RESUMO
Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.
Assuntos
Ataxia Cerebelar , Doença de Machado-Joseph , Humanos , Doença de Machado-Joseph/genética , Estudos Transversais , Ataxia , BiomarcadoresRESUMO
Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3-251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3-208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.
Assuntos
Doença de Machado-Joseph , Humanos , Doença de Machado-Joseph/metabolismo , Ataxina-3/genética , Ataxina-3/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Cerebelo/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND: Intronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat expansions in patients with an unexplained CANVAS-like phenotype. METHODS: We recruited 45 patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the FGF14 repeat locus. Phenotypic features of GAA-FGF14-positive versus GAA-FGF14-negative patients were compared. RESULTS: Frequency of FGF14 GAA repeat expansions was 38% (17/45) in the entire cohort, 38% (5/13) in the subgroup with cerebellar ataxia plus polyneuropathy, 43% (9/21) in the subgroup with cerebellar ataxia plus BVP and 27% (3/11) in patients with all three features. BVP was observed in 75% (12/16) of GAA-FGF14-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-FGF14-positive patients. Family history of ataxia (59% vs 15%; p=0.007) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%; p=0.009) significantly less frequent in GAA-FGF14-positive than in GAA-FGF14-negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R2=0.45; p=0.0031). CONCLUSIONS: GAA-FGF14-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum.
Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Polineuropatias , Doenças Vestibulares , Humanos , Ataxia/genética , Vestibulopatia Bilateral/genética , Vestibulopatia Bilateral/diagnóstico , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , SíndromeRESUMO
Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.
Assuntos
Cerebelo , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Cerebelo/patologia , Cerebelo/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto , Estudos Transversais , Idoso , Índice de Gravidade de Doença , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/genética , Atrofia/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Tamanho do Órgão , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologiaRESUMO
Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes-ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1-whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the Gαi signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts.
Assuntos
Doença de Machado-Joseph , Ataxias Espinocerebelares , Humanos , Doença de Machado-Joseph/genética , Transcriptoma , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/complicações , Ataxina-3/genética , Biomarcadores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas dos Microfilamentos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.
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Doenças do Sistema Nervoso Central , Xeroderma Pigmentoso , Humanos , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/diagnóstico , Atividades Cotidianas , Estudos Prospectivos , Reparo do DNA , Mutação/genéticaRESUMO
PURPOSE: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants. METHODS: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients. RESULTS: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants. CONCLUSION: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.
Assuntos
Epilepsia , Paraplegia Espástica Hereditária , Humanos , Espectrina/genética , Mutação , Epilepsia/genética , Fenótipo , Ataxia , Paraplegia Espástica Hereditária/genética , Convulsões , Paraplegia , LinhagemRESUMO
The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field.
Assuntos
Ataxia Cerebelar , Doença de Machado-Joseph , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , BiomarcadoresRESUMO
BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Humanos , Estilo de Vida , Estudos Prospectivos , Índice de Gravidade de Doença , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/epidemiologiaRESUMO
BACKGROUND: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. OBJECTIVES: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia. METHODS: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year. RESULTS: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset. CONCLUSION: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Machado-Joseph , Ataxia , Estudos de Coortes , Humanos , Doença de Machado-Joseph/complicações , Masculino , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels. RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
Assuntos
Doença de Machado-Joseph , Proteínas de Neurofilamentos , Proteínas tau , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cerebelo/química , Heterozigoto , Humanos , Doença de Machado-Joseph/sangue , Doença de Machado-Joseph/líquido cefalorraquidiano , Doença de Machado-Joseph/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genéticaRESUMO
OBJECTIVES: The aim of the study is to analyze the hemodynamic changes in the middle cerebral artery (MCA) after endovascular revascularization in acute ischemic stroke (AIS) due to large vessel occlusion and its association with the infarct volume size in the control head CT. MATERIALS AND METHODS: Prospective study of patients with AIS due to internal carotid artery terminus or M1 segment of the MCA occlusion, who underwent endovascular treatment with a final TICI 2b-3 score, without concomitant stenosis ≥50% in both cervical carotid arteries. Transcranial Doppler ultrasound (TCD) of both MCAs was carried out at 6 h after the endovascular procedure. Mean flow velocities (MFV) after arterial reperfusion and its association with the infarct volume size in 24-36 h control head CT were determined. RESULTS: 91 patients (51 women) were included with a median age of 78 years and National institute of Health Stroke Scale of 18. The MCA was occluded in 76.92%, and intravenous thrombolysis was administered in 40.7%. The incidence of symptomatic intracranial hemorrhage was 5.5%. At three months, mortality was 19.8% and a 52.7% of patients achieved functional independence (modified Rankin Scale 0-2). After a multivariable logistic regression analysis, an increase in the MFV greater than 50% at 6 h in the treated MCA compared to contralateral MCA, was an independent predictor of large infarct volume in the control head CT with an OR 9.615 (95%CI: 1.908-47.620), p=0.006 CONCLUSIONS: Increased MFV assessed by TCD examination following endovascular recanalization is independently associated with larger infarct volume.
