Publications by authors named "Matej Skorvanek"

46 Publications

Comparison in detection of prodromal Parkinson's disease patients using original and updated MDS research criteria in two independent cohorts.

Parkinsonism Relat Disord 2021 Jun 30;87:48-55. Epub 2021 Apr 30.

Department of Neurology, P. J. Safarik University, Trieda SNP 1, 04011, Kosice, Slovak Republic; Department of Neurology, University Hospital L. Pasteur, Rastislavova 43, 04190, Kosice, Slovak Republic.

Introduction: MDS research criteria for prodromal Parkinson's disease (pPD) were published in 2015 and updated in 2019. We aimed to determine the difference in pPD patient detection rates in two cohorts recruited via gastrointestinal symptoms (PARCAS study) and the presence of a probable REM sleep behaviour disorder (PDBIOM study) using the original and updated criteria.

Methods: We evaluated all risk and prodromal markers, except genetic testing, plasma urate and physical inactivity, in both cohorts and DaT scan, diabetes mellitus type II and cognitive deficit in the PARCAS cohort. Thresholds of 50% probability for possible pPD and 80% for probable pPD were used.

Results: PPD status as identified by the original/updated criteria showed differences for probable pPD (n = 8/9; original/updated criteria) and possible pPD (n = 9/13) in the PARCAS cohort (total n = 158), as well as for probable pPD (n = 19/21) and possible pPD (n = 6/3) in the PDBIOM cohort (total n = 48). A high concordance rate was found between the two criteria sets (p < 0.001 for all groups).

Conclusion: All probable pPD cases remained in the same category after evaluation with both criteria; three possible pPD cases based on the original criteria exceeded the threshold for probable pPD based on the updated criteria, and five possible new pPD cases were detected, with only one shift in the opposite direction. The updated MDS pPD research criteria tend to identify more patients as positive, yet their accuracy needs to be determined in prospective studies.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.028DOI Listing
June 2021

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

Mov Disord 2021 May 5. Epub 2021 May 5.

Klinik für Neurologie, Asklepios Fachklinikum Stadtroda, Stadtroda, Germany.

Background: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications.

Objectives: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity).

Methods: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses.

Results: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81.

Conclusions: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28614DOI Listing
May 2021

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome.

Ann Clin Transl Neurol 2021 04 6;8(4):951-955. Epub 2021 Mar 6.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.
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http://dx.doi.org/10.1002/acn3.51335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045898PMC
April 2021

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Clin Genet 2021 Jul 1;100(1):14-28. Epub 2021 Mar 1.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
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http://dx.doi.org/10.1111/cge.13946DOI Listing
July 2021

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Parkinsonism Relat Disord 2021 03 12;84:129-134. Epub 2021 Feb 12.

Lehrstuhl für Sozialpädiatrie, Technische Universität München, Munich, Germany; Kbo-Kinderzentrum München, Munich, Germany.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia.

Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource.

Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone.

Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.013DOI Listing
March 2021

Neuromodulation Options and Patient Selection for Parkinson's Disease.

Neurol India 2020 Nov-Dec;68(Supplement):S170-S178

Department of Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.

Neuromodulation therapies, including deep brain stimulation (DBS) and pump therapies, are currently the standard of care for PD patients with advanced disease and motor complications that are difficult to control with medical management alone. The quest for alternate lesser invasive approaches led to the development of several novel therapies like intrajejunal levodopa infusions (IJLI), continuous subcutaneous apomorphine infusions (CSAI) and Magnetic Resonance guided Focused Ultrasound (MRgFUS) in recent years. To achieve good outcomes with any of these therapeutic modalities, careful patient selection, multidisciplinary evaluation and technical expertise are equally important. In this review, we will provide an overview of the neuromodulation strategies currently available for PD, emphasizing on patient selection and choosing among the various strategies.
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http://dx.doi.org/10.4103/0028-3886.302473DOI Listing
June 2021

Predictors of outcome events and 6-year mortality after carotid endarterectomy and carotid stenting in patients with carotid artery stenosis.

Neurol Neurochir Pol 2021 26;55(1):67-73. Epub 2020 Nov 26.

