Extrapyramídové ochorenia predstavujú heterogénnu skupinu ochorení, v mnohých prípadoch monogénne podmienenú. Najmä zásluhou technologického pokroku v oblasti sekvenovania došlo v posledných rokoch k významnému posunu diagnostických algoritmov pre túto skupinu ochorení, kde sa čoraz viac využívajú metodiky "next-generation sequencing". V prehľadovom článku je prezentovaný súčasný pohľad na genetickú diagnostiku extrapyramídových ochorení, súčasné možnosti testovania a prichádzajúce trendy so zameraním najmä na priblíženie pragmatických algoritmov testovania.
Movement disorders represent a heterogeneous group of diseases, often with a monogenic background. Especially thanks to technological progress in the field of sequencing, there has been a significant shift in diagnostic algorithms for this group of diseases in recent years, where "next-generation sequencing" methodologies are increasingly being used. The review article presents a current view of the genetic diagnostics of movement disorders, current testing options and upcoming trends, with a particular focus on pragmatic testing algorithms.
- MeSH
- diferenciální diagnóza MeSH
- dystonie diagnóza genetika klasifikace MeSH
- genetické testování metody MeSH
- hyperkinetická porucha diagnóza genetika klasifikace MeSH
- lidé MeSH
- nemoci bazálních ganglií * diagnóza genetika klasifikace MeSH
- parkinsonské poruchy diagnóza genetika klasifikace MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.
- MeSH
- biologie MeSH
- fenotyp MeSH
- lidé MeSH
- parkinsonské poruchy * epidemiologie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- Guadeloupe MeSH
INTRODUCTION: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. METHODS: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. RESULTS: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. CONCLUSIONS: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
- MeSH
- ataxie MeSH
- dihydroxyfenylalanin MeSH
- fenotyp MeSH
- lidé MeSH
- mutace MeSH
- myoklonus * MeSH
- parkinsonské poruchy * farmakoterapie genetika MeSH
- spinocerebelární degenerace * MeSH
- tremor MeSH
- tryptofan-tRNA-ligasa * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
BACKGROUND: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). OBJECTIVE: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. METHODS: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. RESULTS: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. CONCLUSION: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.
- MeSH
- heterozygot MeSH
- lidé MeSH
- Parkinsonova nemoc * genetika MeSH
- parkinsonské poruchy * genetika MeSH
- porucha chování v REM spánku * genetika MeSH
- spánek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- F-box proteiny genetika MeSH
- fenotyp MeSH
- Lewyho tělíska patologie MeSH
- lidé MeSH
- parkinsonské poruchy diagnóza genetika patologie MeSH
- progresivní supranukleární obrna diagnóza genetika patologie MeSH
- senioři nad 80 let MeSH
- vezikulární transportní proteiny genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- Publikační typ
- dopisy MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- region Horňácko,
- MeSH
- genetická predispozice k nemoci genetika MeSH
- genetické testování MeSH
- lidé MeSH
- parkinsonské poruchy genetika MeSH
- Check Tag
- lidé MeSH
- MeSH
- parkinsonské poruchy genetika MeSH
- plagiátorství MeSH
- profesionální etika MeSH
- Publikační typ
- tisková chyba MeSH
Atypické parkinsonské syndromy tvoří pestrou škálu fenotypů charakterizovaných přítomností parkinsonského syndromu s měnlivou akcentací jednotlivých symptomů, motorických, kognitivních i behaviorálních, a s velmi variabilním průběhem. Klasifikace těchto onemocnění prochází rychlým vývojem, a to hlavně díky molekulární genetice a klinicko-patologické korelaci.
Atypical parkinsonian syndromes include a diverse range of phenotypes characterized by the presence of the parkinsonian syndrome with variable accentuation of the different symptoms, motor, cognitive and behavioural, and with very variable course. Classification of these diseases is rapidly evolving, mainly owing to molecular genetics and clinical-pathological correlation.
- Klíčová slova
- Perryho syndrom, autozomálně dominantní spinocerebelární ataxie, atypické parkinsonské syndromy,
- MeSH
- demence s Lewyho tělísky genetika MeSH
- frontotemporální demence genetika MeSH
- lidé MeSH
- multisystémová atrofie genetika MeSH
- Parkinsonova nemoc genetika MeSH
- parkinsonské poruchy * genetika MeSH
- spinocerebelární ataxie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: A higher prevalence of parkinsonism was recently identified in southeastern Moravia (Czech Republic). Further research confirmed 3 large pedigrees with familial autosomal-dominant parkinsonism spanning 5 generations. METHODS: This case report concerns a patient belonging to one of these 3 pedigrees, in whom motor and oculomotor symptoms were accompanied by frontal-type dementia, who finally developed a clinical phenotype of progressive supranuclear palsy. Molecular genetic examinations were performed due to the positive family history. RESULTS: No previously described causal mutation was found. After filtering against common variants (minor allele frequency (MAF) < 0.01), 2 noncoding and 1 synonymous rare mutation potentially associable with parkinsonism were identified: GIGYF2-GRB10 Interacting GYF Protein 2, PARK11 (c.*2030G > A, rs115669549); VPS35 gene-vacuolar protein sorting 35, PARK17 (c.102 + 33G > A, rs192115886); and FBXO7-F-box only protein 7 gene, PARK15 (c.540A > G, rs41311141). CONCLUSION: As to the changes in the FBXO7 and VPS35 genes (despite phylogenetic conservation in primates), probably neither the FBXO7 nor the VPS35 variants will be direct causal mutations. Both described variants, and possibly the influence of their combination, could increase the risk of the disease.
- MeSH
- F-box proteiny genetika MeSH
- genetická predispozice k nemoci MeSH
- genetické testování MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek diagnostické zobrazování MeSH
- mutace MeSH
- parkinsonské poruchy * komplikace diagnóza genetika MeSH
- progresivní supranukleární obrna * diagnóza etiologie patofyziologie MeSH
- rodokmen MeSH
- senioři nad 80 let MeSH
- vezikulární transportní proteiny genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
