Parkinson's disease (PD) affects the language processes, with a significant impact on the patients' daily communication. We aimed to describe specific alterations in the comprehension of syntactically complex sentences in patients with PD (PwPD) as compared to healthy controls (HC) and to identify the neural underpinnings of these deficits using a functional connectivity analysis of the striatum. A total of 20 patients PwPD and 15 HC participated in the fMRI study. We analyzed their performance of a Test of sentence comprehension (ToSC) adjusted for fMRI. A task-dependent functional connectivity analysis of the striatum was conducted using the psychophysiological interaction method (PPI). On the behavioral level, the PwPD scored significantly lower (mean ± sd: 77.3 ± 12.6) in the total ToSC score than the HC did (mean ± sd: 86.6 ± 8.0), p = 0.02, and the difference was also significant specifically for sentences with a non-canonical word order (PD-mean ± sd: 69.9 ± 14.1, HC-mean ± sd: 80.2 ± 11.5, p = 0.04). Using PPI, we found a statistically significant difference between the PwPD and the HC in connectivity from the right striatum to the supplementary motor area [SMA, (4 8 53)] for non-canonical sentences. This PPI connectivity was negatively correlated with the ToSC accuracy of non-canonical sentences in the PwPD. Our results showed disturbed sentence reading comprehension in the PwPD with altered task-dependent functional connectivity from the right striatum to the SMA, which supports the synchronization of the temporal and sequential aspects of language processing. The study revealed that subcortical-cortical networks (striatal-frontal loop) in PwPD are compromised, leading to impaired comprehension of syntactically complex sentences.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia. METHODS: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability. RESULTS: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia. CONCLUSIONS: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.
INTRODUCTION: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum. METHODS: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained. RESULTS: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2. CONCLUSIONS: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.
- MeSH
- dítě MeSH
- dystonie genetika MeSH
- epileptické syndromy komplikace genetika MeSH
- fenotyp MeSH
- forkhead transkripční faktory genetika MeSH
- lidé MeSH
- mladiství MeSH
- nemoci mozku komplikace genetika MeSH
- neurovývojové poruchy komplikace genetika MeSH
- předškolní dítě MeSH
- protein 2 vázající methyl-CpG genetika MeSH
- proteiny nervové tkáně genetika MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go genetika MeSH
- receptory GABA-A genetika MeSH
- receptory GABA-B genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Orfenadrín sa používa na liečbu parkinsonizmu a muskuloskeletálnych bolestivých syndrómov už viac ako 50 rokov. Hlavným dôvodom vedľajších účinkov tohto lieku je jeho anticholínergický efekt. Uvádzame prípady dvoch pacientok s pokročilou Parkinsonovou chorobou, u ktorých kombinovaná analgetická medikácia diklofenak/orfenadrín viedla k zhoršeniu fluktuácií a nástupu ťažkých dyskinéz.
Orphenadrine has been used for treatment of both parkinsonism and musculoskeletal diseases for more than 50 years. Anticholinergic mechanism of action is the main reason for side effects. We report on two patients with advanced Parkinson's disease in whom combined analgetic medication diclofenac/orphenadrine led to worsening of fluctuations and onset of severe dyskinesia.
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- bolesti zad farmakoterapie komplikace MeSH
- diklofenak škodlivé účinky MeSH
- fixní kombinace léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- nežádoucí účinky léčiv etiologie patofyziologie MeSH
- orfenadrin škodlivé účinky MeSH
- Parkinsonova nemoc * farmakoterapie komplikace MeSH
- polékové dyskineze * etiologie patofyziologie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
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.
- MeSH
- algoritmy MeSH
- dystonické poruchy * genetika MeSH
- dystonie * diagnóza genetika MeSH
- genetické testování MeSH
- lidé MeSH
- Parkinsonova nemoc * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- dospělí MeSH
- dystonické poruchy diagnóza genetika MeSH
- dystonie diagnóza genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- sekvenování exomu * MeSH
- variabilita počtu kopií segmentů DNA * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- dítě MeSH
- dystonie diagnóza epidemiologie genetika MeSH
- exom genetika MeSH
- genetická variace genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- sekvenování exomu metody MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Diabetes mellitus (DM) je chronické ochorenie, ktorého prevalencia sa neustále zvyšuje. Okrem všeobecne známych mikro a makrovaskulárnych komplikácií diabetu sa u pacientov vyskytujú aj neuropsychiatrické komplikácie. Strach z hypoglykémie, depresia aj úzkostné poruchy nepriaznivo ovplyvňujú nielen samotný priebeh základného ochorenia, ale majú vplyv aj na ostatné aspekty života pacientov. Preto je nutné tieto komplikácie u pacientov s diabetom cielene vyhľadávať a vykonávať potrebné terapeutické intervencie.
Diabetes mellitus (DM) is a chronic disease with constantly increasing prevalence. In addition to the well known micro and macrovascular complications, patients with diabetes can develop also neuropsychiatric complications. Fear of hypoglycemia, depression and anxiety disorders have an unpleasant impact on the course of disease itself as well as on the other parts of patient's lives. Therefore it is necessary to search for these kinds of complications and to be able to treat them correctly.
