Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.
- MeSH
- ataxie MeSH
- Friedreichova ataxie * MeSH
- genotyp MeSH
- lidé MeSH
- pohyby očí MeSH
- progrese nemoci MeSH
- spinocerebelární degenerace * MeSH
- teleangiektatická ataxie * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms. This narrative review summarizes the current knowledge on neuropsychiatric impairment in SCA and FRDA. We discuss the prevalence, clinical features and treatment approaches in the most commonly reported domains of depression, anxiety, apathy, agitation and impulse dyscontrol, and psychosis. Since these symptoms have a considerable impact on patients' quality of life, we argue that further research is mandated to improve the detection and treatment options of neuropsychiatric co-morbidities in ataxia patients.
- MeSH
- Friedreichova ataxie * komplikace MeSH
- komorbidita MeSH
- kvalita života MeSH
- lidé MeSH
- mozeček MeSH
- spinocerebelární ataxie * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Many patients with spinocerebellar ataxia (SCA) suffer from diverse neuropsychiatric issues, including memory impairments, apathy, depression, or anxiety. These neuropsychiatric aspects contribute per se to the reduced quality of life and worse prognosis. However, the extent to which SCA-related neuropathology directly contributes to these issues remains largely unclear. Behavioral profiling of various SCA mouse models can bring new insight into this question. This paper aims to synthesize recent findings from behavioral studies of SCA patients and mouse models. The role of SCA neuropathology for shaping psychiatric-like impairments may be exemplified in mouse models of SCA1. These mice evince robust cognitive impairments which are shaped by both the cerebellar as well as out-of-cerebellar pathology. Although emotional-related alternations are also present, they seem to be less robust and more affected by the specific distribution and character of the neuropathology. For example, cerebellar-specific pathology seems to provoke behavioral disinhibition, leading to seemingly decreased anxiety, whereas complex SCA1 neuropathology induces anxiety-like phenotype. In SCA1 mice with complex neuropathology, some of the psychiatric-like impairments are present even before marked cerebellar degeneration and ataxia and correlate with hippocampal atrophy. Similarly, complete or partial deletion of the implicated gene (Atxn1) leads to cognitive dysfunction and anxiety-like behavior, respectively, without apparent ataxia and cerebellar degeneration. Altogether, these findings collectively suggest that the neuropsychiatric issues have a biological basis partially independent of the cerebellum. As some neuropsychiatric issues may stem from weakening the function of the implicated gene, therapeutic reduction of its expression by molecular approaches may not necessarily mitigate the neuropsychiatric issues.
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
BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- MeSH
- alfa-synuklein metabolismus MeSH
- autoprotilátky MeSH
- celogenomová asociační studie MeSH
- lidé MeSH
- multisystémová atrofie * genetika patologie MeSH
- olivopontocerebelární atrofie * MeSH
- pitva MeSH
- proteiny nervové tkáně genetika MeSH
- striatonigrální degenerace * MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.
- Klíčová slova
- neurogenetika,
- MeSH
- bulbospinální atrofie vázaná na chromozom X diagnóza genetika MeSH
- Duchennova muskulární dystrofie diagnóza genetika klasifikace MeSH
- hereditární motorické a senzitivní neuropatie diagnóza genetika MeSH
- Huntingtonova nemoc diagnóza genetika MeSH
- Leighova nemoc diagnóza genetika MeSH
- lidé MeSH
- mitochondriální nemoci diagnóza genetika klasifikace MeSH
- myotonická dystrofie diagnóza genetika MeSH
- neurodegenerativní nemoci * diagnóza genetika MeSH
- spinocerebelární ataxie diagnóza genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) je autozomálně recesivní neurodegenerativní onemocnění z okruhu hereditárních ataxií s pozdním začátkem postihující mozeček, senzitivní nervy a vestibulární systém. Jeho genetická příčina byla odhalena v roce 2019 a od roku 2020 je dostupné také diagnostické molekulárně genetické vyšetření. Dle dosavadní literatury se ukazuje, že CANVAS je nejčastější příčinou hereditární ataxie s pozdním nástupem. Ve skupině prvních devíti vyšetřených pacientů s podezřením na toto onemocnění jsme zachytili čtyři případy CANVAS, tři pacienty podrobně popisujeme v této práci.
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease from hereditary ataxias with a late onset that affects the cerebellum, sensory nerves, and the vestibular system. Its genetic cause was discovered in 2019 and since 2020, diagnostic molecular genetic testing has also been available. According to the existing literature, it seems that CANVAS is a major cause of late onset hereditary ataxia. Out of the first nine examined patients with the suspected disease, we confirmed four cases of CANVAS; three of the patients are described in detail in this manuscript.
- Klíčová slova
- CANVAS,
- MeSH
- cerebelární ataxie * diagnóza MeSH
- lidé MeSH
- neuralgie * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spinocerebelární degenerace diagnóza MeSH
- vestibulární neuronitida MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their S-alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group-possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone-induced oxidative stress.
- MeSH
- acetáty chemická syntéza MeSH
- antioxidancia * chemická syntéza chemie farmakologie MeSH
- Caenorhabditis elegans MeSH
- Friedreichova ataxie farmakoterapie metabolismus patologie MeSH
- indoly * chemie farmakologie MeSH
- kultivované buňky MeSH
- kyseliny indoloctové chemie MeSH
- lidé MeSH
- oxadiazoly * chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- thioketony * chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- botulotoxiny terapeutické užití MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dystonické poruchy chirurgie etiologie farmakoterapie klasifikace patologie terapie MeSH
- lidé MeSH
- motorické poruchy * klasifikace patologie terapie MeSH
- mozková obrna diagnóza farmakoterapie klasifikace terapie MeSH
- spinocerebelární ataxie diagnóza etiologie klasifikace MeSH
- tikové poruchy klasifikace patologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