Department of Neurology Pavol Jozef Safarik University and L. Pasteur University Hospital, Trieda SNP 1, 04011 Košice, Slovakia.

Aim: The aim of our study was to evaluate the results of CEA and CAS in patients with carotid artery stenosis, and their effect on long-term mortality and morbidity, as well as to identify predictors of long-term mortality in a single-centre observational study.

Clinical Rationale: While data on short-term morbidity and mortality after carotid endarterectomy (CEA) and carotid stenting (CAS) is robust, there is only a limited amount of literature on long-term mortality and its predictors five years-plus post these procedures.

Material And Methods: Consecutive patients with symptomatic and asymptomatic internal carotid artery stenosis treated with CEA or CAS in a single centre in eastern Slovakia between 2012 and 2014 were included. We recorded basic sociodemographic data, the presence of co-morbidities and periprocedural complications. Clinical and sonographic follow-up was performed three and 12 months after the procedures. Patient survival data and any stroke data was obtained at the end of a six-year follow-up.

Results: We included 259 patients after CEA (mean age 67.4 ± 8.5, 64.5% men) and 321 after CAS (mean age 66.9 ± 8.4, 73.5% men). We did not identify a statistically significant difference in short-term or long-term mortality, survival times, or the presence of short-term or long-term complications between the CEA and CAS groups. Predictors of long-term mortality included age and diabetes mellitus in both cohorts. Repeated interventions were related to increased mortality only in the CAS cohort.

Conclusions: The results of our study show that long-term mortality does not differ between CEA and CAS.
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http://dx.doi.org/10.5603/PJNNS.a2020.0089DOI Listing
March 2021

Monogenic variants in dystonia: an exome-wide sequencing study.

Lancet Neurol 2020 11;19(11):908-918

Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

Funding: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
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http://dx.doi.org/10.1016/S1474-4422(20)30312-4DOI Listing
November 2020

Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations.

Mov Disord 2021 02 6;36(2):283-297. Epub 2020 Oct 6.

Department of Neurology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovak Republic.

Background: We assessed the clinimetric properties of ataxia rating scales and functional tests, and made recommendations regarding their use.

Methods: A systematic literature search was conducted to identify the instruments used to rate ataxia symptoms. The identified rating scales and functional ability tests were reviewed and ranked by the panel as "recommended," "suggested," or "listed" for the assessment of patients with discrete cerebellar disorders, using previously established criteria.

Results: We reviewed 14 instruments (9 rating scales and 5 functional tests). "Recommended" rating scales for the assessment of symptoms severity were: for Friedreich's ataxia, the Friedreich's Ataxia Rating Scale, the International Cooperative Ataxia Rating Scale (ICARS), and the Scale for the Assessment and Rating of Ataxia (SARA); for spinocerebellar ataxias, ICARS and SARA; for ataxia telangiectasia: ICARS and SARA; for brain tumors, SARA; for congenital disorder of glycosylation-phosphomannomutase-2 deficiency, ICARS; for cerebellar symptoms in multiple sclerosis, ICARS; for cerebellar symptoms in multiple system atrophy: Unified Multiple System Atrophy Rating Scale and ICARS; and for fragile X-associated tremor ataxia syndrome, ICARS. "Recommended" functional tests were: for Friedreich's ataxia, Ataxia Functional Composite Score and Composite Cerebellar Functional Severity Score; and for spinocerebellar ataxias, Ataxia Functional Composite Score, Composite Cerebellar Functional Severity Score, and SCA Functional Index.

Conclusions: We identified some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28313DOI Listing
February 2021

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

Ann Neurol 2020 11 21;88(5):867-877. Epub 2020 Sep 21.

Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Objectives: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses.

Methods: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells.

Results: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 10 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function.

Interpretation: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.
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http://dx.doi.org/10.1002/ana.25879DOI Listing
November 2020

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

J Parkinsons Dis 2020 ;10(4):1833-1843

Department of Neurology, Pauls Stradiņš Clinical University Hospital, Riga, Latvia.

Background: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa.

Objective: To survey the accessible MD clinical training in these regions.

Methods: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs.

