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PURPOSE: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C2H2 domain-containing transcription factor. METHODS: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals. RESULTS: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia. CONCLUSION: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.
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Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Transativadores/genética , Adolescente , Adulto , Criança , Estudos de Coortes , Biologia Computacional/métodos , Distonia/genética , Família , Feminino , Humanos , Deficiência Intelectual/genética , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Convulsões/genética , Distúrbios da Fala/genética , Transativadores/metabolismo , Sequenciamento do ExomaRESUMO
BACKGROUND: Patients with functional movement disorders also typically have functional somatic symptoms, including pain, fatigue, and sensory disturbance. A potentially unifying mechanism for such symptoms is a failure in processing of sensory inputs. Prepulse inhibition is a neurophysiological method that allows for the study of preconscious somatosensory processing. OBJECTIVE: The objective of this study was to assess prepulse inhibition in patients with functional movement disorders and healthy control subjects. METHODS: We analyzed the effect of a weak electrical stimulus to the index finger (prepulse) on the magnitude of the R2 response of the blink reflex induced by electrical stimuli delivered to the supraorbital nerve in 22 patients with clinically established functional movement disorders and 22 matched controls. Pain, depression, anxiety, and obsessive-compulsive symptoms were assessed using self-rated questionnaires. In addition, in patients we assessed motor symptom severity. RESULTS: Prepulses suppressed the R2 response of the blink reflex in both groups, by 36.4% (standard deviation: 25.6) in patients and by 67.3% (standard deviation: 16.4) in controls. This difference was significant (P < 0.001). There was no significant correlation between motor and nonmotor symptom measures and prepulse inhibition size. CONCLUSIONS: Impaired prepulse inhibition of the blink reflex suggests an abnormal preconscious processing of somatosensory inputs, which can be interpreted within predictive coding accounts of both functional movement disorders and functional somatic syndromes. Our results, along with previous findings of a reduced prepulse inhibition in fibromyalgia syndrome, support a possible unified pathophysiology across functional neurological and somatic syndromes with noteworthy implications for diagnostic classification and development of novel biomarkers and treatments. © 2019 International Parkinson and Movement Disorder Society.
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Piscadela/fisiologia , Transtornos dos Movimentos/fisiopatologia , Inibição Neural/fisiologia , Inibição Pré-Pulso/fisiologia , Adulto , Estimulação Elétrica/métodos , Feminino , Dedos/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Reflexo de Sobressalto/fisiologiaRESUMO
Pallidal deep-brain stimulation of the internal globus pallidus (GPi-DBS) is an effective treatment for dystonia. However, GPi-DBS may cause important stimulation-induced side effects such as hypokinetic dysarthria, which is particularly manifested by articulation rate abnormalities. However, little data regarding the effect of the location of the electrode and stimulation parameters for pallidal stimulation on articulation rate in dystonia is available. Speech data were acquired from 18 dystonic patients with GPi-DBS and 18 matched healthy controls. Each of dystonic patients was tested twice within 1 day in both the GPi-DBS ON and GPi-DBS OFF stimulation conditions. Compared to healthy controls, the decreased diadochokinetic rate and slower articulation rate in dystonic patients were observed in both stimulation conditions. No significant differences in speech rate measures between stimulation conditions were detected with no relation to contact localization and stimulation intensity. Our findings do not support the use articulation rate as a surrogate marker of stimulation-induced changes to the speech apparatus in dystonia.
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Estimulação Encefálica Profunda/efeitos adversos , Disartria/etiologia , Distúrbios Distônicos/terapia , Globo Pálido , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.
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Distonia/genética , Distúrbios Distônicos/genética , Exoma/genética , Mutação/genética , Adenilil Ciclases/genética , Adulto , Distonia/diagnóstico , Distúrbios Distônicos/diagnóstico , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
BACKGROUND: Recently a novel syndrome of childhood-onset generalized dystonia originating from mutations in lysine-specific methyltransferase 2B (KMT2B) has been reported. METHODS: We sequenced the exomes of 4 generalized dystonia-affected probands recruited from a Prague movement disorders center (Czech Republic). Bioinformatics analyses were conducted to select candidate causal variants in described dystonia-mutated genes. After cosegregation testing, checklists from the American College of Medical Genetics and Genomics were adopted to judge variant pathogenicity. RESULTS: Three novel, predicted protein-damaging missense variants in KMT2B were identified (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln). Meeting pathogenicity criteria, p.Glu1234Lys was absent from population-based controls, situated in a key protein domain, and had occurred de novo. The associated phenotype comprised adolescence-onset generalized isolated dystonia with prominent speech impairment. Although linked to a similar clinical expression, p.Ala1541Val and p.Arg1779Gln remained of uncertain significance. CONCLUSIONS: Rare missense variation in KMT2B represents an additional cause of generalized dystonia. Application of sequence interpretation standards is required before assigning pathogenicity to a KMT2B missense variant. © 2017 International Parkinson and Movement Disorder Society.
