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1.
Cell ; 172(5): 897-909.e21, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474918

RESUMO

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.


Assuntos
Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genoma Humano , Transcriptoma/genética , Processamento Alternativo/genética , Elementos Alu/genética , Sequência de Bases , Sistemas CRISPR-Cas/genética , Estudos de Coortes , Família , Feminino , Loci Gênicos , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Íntrons/genética , Masculino , Repetições Minissatélites/genética , Modelos Genéticos , Degeneração Neural/genética , Degeneração Neural/patologia , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elementos Nucleotídeos Curtos e Dispersos , Fatores Associados à Proteína de Ligação a TATA/genética , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/genética , Fator de Transcrição TFIID/metabolismo
2.
Mov Disord ; 36(1): 206-215, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32975318

RESUMO

BACKGROUND: X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript. OBJECTIVES: The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism. METHODS: RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array. RESULTS: In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79. CONCLUSIONS: TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Fatores Associados à Proteína de Ligação a TATA , Adulto , Biomarcadores , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Histona Acetiltransferases/genética , Humanos , Filamentos Intermediários , Masculino , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética
3.
J Neural Transm (Vienna) ; 128(4): 575-587, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33439365

RESUMO

X-Linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease affecting individuals with ancestry to the island of Panay in the Philippines. In recent years there has been considerable progress at elucidating the genetic basis of XDP and candidate disease mechanisms in patient-derived cellular models, but the neural substrates that give rise to XDP in vivo are still poorly understood. Previous studies of limited XDP postmortem brain samples have reported a selective dropout of medium spiny neurons within the striatum, although neuroimaging of XDP patients has detected additional abnormalities in multiple brain regions beyond the basal ganglia. Given the need to fully define the CNS structures that are affected in this disease, we created a brain bank in Panay to serve as a tissue resource for detailed studies of XDP-related neuropathology. Here we describe this platform, from donor recruitment and consent to tissue collection, processing, and storage, that was assembled within a predominantly rural region of the Philippines with limited access to medical and laboratory facilities. Thirty-six brains from XDP individuals have been collected over an initial 4 years period. Tissue quality was assessed based on histologic staining of cortex, RNA integrity scores, detection of neuronal transcripts in situ by fluorescent hybridization chain reaction, and western blotting of neuronal and glial proteins. The results indicate that this pipeline preserves tissue integrity to an extent compatible with a range of morphologic, molecular, and biochemical analyses. Thus the algorithms that we developed for working in rural communities may serve as a guide for establishing similar brain banks for other rare diseases in indigenous populations.


Assuntos
Distonia , Distúrbios Distônicos , Doenças Neurodegenerativas , Encéfalo/diagnóstico por imagem , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X , Humanos
4.
Neurobiol Dis ; 144: 105032, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739252

RESUMO

Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP prefrontal cortex (PFC) compared to control. Furthermore, there is a significant increase in histone H3 citrullination (H3R2R8R17cit3) with a concomitant increase in peptidylarginine deaminase 2 (PAD2) and 4 (PAD4), the enzymes catalyzing citrullination, in XDP post-mortem PFC. While there is a significant increase in myeloperoxidase (MPO) levels in XDP PFC, neutrophil elastase (NE) levels are not altered, suggesting that MPO may be released by activated microglia or reactive astrocytes in the brain. Similarly, there was an increase in H3R2R8R17cit3, PAD2 and PAD4 levels in XDP-derived fibroblasts. Importantly, treatment of fibroblasts with Cl-amidine, a pan inhibitor of PAD enzymes, reduced histone H3 citrullination and pro-inflammatory chemokine expression, without affecting cell survival. Taken together, our results demonstrate that inflammation is increased in XDP post-mortem brain and fibroblasts and unveil a new epigenetic potential therapeutic target.


