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Database : the Journal of Biological... Aug 2023Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by abnormally expanded Cytosine, Adenine, Guanine (CAG) triplet repeat sequences in the coding...
Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by abnormally expanded Cytosine, Adenine, Guanine (CAG) triplet repeat sequences in the coding region of otherwise unrelated genes. Until now, nine different polyQ diseases have been described: Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy and six types of spinocerebellar ataxias-1, 2, 3, 6, 7 and 17. The pathogenic expansion translates into an aberrant tract of glutamines in the encoded proteins, compromising several cellular functions and biological processes. There is currently no cure available for the progressive neurodegenerative disorders caused by the ensuing cytotoxic alterations. Although each disease is considered rare, polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. Information about these disorders is scattered among several books, articles and general databases, hindering exploration by students and researchers, but also by patients and their families. Therefore, we aimed to develop a free online database to fill this gap, by centralizing relevant available information. The PolyQ Database is a platform that focuses on all nine polyQ diseases and offers information about topics that are pertinent for scientists, clinicians and the general public, including epidemiology, the characteristics of the causative genes and the codified proteins, the pathophysiology of the diseases and the main clinical manifestations. The database is available at https://polyq.pt/, and it is the first of its kind, focusing exclusively on this group of rare diseases. The database was conceived to be continuously updated and allow incorporation and dissemination of the latest information on polyQ diseases.
Topics: Humans; Peptides; Cytosine; Databases, Factual; Olivopontocerebellar Atrophies
PubMed: 37599593
DOI: 10.1093/database/baad060 -
BMC Medical Genomics Jun 2023Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar...
Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5'UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient's fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.
Topics: Humans; Cerebellar Diseases; Olivopontocerebellar Atrophies; RNA, Messenger; Arginine-tRNA Ligase
PubMed: 37344844
DOI: 10.1186/s12920-023-01582-z -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2023To describe the features of the clinical presentation and evaluate the incidence of HIV-associated cerebellar degeneration in patients with progressive cerebellar ataxia.
OBJECTIVE
To describe the features of the clinical presentation and evaluate the incidence of HIV-associated cerebellar degeneration in patients with progressive cerebellar ataxia.
MATERIAL AND METHODS
Three hundred and seventy-seven patients with progressive cerebellar ataxia were studied. Brain MRI study, assessment by the Scale for the Assessment and Rating of Ataxia (SARA), screening for cognitive impairment by the Montreal Cognitive Assessment Scale (MoCA) were performed. In patients with HIV infection, autoimmune, deficient and other causes of ataxia, as well as opportunistic infections, multiple system atrophy and frequent forms of hereditary spinocerebellar ataxias were excluded.
RESULTS
Five patients (1.3%) were identified with a combination of cerebellar ataxia and HIV infection (2 men, 3 women, aged 31 to 52 years). The median duration of HIV infection was 5 years, the duration of ataxia was 1 year. In the clinical findings, in addition to progressive ataxia, pyramidal signs, dysphagia, less often ophthalmoparesis, dystonia, postural hand tremor, affective and mild cognitive impairment were observed. In three patients, brain MRI revealed signs of olivopontocerebellar atrophy, two patients had isolated cerebellar degeneration (mainly of the vermis). All patients received combination of antiretroviral therapy in various regimens, but despite this, ataxia was progressive.
CONCLUSION
HIV infection is a rare cause of cerebellar degeneration. This diagnosis remains a diagnosis of exclusion to this day. Cerebellar degeneration can occur and progress even after achieving a stable remission of HIV infection while taking highly active antiretroviral therapy.
Topics: Male; Humans; Female; Cerebellar Ataxia; HIV Infections; Cerebellar Diseases; Neurodegenerative Diseases; Ataxia
PubMed: 37315251
DOI: 10.17116/jnevro2023123051123 -
Physiotherapy Theory and Practice May 2023Amplitude-based exercise training has been shown to be effective in the motor performance of individuals with idiopathic Parkinson's disease, with limited research...
BACKGROUND
Amplitude-based exercise training has been shown to be effective in the motor performance of individuals with idiopathic Parkinson's disease, with limited research investigating its effects on Parkinson plus syndromes such as olivopontocerebellar atrophy (OPCA). The purpose of this clinical case report is to examine the effects of amplitude-based training exercises on an individual with OPCA.
CASE DESCRIPTION
A 68-year-old man with a 14-month history of OPCA presented to physical therapy with bradykinesia, rigidity, and postural instability. The individual participated in 34 intervention sessions. Pre- and post-test measurements were collected for the following outcome measures: Five Times Sit to Stand (FTSTS); Functional Gait Assessment (FGA); Activities-Specific Balance Confidence Scale (ABC-6); 9 Hole Peg Test (9HPT); preferred and maximal gait speed.
OUTCOMES
Improvements reaching Minimum Detectable Change (MDC) or Minimal Clinically Important Difference (MCID) were recorded with a pre (Week 1) and post (Week 20) intervention: FGA score (4-point improvement (MDC = 4 points), preferred gait speed (0.09 meters/second improvement (MCID = 0.05 meters/second)), FTSTS (6-second improvement (MDC = 2.3 seconds)), and 9HPT on the dominant hand (3-second improvement (MDC = 2.6 seconds)). Fluctuations during the plan of care were observed for these measures, and additional outcomes did not demonstrate a worsening of function.