Results: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology.

Conclusion: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.
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http://dx.doi.org/10.3233/JPD-202000DOI Listing
January 2020

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia.

Parkinsonism Relat Disord 2020 08 29;77:70-75. Epub 2020 Jun 29.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.

Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.

Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed.

Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date.

Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.
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http://dx.doi.org/10.1016/j.parkreldis.2020.06.027DOI Listing
August 2020

Prevalence of non-motor symptoms and their association with quality of life in cervical dystonia.

Acta Neurol Scand 2020 Dec 13;142(6):613-622. Epub 2020 Jul 13.

Department of Community and Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Objectives: Non-motor symptoms (NMS) are commonly present along with motor impairment in patients with cervical dystonia (CD) and have a significant impact on health-related quality of life (HRQoL). However, the prevalence of NMS and their association with dystonia are still unclear. The aim of our study was to assess the prevalence of depression, anxiety, fatigue, apathy, pain, sleep problems, and excessive daytime sleepiness (EDS) in CD using different evaluation approaches and to explore their association with HRQoL relative to that of motor symptoms.

Materials And Methods: We enrolled 102 Slovak patients with CD. The severity of both motor and non-motor symptoms was assessed using validated scales. HRQoL was determined by the 36-item Short Form Health Survey (SF-36). Association of NMS with poor HRQoL was assessed using multiple regressions.

Results: The most frequent NMS in our sample were sleep impairment (67.3%), anxiety (65.5%), general and physical fatigue (57.5% and 52.9%, respectively), depression (47.1%), mental fatigue (31.4%), apathy (30.4%), reduced activity (29.4%), EDS (20.2%), and reduced motivation (18.6%). Univariate analysis showed that NMS, but not motor symptoms, were significantly linked to poor HRQoL, with EDS being most commonly associated with poor HRQoL, followed by disrupted sleep, depression, and fatigue.

Conclusions: The prevalence of NMS among patients with CD is high, and some NMS are strongly associated with poor HRQoL, while motor impairment was not associated with the severity of NMS or poor HRQoL. Actively diagnosing and treating NMS should therefore be a routine part of the clinical management of patients with CD.
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http://dx.doi.org/10.1111/ane.13304DOI Listing
December 2020

Update on the Management of Parkinson's Disease for General Neurologists.

Parkinsons Dis 2020 26;2020:9131474. Epub 2020 Mar 26.

Department of Neurology. Medical Faculty, P. J. Safarik University and Department of Neurology University Hospital of L. Pasteur, Kosice, Slovakia.

Management of Parkinson's disease (PD) is complicated due to its progressive nature, the individual patient heterogeneity, and the wide range of signs, symptoms, and daily activities that are increasingly affected over its course. The last 10-15 years have seen great progress in the identification, evaluation, and management of PD, particularly in the advanced stages. Highly specialized information can be found in the scientific literature, but updates do not always reach general neurologists in a practical and useful way, potentially creating gaps in knowledge of PD between them and neurologists subspecialized in movement disorders, resulting in several unmet patient needs. However, general neurologists remain instrumental in diagnosis and routine management of PD. This review provides updated practical information to identify problems and resolve common issues, particularly when the advanced stage is suspected. Some tips are provided for efficient communication with the members of a healthcare team specialized in movement disorders, in order to find support at any stage of the disease in a given patient, and especially for a well-timed decision on referral.
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http://dx.doi.org/10.1155/2020/9131474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136815PMC
March 2020

Whole exome sequencing identifies a homozygous POLG2 missense variant in an adult patient presenting with optic atrophy, movement disorders, premature ovarian failure and mitochondrial DNA depletion.

Eur J Med Genet 2020 Apr 26;63(4):103821. Epub 2019 Nov 26.

