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1.
Mol Genet Metab ; 138(1): 106970, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36610259

RESUMO

BACKGROUND: Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described. OBJECTIVES: To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic. METHODS: We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP. RESULTS: Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech. CONCLUSION: ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions.


Assuntos
Paralisia Cerebral , Coreia , Estimulação Encefálica Profunda , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Mioclonia , Humanos , Paralisia Cerebral/genética , Paralisia Cerebral/terapia , Paralisia Cerebral/complicações , Coreia/complicações , Coreia/terapia , Distúrbios Distônicos/genética , Globo Pálido , Transtornos dos Movimentos/genética , Estudos Retrospectivos , Resultado do Tratamento , Criança , Adolescente
3.
Mov Disord ; 37(7): 1547-1554, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35722775

RESUMO

BACKGROUND: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. OBJECTIVE: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. METHODS: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. RESULTS: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. CONCLUSION: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Distonia , Distúrbios Distônicos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Transtornos dos Movimentos , Transtornos Parkinsonianos , Distonia/genética , Distúrbios Distônicos/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Humanos , Transtornos dos Movimentos/genética , Transtornos Parkinsonianos/genética , Fenótipo
5.
Ann Clin Transl Neurol ; 8(10): 1986-1990, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34415117

RESUMO

Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystonia-dominant phenotypes.


Assuntos
Proteínas de Ligação a DNA/genética , Distúrbios Distônicos/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Idade de Início , Estimulação Encefálica Profunda , Progressão da Doença , Distúrbios Distônicos/fisiopatologia , Distúrbios Distônicos/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/fisiopatologia
6.
Brain ; 143(11): 3242-3261, 2020 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-33150406

RESUMO

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.


Assuntos
Distúrbios Distônicos/genética , Histona-Lisina N-Metiltransferase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Estudos de Coortes , Simulação por Computador , Estimulação Encefálica Profunda , Progressão da Doença , Distúrbios Distônicos/terapia , Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/genética , Feminino , Retardo do Crescimento Fetal/genética , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/terapia , Humanos , Doenças da Laringe/etiologia , Doenças da Laringe/terapia , Masculino , Mutação , Mutação de Sentido Incorreto , Fenótipo , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
7.
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
8.
Mov Disord ; 33(7): 1168-1173, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29786895

RESUMO

BACKGROUND: Status dystonicus (SD) is a life-threatening condition. OBJECTIVE AND METHODS: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them. RESULTS: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes. CONCLUSION: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society.


Assuntos
Estimulação Encefálica Profunda/métodos , Distonia/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Distonia/diagnóstico por imagem , Distonia/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento , Adulto Jovem
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