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Distúrbios Distônicos/genética , Histona-Lisina N-Metiltransferase/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido IncorretoRESUMO
BACKGROUND: Deep brain stimulation of the internal globus pallidus (GPi DBS) is an invasive therapeutic modality intended to retune abnormal central nervous system patterns and relieve the patient of dystonic or other motor symptoms. OBJECTIVES: The aim of the presented research was to determine the neuroanatomical signature of GPi DBS modulation and its association with the clinical outcome. METHODS: This open-label fixed-order study with cross-sectional validation against healthy controls analysed the resting-state functional MRI activity changes induced by GPi DBS in 18 dystonia patients of heterogeneous aetiology, focusing on both global (full brain) and local connectivity (local signal homogeneity). RESULTS: Compared to the switched-off state, the activation of GPi DBS led to the restoration of global subcortical connectivity patterns (in both putamina, diencephalon and brainstem) towards those of healthy controls, with positive direct correlation over large-scale cortico-basal ganglia-thalamo-cortical and cerebellar networks with the clinical improvement. Nonetheless, on average, GPi DBS also seemed to bring local connectivity both in the cortical and subcortical regions farther away from the state detected in healthy controls. Interestingly, its correlation with clinical outcome showed that in better DBS responders, local connectivity defied this effect and approached healthy controls. CONCLUSIONS: All in all, the extent of restoration of both these main metrics of interest towards the levels found in healthy controls clearly correlated with the clinical improvement, indicating that the restoration of network state towards more physiological condition may be a precondition for successful GPi DBS outcome in dystonia.
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Estimulação Encefálica Profunda , Distonia , Estudos Transversais , Distonia/terapia , Globo Pálido/fisiologia , Humanos , Resultado do TratamentoRESUMO
Background: Everyday functioning and instrumental activities of daily living (IADL) play a vital role in preserving the quality of life in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS). Objective: The main goal of the current study was to examine IADL change in pre-and post-surgery of the STN-DBS. We also analyzed the influence of the levodopa equivalent daily dose (LEDD) and global cognitive performance (Dementia Rating Scale; DRS-2) as covariates in relation to IADL. Methods: Thirty-two non-demented PD patients were administered before and after STN-DBS neurosurgery the Penn Parkinson's Daily Activities Questionnaire (PDAQ; self-report), the DRS-2 and Beck Depression Inventory (BDI-II) to assess IADL change, global cognition, and depression. Results: We found a positive effect of STN-DBS on IADL in the post-surgery phase. Moreover, lower global cognition and lower LEDD are predictive of lower IADL in both pre-surgery and post-surgery examinations. Summary/Conclusion: STN-DBS in PD is a safe method for improvement of everyday functioning and IADL. In the post-surgery phase, we show a relation of IADL to the severity of cognitive impairment in PD and to LEDD.
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OBJECTIVE: Authors warn of difficulties in diagnostic of solitary epileptic seizure and epilepsy. MATERIAL AND METHODS: Our groups have been made up of patients, who have been dismissed from our clinic in the period from January 1997 to January 2007 with diagnosis of solitary unprovoked epileptic seizure (n=84) and epilepsy with sporadic epileptic seizure (n=179). We have evaluated the clinical typology of epileptic seizure, EEG findings and results of imaging methods and we determined the part of patients with complete diagnostic concordance between clinical image of epileptic seizure and results of auxiliary diagnostic methods. RESULTS: We have denoted the complete diagnostic concordance among the clinical image, EEG findings and results of imaging methods only in 13.1% of patients after solitary unprovoked epileptic seizure and in 24.02% of patients with diagnosis of epilepsy with sporadic epileptic seizures. The receiving diagnosis of unclear seizure status was determined at 49.14% of patients dismissed with diagnosis of solitary epileptic seizure and at 40.78% of patients dismissed with diagnosis of epilepsy with sporadic epileptic seizures in 10 year time period. CONCLUSION: Our results repeat the confirmation that the diagnostic of seizure disorders, with and without disturbance of consciousness, belong to the difficult part in the clinical praxis.