CONCLUSION
In an individual with OPCA, amplitude-based exercise training as a component of the plan of care increased dynamic balance in walking, gait speed, and hand dexterity. However, these results need to be validated on a larger sample of individuals with OPCA through randomized controlled trials.
PubMed: 37165996
DOI: 10.1080/09593985.2023.2210218 -
Nature Reviews. Neuroscience Jun 2023Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and... (Review)
Review
Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and autonomic brain centres. It causes complex cumulative motor and non-motor disability with fast progression and effective therapy is currently lacking. The difficulties in the diagnosis and treatment of MSA are largely related to the incomplete understanding of the pathogenesis of the disease. The MSA pathogenic landscape is complex, and converging findings from genetic and neuropathological studies as well as studies in experimental models of MSA have indicated the involvement of genetic and epigenetic changes; α-synuclein misfolding, aggregation and spreading; and α-synuclein strain specificity. These studies also indicate the involvement of myelin and iron dyshomeostasis, neuroinflammation, mitochondrial dysfunction and other cell-specific aspects that are relevant to the fast progression of MSA. In this Review, we discuss these findings and emphasize the implications of the complexity of the multifactorial pathogenic cascade for future translational research and its impact on biomarker discovery and treatment target definitions.
Topics: Humans; Multiple System Atrophy; alpha-Synuclein; Brain; Oligodendroglia; Myelin Sheath
PubMed: 37085728
DOI: 10.1038/s41583-023-00697-7 -
American Journal of Medical Genetics.... Jul 2023Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and...
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3' end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3-month-old female with PCH and additional clinical features not previously reported to be associated with PCH1, including dilated cardiomyopathy. On assessment, failure to thrive, microcephaly, distinctive facial features, and bluish sclera, were noted. Whole-exome sequencing was performed and revealed a novel homozygous missense variant c.547C > T (p.Arg183Trp) in the EXOSC1 gene. Functional studies in a budding yeast model that expresses the human EXOSC1 variant Arg183Trp show a slow-growth phenotype, whereas the previously identified PCH1F allele EXOSC1-Ser35Leu is lethal, indicating impaired exosome function for both of these variants. The protein levels of both EXOSC1 variants are reduced compared with wild-type when expressed in budding yeast. Herein, we ascertain the second case of PCH associated with a EXOSC1 variant that causes defects in RNA exosome function and provide a model organism system to distinguish between benign and pathogenic variants in EXOSC1.
Topics: Humans; Female; Infant; Microcephaly; Cerebellar Diseases; Olivopontocerebellar Atrophies; Mutation; Nervous System Malformations; Exosome Multienzyme Ribonuclease Complex; RNA-Binding Proteins
PubMed: 37024942
DOI: 10.1002/ajmg.a.63198 -
Cells Feb 2023Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in... (Review)
Review
Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. MSA patients have a prodromal phase subsequent to the insidious onset of neuropathology. Therefore, understanding the early pathological events is important in determining the pathogenesis, which will assist with developing disease-modifying therapy. Although the definite diagnosis of MSA relies on the positive post-mortem finding of oligodendroglial inclusions composed of α-synuclein, only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. We review up-to-date knowledge of human oligodendrocyte lineage cells and their association with α-synuclein, and discuss the postulated mechanisms of how oligodendrogliopathy develops, oligodendrocyte progenitor cells as the potential origins of the toxic seeds of α-synuclein, and the possible networks through which oligodendrogliopathy induces neuronal loss. Our insights will shed new light on the research directions for future MSA studies.
Topics: Humans; alpha-Synuclein; Cell Lineage; Multiple System Atrophy; Neurons; Parkinsonian Disorders
PubMed: 36899876
DOI: 10.3390/cells12050739 -
Brain & Development May 2023The inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological...
BACKGROUND
The inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological illnesses with clinically significant pons and cerebellum involvement.
CASE REPORTS
A seven-year-old girl with pontocerebellar hypoplasia, resistant myoclonic epilepsy with axial hypotonia, microcephaly, atypical facial appearance, nystagmus, ophthalmoplegia, hyperactive tendon reflexes, spasticity, clonus, extensor plantar response, contractures in wrists and ankles and growth retardation, whole-exome sequencing was performed and a homozygous "NM_001134225.2:c.646C > T, p.(Arg216Ter)" variant was found in the INPP4A gene.
CONCLUSION
INPP4A mutations should be kept in mind in cases with severely delayed psychomotor development, progressive microcephaly, resistant myoclonic epilepsy, isolated cerebellum, and pons involvement.
Topics: Female; Humans; Child; Microcephaly; Olivopontocerebellar Atrophies; Nervous System Malformations; Mutation; Epilepsies, Myoclonic
PubMed: 36759255
DOI: 10.1016/j.braindev.2023.01.006 -
Movement Disorders : Official Journal... Feb 2023Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.
BACKGROUND
Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.
OBJECTIVE
The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions.
METHODS
We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP).
RESULTS
We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions.
CONCLUSIONS
The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Multiple System Atrophy; alpha-Synuclein; DNA Copy Number Variations; In Situ Hybridization, Fluorescence; Olivopontocerebellar Atrophies
PubMed: 36448620
DOI: 10.1002/mds.29291