Dept. of Medical Genetics, Medical University of Warsaw, Warsaw, Poland. Electronic address:

POLG2 associated disorders belong to the group of mitochondrial DNA (mtDNA) diseases and present with a heterogeneous clinical spectrum, various age of onset, and disease severity. We report a 39-year old female presenting with childhood-onset and progressive neuroophthalmic manifestation with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia and generalized chorea associated with mtDNA depletion. Whole-exome sequencing identified an ultra-rare homozygous missense mutation located at Chr17: 062474101-C > A (p.Asp433Tyr) in nuclear POLG2 gene encoding PolγB, an accessory subunits of mitochondrial polymerase γ responsible for mtDNA replication. The healthy parents and 2 sisters of the patient were heterozygous for the variant. To our best knowledge, this is the first case of homozygous variant in the POLG2 gene resulting in mitochondrial depletion syndrome in an adult patient and its clinical manifestations extend the clinical spectrum of POLG2 associated diseases.
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http://dx.doi.org/10.1016/j.ejmg.2019.103821DOI Listing
April 2020

Adherence to Pharmacotherapy in Patients With Parkinson's Disease Taking Three and More Daily Doses of Medication.

Front Neurol 2019 31;10:799. Epub 2019 Jul 31.

Second Department of Neurology, Comenius University in Bratislava Faculty of Medicine, University Hospital Bratislava, Bratislava, Slovakia.

Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence. The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study. From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness. Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.
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http://dx.doi.org/10.3389/fneur.2019.00799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684743PMC
July 2019

Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia.

Genet Med 2019 11 30;21(11):2532-2542. Epub 2019 Apr 30.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

Purpose: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a CH domain-containing transcription factor.

Methods: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals.

Results: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia.

Conclusion: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.
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http://dx.doi.org/10.1038/s41436-019-0523-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821592PMC
November 2019

Ataxia Telangiectasia Gene Mutation in Isolated Segmental Dystonia Without Ataxia and Telangiectasia.

Mov Disord Clin Pract 2018 Jan-Feb;5(1):89-91. Epub 2017 Dec 3.

Department of Neurology and Center of Clinical Neuroscience First Faculty of Medicine Charles University and General Faculty Hospital Prague Czech Republic.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1.htm.
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http://dx.doi.org/10.1002/mdc3.12564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090590PMC
December 2017

Reply: Hoehn and Yahr stage 3 and Postural stability item in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

Mov Disord 2018 07;33(7):1189-1190

Rush University Medical Center, Department of Neurological Sciences, Section of Parkinson Disease and Movement Disorders, Chicago, IL, USA.

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http://dx.doi.org/10.1002/mds.27452DOI Listing
July 2018

Accuracy of Rating Scales and Clinical Measures for Screening of Rapid Eye Movement Sleep Behavior Disorder and for Predicting Conversion to Parkinson's Disease and Other Synucleinopathies.

Front Neurol 2018 25;9:376. Epub 2018 May 25.

Department of Neurology, Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by repeated episodes of REM sleep-related vocalizations and/or complex motor behaviors. Definite diagnosis of RBD is based on history and polysomnography, both of which are less accessible due to the lack of trained specialists and high cost. While RBD may be associated with disorders like narcolepsy, focal brain lesions, and encephalitis, idiopathic RBD (iRBD) may convert to Parkinson's disease (PD) and other synucleinopathies in more than 80% of patients and it is to date the most specific clinical prodromal marker of PD. Identification of individuals at high risk for development of PD is becoming one of the most important topics for current PD-related research as well as for future treatment trials targeting prodromal PD. Furthermore, concomitant clinical symptoms, such as subtle motor impairment, hyposmia, autonomic dysfunction, or cognitive difficulties, in subjects with iRBD may herald its phenoconversion to clinically manifest parkinsonism. The assessment of these motor and non-motor symptoms in iRBD may increase the sensitivity and specificity in identifying prodromal PD subjects. This review evaluates the diagnostic accuracy of individual rating scales and validated single items for screening of RBD and the role and accuracy of available clinical, electrophysiological, imaging, and tissue biomarkers in predicting the phenoconversion from iRBD to clinically manifest synucleinopathies.
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http://dx.doi.org/10.3389/fneur.2018.00376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980959PMC
May 2018

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

Parkinsonism Relat Disord 2018 07 28;52:83-89. Epub 2018 Mar 28.

Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS_1127, CIC_1422, CNRS UMR_7225, AP-HP, ICM, Hôpital Pitié-Salpêtrière, Département des maladies du système nerveux, F-75013, Paris, France.