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Eletroencefalografia , Epilepsia/diagnóstico , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Adulto , Diagnóstico Diferencial , Epilepsia/diagnóstico por imagem , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Convulsões/diagnósticoRESUMO
BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
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Distonia/diagnóstico , Distonia/genética , Sequenciamento do Exoma/métodos , Exoma/genética , Variação Genética/genética , Adolescente , Criança , Pré-Escolar , Distonia/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Adulto JovemRESUMO
BACKGROUND: Although pallidal deep brain stimulation (GPi-DBS) is an effective treatment for dystonia, it may cause important stimulation-induced side-effects such as hypokinetic dysarthria or stuttering. However, the reasons behind the occurrence of these side-effects remain unknown. OBJECTIVE: To objectively investigate the impact of GPi-DBS on patients with dystonia on speech fluency, intelligibility, and key aspects of hyperkinetic and hypokinetic dysarthria. METHODS: Speech was systematically evaluated in 19 dystonic patients with GPi-DBS. Each patient was tested twice within one day in both the GPi-DBS ON and GPi-DBS OFF stimulation conditions. A control sample of 19 matched healthy speakers underwent the same speech assessment. RESULTS: We observed an improvement of hyperkinetic dysarthria symptoms in 47% and an aggravation of hypokinetic dysarthria symptoms in 26% of patients with the GPi-DBS switched ON. A higher stimulus intensity was found in a group of patients in whom the hypokinetic dysarthria worsened with the GPi-DBS ON when compared to other dystonic patients (pâ¯=â¯0.02). Furthermore, we revealed a significant increase of dysfluent words in the GPi-DBS ON when compared to OFF condition (pâ¯=â¯0.001) associated with the shorter distance of the active contact localization along the medio-lateral direction (râ¯=â¯-0.70, pâ¯=â¯0.005). CONCLUSION: This study provides evidence of dualistic effects of GPi-DBS on speech in dystonia manifested as an improvement of hyperkinetic or a deterioration of hypokinetic dysarthria. Our findings suggest that lower stimulation parameters and placement of active contacts more laterally in the internal globus pallidus should be preferred to avoid the possible side effects of hypokinetic dysarthria and dysfluency.
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Estimulação Encefálica Profunda/métodos , Distonia/fisiopatologia , Distonia/terapia , Globo Pálido/fisiologia , Distúrbios da Fala/fisiopatologia , Distúrbios da Fala/terapia , Adolescente , Adulto , Idoso , Estudos Transversais , Estimulação Encefálica Profunda/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distúrbios da Fala/etiologia , Resultado do Tratamento , Adulto JovemRESUMO
https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1.htm.
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Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.
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Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Hipercinese/genética , Deficiência Intelectual/genética , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Ataxia Cerebelar/genética , Códon sem Sentido/genética , Exoma , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Mutação com Ganho de Função/genética , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Splicing de RNA/genética , Sequenciamento do ExomaRESUMO
Clinical benefits of pallidal deep brain stimulation (GPi DBS) in dystonia increase relatively slowly suggesting slow plastic processes in the motor network. Twenty-two patients with dystonia of various distribution and etiology treated by chronic GPi DBS and 22 healthy subjects were examined for short-latency intracortical inhibition of the motor cortex elicited by paired transcranial magnetic stimulation. The relationships between grey matter volume and intracortical inhibition considering the long-term clinical outcome and states of the GPi DBS were analysed. The acute effects of GPi DBS were associated with a shortening of the motor response whereas the grey matter of chronically treated patients with a better clinical outcome showed hypertrophy of the supplementary motor area and cerebellar vermis. In addition, the volume of the cerebellar hemispheres of patients correlated with the improvement of intracortical inhibition which was generally less effective in patients than in controls regardless of the DBS states. Importantly, good responders to GPi DBS showed a similar level of short-latency intracortical inhibition in the motor cortex as healthy controls whereas non-responders were unable to increase it. All these results support the multilevel impact of effective DBS on the motor networks in dystonia and suggest potential biomarkers of responsiveness to this treatment.
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Estimulação Encefálica Profunda/métodos , Distonia/terapia , Globo Pálido/fisiologia , Córtex Motor/fisiologia , Inibição Neural , Adolescente , Adulto , Idoso , Cerebelo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna is an effective tool for the treatment of dystonia with possible distant effects reaching beyond the basal ganglia network. AIM: We analyzed the cortical silent period (CoSP) to test inhibitory circuits at the cortical level, and the cutaneous silent period (CuSP) and the H-reflex to test inhibitory circuits at the spinal level. METHODS: The upper limb muscles of 16 patients (9F, aged 54±(SD)16years) with generalized (N=9) and cervical (N=7) dystonia treated with DBS bilaterally were examined by the CoSP, CuSP and H-reflex in two states with random order: (i) in DBS ON and (ii) in DBS OFF condition two hours later, and compared with healthy controls. RESULTS: While the CuSP and H-Reflex did not differ between groups and remained unaffected by DBS, the CoSP was influenced significantly in dystonia. The CoSP onset latency was shortened (p<0.05 corrected) and the CoSP duration prolonged (p<0.01 corrected) in ON versus OFF condition. This effect was especially larger in generalized or phasic type of dystonia. Compared to healthy controls, the CoSP latency and duration became shorter in patients during the OFF condition only. CONCLUSION: The pallidal DBS did not affect the spinal inhibitory circuitry in dystonia. However, the abnormally low cortical inhibition was normalized after DBS possibly offering more efficient suppression of aberrant dystonic movements.