Assuntos
Infarto da Artéria Cerebral Média , AVC Isquêmico , Idoso , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/fisiopatologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/fisiopatologia , AVC Isquêmico/cirurgia , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Reperfusão , Resultado do Tratamento , Ultrassonografia Doppler TranscranianaRESUMO
BACKGROUND: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. OBJECTIVE: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). METHODS: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. RESULTS: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. CONCLUSIONS: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Machado-Joseph , Doenças Neurodegenerativas , Ataxina-3/genética , Estudos Transversais , Humanos , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/genética , PeptídeosRESUMO
BACKGROUND: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. OBJECTIVE: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. METHODS: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. RESULTS: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. CONCLUSION: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Encéfalo/diagnóstico por imagem , Cerebelo , Humanos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genéticaRESUMO
Friedreich's ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5' and 3' ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3' interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5' interruption, 3' interruption, both 5' and 3' interruptions or lacking interruption. Those patients with 3' interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3' interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5' and 3' interruptions. This highlights the key role of interruptions at the 3' end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.
Assuntos
Ataxia de Friedreich/epidemiologia , Ataxia de Friedreich/genética , Fenótipo , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto JovemRESUMO
Background Infratrochlear neuralgia is a recently described painful cranial neuropathy that causes pain in the internal angle of the orbit and the medial upper eyelid, the upper bridge of the nose and/or the lacrimal caruncle. We aim to present seven new cases of infratrochlear neuralgia treated with anaesthetic nerve blocks. Methods Over an 18-month period, we prospectively identified seven cases of infratrochlear neuralgia among the patients attending the Headache Unit in a tertiary hospital. Anaesthetic blocks were performed by injecting 0.5 cc of bupivacaine 0.5% at the emergence of the nerve above the internal canthus. Results All patients were women, and the mean age was 49.1 years (standard deviation, 17.9). The pain appeared at the internal angle of the orbit and/or the medial upper eyelid in six cases, and the whole territory of the infratrochlear nerve in one case. Six patients had continuous pain and one had episodes lasting 8-24 hours. All patients showed sensory disturbances within the painful area and tenderness upon palpation of the infratrochlear nerve. Nerve blocks resulted in complete and long-lasting relief in four patients and short-lasting relief in the other three patients. Conclusions Infratrochlear neuralgia should be considered among the neuralgic causes of orbital and periorbital pain. Anaesthetic blocks may assist clinicians in the diagnosis and may also be an effective therapy.