Background: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients.

Methods: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items.

Results: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue.

Conclusions: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2018.03.027DOI Listing
July 2018

Reply: MoCA for cognitive screening in Parkinson's disease: Beware of floor effect.

Mov Disord 2018 03 20;33(3):499-500. Epub 2018 Feb 20.

National Centre of Epidemiology and CIBERNED, Carlos III Institute of Health, Madrid, Spain.

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http://dx.doi.org/10.1002/mds.27339DOI Listing
March 2018

Randomised controlled trial of escitalopram for cervical dystonia with dystonic jerks/tremor.

J Neurol Neurosurg Psychiatry 2018 06 11;89(6):579-585. Epub 2018 Jan 11.

Department of Neurology, University Medical Center, Groningen, The Netherlands.

Objective: Trials for additional or alternative treatments for cervical dystonia (CD) are scarce since the introduction of botulinum neurotoxin (BoNT). We performed the first trial to investigate whether dystonic jerks/tremor in patients with CD respond to the selective serotonin reuptake inhibitor (SSRI) escitalopram.

Methods: In a randomised, double-blind, crossover trial, patients with CD received escitalopram and placebo for 6 weeks. Treatment with BoNT was continued, and scores on rating scales regarding dystonia, psychiatric symptoms and quality of life (QoL) were compared. Primary endpoint was the proportion of patients that improved at least one point on the Clinical Global Impression Scale for jerks/tremor scored by independent physicians with experience in movement disorders.

Results: Fifty-threepatients were included. In the escitalopram period, 14/49 patients (29%) improved on severity of jerks/tremor versus 11/48 patients (23%) in the placebo period (P=0.77). There were no significant differences between baseline and after treatment with escitalopram or placebo on severity of dystonia or jerks/tremor. Psychiatric symptoms and QoL improved significantly in both periods compared with baseline. There were no significant differences between treatment with escitalopram and placebo for dystonia, psychiatric or QoL rating scales. During treatment with escitalopram, patients experienced slightly more adverse events, but no serious adverse events occurred.

Conclusion: In this innovative trial, no add-on effect of escitalopram for treatment of CD with jerks was found on motor or psychiatric symptoms. However, we also did not find a reason to withhold patients treatment with SSRIs for depression and anxiety, which are common in dystonia.

Trial Registration Number: NTR2178.
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http://dx.doi.org/10.1136/jnnp-2017-317352DOI Listing
June 2018

Global scales for cognitive screening in Parkinson's disease: Critique and recommendations.

Mov Disord 2018 02 23;33(2):208-218. Epub 2017 Nov 23.

National Centre of Epidemiology and CIBERNED, Carlos III Institute of Health, Madrid, Spain.

Background: Cognitive impairment is a common nonmotor manifestation of Parkinson's disease, with deficits ranging from mild cognitive difficulties in 1 or more of the cognitive domains to severe dementia. The International Parkinson and Movement Disorder Society commissioned the assessment of the clinimetric properties of cognitive rating scales measuring global cognitive performance in PD to make recommendations regarding their use.

Methods: A systematic literature search was conducted to identify the scales used to assess global cognitive performance in PD, and the identified scales were reviewed and rated as "recommended," "recommended with caveats," "suggested," or "listed" by the panel using previously established criteria.

Results: A total of 12 cognitive scales were included in this review. Three scales, the Montreal Cognitive Assessment, the Mattis Dementia Rating Scale Second Edition, and the Parkinson's Disease-Cognitive Rating Scale, were classified as "recommended." Two scales were classified as "recommended with caveats": the Mini-Mental Parkinson, because of limited coverage of executive abilities, and the Scales for Outcomes in Parkinson's Disease-Cognition, which has limited data on sensitivity to change. Six other scales were classified as "suggested" and 1 scale as "listed."

Conclusions: Because of the existence of "recommended" scales for assessment of global cognitive performance in PD, this task force suggests that the development of a new scale for this purpose is not needed at this time. However, global cognitive scales are not a substitute for comprehensive neuropsychological testing. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27233DOI Listing
February 2018