Assuntos
Citrulinação , Distúrbios Distônicos/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Histonas/metabolismo , Inflamação/metabolismo , Córtex Pré-Frontal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Astrócitos/patologia , Autopsia , Sobrevivência Celular , Quimiocinas/efeitos dos fármacos , Quimiocinas/metabolismo , Citrulinação/efeitos dos fármacos , Distúrbios Distônicos/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gliose/metabolismo , Gliose/patologia , Histonas/efeitos dos fármacos , Humanos , Inflamação/patologia , Elastase de Leucócito/metabolismo , Masculino , Microglia/metabolismo , Microglia/patologia , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/farmacologia , Peroxidase/metabolismo , Córtex Pré-Frontal/patologia , Proteína-Arginina Desiminase do Tipo 2/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo
5.
Proc Natl Acad Sci U S A ; 114(51): E11020-E11028, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29229810

RESUMO

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1 This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.


Assuntos
Expansão das Repetições de DNA , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Histona Acetiltransferases/genética , Retroelementos , Elementos Nucleotídeos Curtos e Dispersos , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Ordem dos Genes , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Modelos Biológicos , Linhagem , Fenótipo , Regiões Promotoras Genéticas , Ativação Transcricional
6.
Sci Rep ; 14(1): 13229, 2024 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853162

RESUMO

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.


Assuntos
Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Aprendizado de Máquina , Dispositivos Eletrônicos Vestíveis , Humanos , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Masculino , Adulto , Pessoa de Meia-Idade , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/diagnóstico , Índice de Gravidade de Doença , Feminino , Marcha
7.
Parkinsonism Relat Disord ; 120: 105991, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38184995

RESUMO

INTRODUCTION: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder that may result in severe speech impairment. The literature suggests that there are differences in the speech of individuals with XDP and healthy controls. This study aims to examine the motor speech characteristics of the mixed dystonia-parkinsonism phase of XDP. METHOD: We extracted acoustic features representing coordination, consistency, speed, precision, and rate from 26 individuals with XDP and 26 controls using Praat, MATLAB, and R software. Group demographics were compared using descriptive statistics. A one-way analysis of variance (ANOVA) with Tukey's post hoc test was used to test for acoustic differences between the two groups. RESULTS: The XDP group had significantly lower consistency, speed, precision, and rate than controls (p < 0.05). For coordination, the XDP group had a smaller ratio of pause duration during transitions when compared to controls. DISCUSSION: To our knowledge, this study is the first to describe the motor speech characteristics of the mixed dystonia-parkinsonism phase of XDP. The motor speech of mixed dystonia-parkinsonism XDP is similar to prior characterizations of mixed hyperkinetic-hypokinetic dysarthria with noted differences in articulatory coordination, consistency, speed, precision, and rate from healthy controls. Identifying the motor speech components of all three phenotypes of XDP (i.e., dystonia-dominant phase, parkinsonism-dominant phase, and mixed dystonia-parkinsonism phase) is needed to establish markers of speech impairment to track disease progression.


Assuntos
Distonia , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Transtornos Parkinsonianos , Humanos , Distonia/genética , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos Parkinsonianos/genética , Disartria
8.
J Voice ; 37(1): 134-138, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33334627

RESUMO

OBJECTIVE: To characterize the evolution of swallowing and voice in patients with X-linked dystonia parkinsonism (XDP). STUDY DESIGN: Retrospective case series. METHODS: Retrospective review of 59 patients with XDP from January 2016 to January 2018. All patients underwent complete examinations and quality of life (QOL) surveys (Swallowing Quality of Life questionnaire [SWAL-QOL], Voice-Related Quality of Life [V-RQOL], and Voice Handicap Index [VHI]), and functional endoscopic examination of swallowing. We excluded patients with incomplete records or patients lost to follow-up. Univariate analysis was used to compare 2016 to 2018 Penetration-Aspiration Scale (PAS), SWAL-QOL, V-RQOL, and VHI scores. RESULTS: Ten patients met the inclusion criteria. Nine patients had oromandibular dystonia. Voice-related measures significantly worsened with an increase in mean VHI from 81 to 109.9 (P = 0.026) and decrease in mean V-RQOL from 58 to 28 (P = 0.013). Vocal strain also significantly worsened 0.4 to 1.4 (P = 0.001). Mean PAS scores increased from 4.2 to 5.1 (P = 0.068) and mean SWAL-QOL decreased from 50.4 to 43.5 (P = 0.157). In the SWAL-QOL, the mean Eating Duration score worsened from 0.9 to 0.4 (P = 0.052) and Mental Health score declined from 10.1 to 6.1 (P = 0.077). CONCLUSIONS: Both vocal strain and voice-related QOL measures considerably worsened over the 2-year interval in our limited group of XDP patients with no significant change in PAS scores or swallowing QOL. The findings demonstrated that the pace of disease affecting voice symptoms was different from swallowing symptoms in our study group and that changes in communication ability may be a more sensitive marker for disease progression than swallowing dysfunction.


Assuntos
Distonia , Transtornos Parkinsonianos , Voz , Humanos , Qualidade de Vida/psicologia , Estudos Retrospectivos , Distonia/diagnóstico , Inquéritos e Questionários
9.
Brain Commun ; 5(3): fcad106, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37265597

RESUMO

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.

10.
Acta Neuropathol Commun ; 10(1): 49, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35395816

RESUMO

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington's disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.


Assuntos
Distonia , Distúrbios Distônicos , Doença de Huntington , Transtornos Parkinsonianos , Adulto , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Doença de Huntington/genética , Masculino , Transtornos Parkinsonianos/genética , Retroelementos
11.
Nat Commun ; 12(1): 3216, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050153

RESUMO

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10-8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.


Assuntos
Distúrbios Distônicos/genética , Genes Modificadores , Doenças Genéticas Ligadas ao Cromossomo X/genética , Loci Gênicos , Penetrância , Adulto , Idade de Início , Idoso , Alelos , Estudos de Casos e Controles , Reparo de Erro de Pareamento de DNA , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Adulto Jovem
12.
Mov Disord Clin Pract ; 7(4): 448-452, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32373662

RESUMO

BACKGROUND: X-linked dystonia parkinsonism (XDP) is a rare disorder characterized by adult-onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism. Gait impairment is common. METHODS: Case series of 4 XDP patients with a unique gait disorder. RESULTS: The patients displayed a characteristic gait disorder with combined dystonic and parkinsonian gait features, with phasic knee bending. Of these patients, all had parkinsonism and three-quarters had prominent dystonic features, but 1 had predominant parkinsonism and subtle dystonic features. CONCLUSION: Although XDP is a classic form of dystonia parkinsonism, some cases can mimic idiopathic Parkinson's disease. We describe a gait disorder which appears unique to XDP, involving phasic dystonic knee bending superimposed on parkinsonian shuffling, and may help clinically differentiate one of our parkinsonian-predominant patients from more-common forms of parkinsonism. The gait is distinct from other complex dystonic disorders with gait involvement.

13.
Laryngoscope ; 130(1): 171-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30889292

RESUMO

OBJECTIVES: To systematically characterize and describe voice and swallowing manifestations in patients with X-linked dystonia parkinsonism (XDP) and correlate with quality-of-life (QOL) measures. METHODS: Thirty-four patients with XDP with communication and swallowing difficulties underwent neurological examination, head and neck examination, nasopharyngoscopy, QOL surveys (Swallowing Quality of Life questionnaire [SWAL-QOL] and Voice Handicap Index [VHI]), and functional endoscopic evaluation of swallowing (FEES) to assess the extent of dysfunction. RESULTS: All patients showed high rates of lingual, oromandibular, and laryngeal dysfunction, as well as severe QOL changes in swallowing and communication ability. The most common head and neck manifestations of dystonic symptoms were difficulty coordinating the mouth and tongue (79%), uncontrollable tongue thrusting (53%), and jaw opening (35%). Laryngeal symptoms including vocal strain (adductor voice breaks) or stridor (32%), as well as velopharyngeal insufficiency (20%), were also identified. Of the patients with laryngeal symptoms, 18% had respiratory dystonia. Swallowing assessments showed significant abnormalities in oral bolus control and oropharyngeal dysphagia. FEES examinations showed that 87.5% of the study group had penetration or aspiration. QOL scores showed an average VHI of 94.4 (severe dysfunction), and SWAL-QOL showed an average of 37.7 (severe dysfunction). CONCLUSION: Swallowing and voice impairment in XDP is not well characterized and presents a more distinctive phenomenology than other neurological disorders, with a unique set of challenges for treatment. This is the first study to systematically evaluate laryngeal and pharyngeal dysfunction in XDP patients and correlate with QOL measures. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:171-177, 2020.


Assuntos
Transtornos de Deglutição/etiologia , Distúrbios Distônicos/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Qualidade de Vida , Distúrbios da Voz/etiologia , Correlação de Dados , Humanos , Masculino , Pessoa de Meia-Idade
14.
Front Neurol ; 11: 591418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329340

RESUMO

Background: Cervical dystonia (CD) is a rare disorder, and health care providers might be unfamiliar with its presentation, thus leading to delay in the initial diagnosis. The lack of awareness displays the need to highlight the clinical features and treatment in cervical dystonia. In our cohort, we have identified an earlier age of onset in men, despite an overall preponderance of affected women. Objective: We aim to identify the prevalence, age of onset, spread, and treatment modalities of CD in the population. We also highlight the barriers which patients encounter related to diagnosis, follow-up, and treatment. Methods: We reviewed 149 CD patients who attended specialized Dystonia Clinics over a 14-year period. Dystonia severity was rated using the Burke-Fahn-Marsden (BFM), Tsui, and Toronto Western Spasmodic Torticollis Rating Scales (TWSTRS). Mood and quality of life were assessed using Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and 36-Item Short Form Health Survey (SF-36). Results: CD patients were majority White (91.3%) and more commonly female (75.8%). Men had an earlier median age of onset, 40.5 years (p = 0.044). BAI revealed a mean score of 7.2 (±6.4, n = 50) indicating minimal anxiety while BDI revealed a mean score of 7.30 (±7.6, n = 50) indicating minimal depression. The only SF-36 subscales associated with CD severity were physical functioning (p = 0.040) pain (p = 0.008) and general health (p = 0.014). Conclusion: There appear to be gender differences in both the prevalence and age of onset of the disease. There was a 3-fold higher incidence in women than in men. CD patients of both sexes experience barriers to care, which can be reflected in their quality of life and time-to-diagnosis. In addition, males were less likely to experience an objective benefit with botulinum toxin treatment and more likely to discontinue care. Greater awareness of CD by health care providers is important to reduce the time-to-diagnosis.

15.
PLoS One ; 15(12): e0243655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315879

RESUMO

X-linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease linked to an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This SVA insertion induces aberrant TAF1 splicing and partial intron retention, thereby decreasing levels of the full-length transcript. Here we sought to determine if these altered transcriptional dynamics caused by the SVA are also accompanied by local changes in histone acetylation, given that these modifications influence gene expression. Because TAF1 protein may itself exhibit histone acetyltransferase activity, we also examined whether decreased TAF1 expression in XDP cell lines and post-mortem brain affects global levels of acetylated histone H3 (AcH3). The results demonstrate that total AcH3 are not altered in XDP post-mortem prefrontal cortex or cell lines. We also did not detect local differences in AcH3 associated with TAF1 exons or intronic sites flanking the SVA insertion. There was, however, a decrease in AcH3 association with the exon immediately proximal to the intronic SVA, and this decrease was normalized by CRISPR/Cas-excision of the SVA. Collectively, these data suggest that the SVA insertion alters histone status in this region, which may contribute to the dysregulation of TAF1 expression.


Assuntos
Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Histona Acetiltransferases/genética , Histonas/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Acetilação , Células Cultivadas , Distúrbios Distônicos/metabolismo , Fibroblastos/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Íntrons , Retroelementos
17.
Pediatrics ; 128(4): 723-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21890829

RESUMO

OBJECTIVES: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Children's Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes. RESULTS: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes. CONCLUSIONS: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.


Assuntos
Síndrome de Stevens-Johnson , Adolescente , Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Recidiva , Estudos Retrospectivos , Síndrome de Stevens-Johnson/tratamento farmacológico , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/mortalidade , Resultado do Tratamento , Adulto Jovem
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