Assuntos
Neuralgia Facial/cirurgia , Bloqueio Nervoso/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestésicos Locais/uso terapêutico , Bupivacaína/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Nervo Troclear/efeitos dos fármacosRESUMO
Introduction Epicrania fugax (EF) is a primary headache whose main feature is the dynamic character of the pain. EF pain typically moves across different dermatomes in a linear or zigzag trajectory. Recently, a facial variant of EF has been described, with the pain starting in the lower face and radiating upwards. Aim We report eight patients with an EF-type of pain of facial location and either upward or downward radiation. Methods For each patient, we recorded relevant demographic and clinical data. Magnetic resonance imaging (MRI) with fast imaging employing steady state acquisition (FIESTA) was obtained in all cases for the assessment of neurovascular compression of the trigeminal nerve. Results There were seven women and one man, and the mean age was 76.1 years (standard deviation, 11.3). Six patients had a paroxysmal pain starting at the lower face and moving upwards, while two patients had downward radiation. The pain always followed a fixed linear trajectory across different dermatomes. All cases had triggers, and pain intensity was consistently severe. Half of the patients had accompanying autonomic features. Neurovascular compression with imprinting over the trigeminal root on the symptomatic side was identified in three patients. All cases responded to antiepileptic drugs, and three had spontaneous remissions. Conclusions This series reinforces the facial variant of EF and extends the phenotype with cases of downward radiation. It also contributes to enriching the differential diagnosis of facial pain. Neurovascular compression of the trigeminal nerve may be found in some cases, although a possible pathogenic link needs further research.
Assuntos
Neuralgia Facial , Transtornos da Cefaleia Primários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: Our aim was to report three new cases of lacrimal neuralgia and their response to superficial nerve blocks. BACKGROUND: Lacrimal neuralgia has been recently described as a pain in the territory supplied by the lacrimal nerve, at the lateral upper eyelid and/or the adjacent area of the temple. The pain is typically accompanied by tenderness on palpation of the lacrimal nerve at the superoexternal angle of the orbit. METHODS: Between January 2015 and June 2016, we prospective identified three cases of lacrimal neuralgia among the patients attending the Headache Unit in a tertiary hospital. Anesthetic blocks were performed in all cases by inserting a 30-G needle on the emergence of the nerve and injecting 0.5 cc of bupivacaine 0.5% subcutaneously. RESULTS: Three women aged 44, 49, and 51 presented with pain in the territory supplied by the lacrimal nerve. Two of them localized their pain in a small area of the right temple, while the remaining patient had pain in the right upper lateral eyelid and a small area of the lower lateral eyelid. The pain was continuous in two patients and episodic with attacks lasting 48 hours in one patient. All patients had tenderness on palpation of the lacrimal nerve. Anesthetic blocks confirmed the diagnosis of lacrimal neuralgia and provided the patients with long-lasting pain relief. CONCLUSIONS: Lacrimal neuralgia should be considered among the neuralgic causes of orbital and periorbital pain. Superficial nerve blocks may assist clinicians in the diagnosis and may also be a therapeutic option.
Assuntos
Bloqueio Nervoso/métodos , Neuralgia/terapia , Adulto , Anestésicos Locais/uso terapêutico , Bupivacaína/uso terapêutico , Feminino , Humanos , Aparelho Lacrimal , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: Atypical odontalgia (AO), a subform of persistent idiopathic facial pain, is defined as a continuous toothache in which a thorough examination reveals no dental pathology. AO is believed to be a neuropathic condition, given that some cases are preceded by dental procedures. Different topical and systemic medications have been used for the treatment of AO, but their effect is often unsatisfactory. The authors aimed to assess the effect and safety of botulinum neurotoxin type-A (BoNTA) in a series of patients with AO. METHODS: Four patients with refractory AO (2 males and 2 females, aged 31-72) were treated with local injections of BoNTA to the painful area. BoNTA was injected at various sites into the gums, and two patients had additional injections in the hard palate or the upper lip. The total dose of BoNTA for each procedure was 15-30 U, and the total number of injection points was 6-12. The follow-up ranged from 6 to 20 months. Two patients received two cycles of BoNTA, while the remaining patients received three and five cycles each, respectively. RESULTS: All patients obtained significant relief with complete or almost complete reduction of pain. The analgesic effect was apparent after a latency period of 3-14 days, and the effect persisted for 2-6 months. There were no adverse events reported from any of the interventions. CONCLUSIONS: The responses to BoNTA injections in this series agree with those previously observed in neuropathic pain. BoNTA injections may be a safe and effective option for the treatment of AO.