratier, Philippe; Vourc'h, Patrick; Hardiman, Orla; McLaughin, Russell; Gotkine, Marc; Drory, Vivian; Ticozzi, Nicola; Silani, Vincenzo; de Carvalho, Mamede; Mora Pardina, Jesus S.; Povedano, Monica; Andersen, Peter M.; Weber, Markus; Chen, Xiao; Eberle, Michael A.; Al-Chalabi, Ammar; Shaw, Chris; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Robberecht, Wim; van Es, Michael; van den Berg, Leonard; Veldink, Jan; Van Damme, Philip; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies.