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1.
Ann Neurol ; 88(5): 867-877, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32808683

RESUMO

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.


Assuntos
Distonia/genética , Doenças por Armazenamento dos Lisossomos/genética , Proteínas de Transporte Vesicular/genética , Adulto , Efeitos Psicossociais da Doença , Distonia/patologia , Exoma/genética , Feminino , Fibroblastos/patologia , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem
2.
Mov Disord ; 29(6): 729-35, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24753288

RESUMO

Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincent's Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra-laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra-laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare.


Assuntos
Tosse/etiologia , Distonia/complicações , Doenças da Laringe/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Toxinas Botulínicas/uso terapêutico , Tosse/tratamento farmacológico , Distonia/classificação , Distonia/tratamento farmacológico , Feminino , Humanos , Doenças da Laringe/tratamento farmacológico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Neurotoxinas/uso terapêutico , Observação , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
3.
J Neural Transm (Vienna) ; 121(10): 1297-301, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24663496

RESUMO

Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle-brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Síndromes de Compressão Nervosa/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Adolescente , Adulto , Idoso , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Síndromes de Compressão Nervosa/diagnóstico , Síndromes de Compressão Nervosa/diagnóstico por imagem , Síndromes de Compressão Nervosa/fisiopatologia , Resultado do Tratamento , Ultrassonografia , Adulto Jovem
4.
Parkinsonism Relat Disord ; 124: 107010, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38772265

RESUMO

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.


Assuntos
Distonia , Distúrbios Distônicos , Humanos , Masculino , Feminino , Adulto , Distúrbios Distônicos/genética , Distúrbios Distônicos/diagnóstico , Distonia/genética , Distonia/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem , Sequenciamento Completo do Genoma , Adolescente , Criança , Fenótipo
5.
Mol Genet Genomic Med ; 10(5): e1923, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35293157

RESUMO

BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood-onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon-trapping assay. The genomic region of KMT2B exons 23-26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site-directed mutagenesis. The KMT2B wild-type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. RESULTS: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5-bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). CONCLUSION: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B-related dystonia.


Assuntos
Distonia , Distúrbios Distônicos , Histona-Lisina N-Metiltransferase , Animais , Criança , Distonia/genética , Distúrbios Distônicos/genética , Células HeLa , Histona-Lisina N-Metiltransferase/genética , Humanos , Mutação , Fenótipo , Sítios de Splice de RNA , Ratos
6.
Parkinsonism Relat Disord ; 69: 111-118, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31731261

RESUMO

INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.


Assuntos
Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Sequenciamento Completo do Genoma/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
7.
Parkinsonism Relat Disord ; 35: 1-7, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27825543

RESUMO

Dystonia is a hyperkinetic movement disorder that can be highly stigmatizing and disabling. Substantial evidence from animal models, neuropathological, neurophysiological, neuroimaging and clinical studies emphasizes the role of dopaminergic dysfunction in the pathophysiology of dystonia, illustrating possible pathophysiological overlap with parkinsonism. Furthermore, basal ganglia dysfunction has been implicated in the pathogenesis of dystonia, and is well established to underlie the manifestations of Parkinson's disease. Clinically, parkinsonian features are a key characteristic of some combined dystonias, including dopa-responsive dystonia, and Parkinson's disease often presents with dystonia. Moreover, many treatments effective in Parkinson's disease, both medical and surgical, also offer some benefit in dystonia. Therefore, mild parkinsonian features might logically accompany idiopathic and inherited isolated dystonias. However, as the current literature is particularly scant, the present review aimed to investigate mild parkinsonism in idiopathic and inherited dystonia. We found limited evidence alluding to the presence of mildly reduced arm-swing, increased tone, and non-decremental bradykinesia in adult-onset focal dystonia. Tremor, with postures, action and rest, also occurs commonly in idiopathic isolated dystonia, and can simulate Parkinson's disease tremor and be a cause of 'scans without evidence of dopaminergic deficit'. Parkinsonian features in monogenic isolated dystonias have been less well investigated, despite the potential benefit of correlating pathophysiological and clinical findings. The recognition and improved clinical characterization of parkinsonian features in idiopathic and inherited isolated dystonia extends the clinical spectrum of motor features in dystonia, which may help avoid incorrect diagnosis and inform therapeutic research.


Assuntos
Distonia/diagnóstico , Distonia/epidemiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Estimulação Encefálica Profunda/métodos , Distonia/terapia , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/terapia , Humanos , Doença de Parkinson/terapia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/terapia
8.
J Voice ; 31(5): 638-642, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28320626

RESUMO

OBJECTIVES/HYPOTHESIS: The objective of this study was to better define the relationship of laryngeal electromyography and video laryngostroboscopy in the diagnosis of vocal fold paralysis. STUDY DESIGN: Retrospective diagnostic cohort study with cross-sectional data analysis METHODS: Data were obtained from 57 patients with unilateral vocal fold paralysis who attended a large tertiary voice referral center. Electromyographic findings were classified according to recurrent laryngeal nerve, superior laryngeal nerve, and high vagal/combined lesions. Video laryngostroboscopy recordings were classified according to the position of the immobile fold into median, paramedian, lateral, and a foreshortened/hooded vocal fold. The position of the paralyzed vocal fold was then analyzed according to the lesion as determined by electromyography. RESULTS: The recurrent laryngeal nerve was affected in the majority of cases with left-sided lesions more common than right. Vocal fold position differed between recurrent laryngeal and combined vagal lesions. Recurrent laryngeal nerve lesions were more commonly associated with a laterally displaced immobile fold. No fold position was suggestive of a combined vagal lesion. The inter-rater reliability for determining fold position was high. CONCLUSION: Laryngeal electromyography is useful in diagnosing neuromuscular dysfunction of the larynx and best practice recommends its continued implementation along with laryngostroboscopy. While recurrent laryngeal nerve lesions are more likely to present with a lateral vocal fold, this does not occur in all cases. Such findings indicate that further unknown mechanisms contribute to fold position in unilateral paralysis.


Assuntos
Eletromiografia , Laringoscopia , Estroboscopia , Gravação em Vídeo , Paralisia das Pregas Vocais/diagnóstico , Prega Vocal/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Paralisia das Pregas Vocais/diagnóstico por imagem , Paralisia das Pregas Vocais/fisiopatologia , Prega Vocal/fisiopatologia , Adulto Jovem
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