Sonia Maria Cesar Azevedo Silva

Tremor postural e distonia: aspectos clínicos e considerações fisiopatológicas

The coexistence of tremor and dystonia is usually seen but there is not a satisfactory explanation for it. Some consider that essential tremor (ET) and idiopathic dystonia (ID) may be genetically linked. To clarify this relationship we evaluated the frequency of postural hand tremor in ID and symptomatic dystonia (SD) patients. We studied the records of patients with dystonia seen in our Movement Disorders Unit. ID was considered when there was no other neurological abnormality in the examination aside from dystonia, normal laboratorial tests and neuroimaging related to dystonia, and a negative past history for any known cause for it, except for genetic predisposition. We analyzed the clinical characteristics of dystonia and the occurrence of postural tremor. We collected 185 patients, being 120 with ID and 65 with SD. Tremor was seen in 27 (22.5%) of ID and 14 (21.5%) of SD. Tremor was present in either focal, segmental or generalized dystonia in both ID and SD. Family history for ET was absent in all patients. The similar frequency of tremor in ID and SD patients suggests that the pathophysiologic derangement resulting in dystonia can favor the development of tremor.A presenca de tremor e distonia de torcao no mesmo paciente e frequente mas nao ha uma explicacao satisfatoria para isso. Suspeita-se que haja uma associacao da distonia idiopatica (DI) com o tremor essencial (TE). O objetivo deste estudo e analisar a frequencia de tremor postural das maos em pacientes com DI e distonia sintomatica (DS). Foram estudados os prontuarios de 185 pacientes com o diagnostico sindromico de distonia atendidos no Setor de Investigacao em Molestias Extrapiramidais da Escola Paulista de Medicina. DI foi diagnosticada quando nao havia anormalidade no exame neurologico alem da distonia e havia exames laboratoriais e de neuroimagem, relacionados a distonia, normais e historia pregressa negativa para fatores causais de distonia. Foram analisadas as caracteristicas clinicas da distonia e a presenca de tremor postural nas maos. Havia 185 pacientes, 120 com DI e 65 com DS. Tremor postural das maos ocorreu em 27 (22,5%) das DI e 14 (21,5%) das DS. Tremor esteve presente nos quadros focais, segmentares e generalizados e tambem nos diversos tipos clinicos de DI e DS em proporcoes semelhantes. Historia familiar de TE estava ausente em todos os casos com tremor. A presenca de tremor postural das maos em pacientes com DI e DS pode sugerir que a desorganizacao fisiopatologica que produz a distonia pode favorecer o aparecimento do tremor.

Novel THAP1 variants in Brazilian patients with idiopathic isolated dystonia

THAP1 mutations are associated with idiopathic isolated dystonia in different ethnicities, but the importance of this gene as a cause of dystonia in the Brazilian population has not been determined. The aim of this study was to investigate the prevalence of THAP1 variants in Brazilian patients with idiopathic dystonia and to describe their clinical characteristics including non-motor symptoms. One hundred and ten unrelated patients with non-TOR1A (DYT1) idiopathic isolated dystonia and family members were evaluated and screened for genetic variants. Variants with a potential pathological role were observed in 9.0% of families studied, of which four were novel. The variants were identified in approximately 12% of patients with the age of onset below 40 years. In most of the patients, the onset of the disease was before early adulthood. The upper limb was the most common site of the onset, and approximately half of the patients had dysphonia. Pain, anxiety, and sleep-onset insomnia were the most prevalent non-motor symptoms, and their prevalence was not different from that observed in THAP1-negative patients. Therefore, THAP1 variants are an important cause of dystonia among individuals with an early-onset disease and a positive family history. The phenotypical heterogeneity among patients carrying similar variants shows that other factors may be modulating the disease.

Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function.

GNAL was identified as a cause of dystonia in patients from North America, Europe and Asia. In this study, we aimed to investigate the prevalence of GNAL variants in Brazilian patients with dystonia. Ninety-one patients with isolated idiopathic dystonia, negative for THAP1 and TOR1A mutations, were screened for GNAL variants by Sanger sequencing. Functional characterization of the Gαolf protein variant was performed using the bioluminescence resonance energy transfer assay. A novel heterozygous nonsynonymous variant (p. F133L) was identified in a patient with cervical and laryngeal dystonia since the third decade of life, with no family history. This variant was not identified in healthy Brazilian controls and was not described in 63,000 exomas of the ExAC database. The F133L mutant exhibited significantly elevated levels of basal BRET and severely diminished amplitude of response elicited by dopamine, that both indicate substantial functional impairment of Gαolf in transducing receptor signals, which could be involved in dystonia pathophysiology. GNAL mutations are not a common cause of dystonia in the Brazilian population and have a lower prevalence than THAP1 and TOR1A mutations. We present a novel variant that results in partial Gαolf loss of function.

Clinical features and treatment with botulinum toxin in blepharospasm: a 17-year experience.

OBJECTIVE It was to analyze clinical aspects of patients with blepharospasm, including outcomes of botulinum toxin treatment. Additionally, clinical characteristics of isolated blepharospasm were compared to those of blepharospasm plus other movement disorders. METHODS Clinical data recorded during 17 years were reviewed. The variables included age, gender, age of onset, past medical history, head trauma, smoking history, family history of dystonia, severity, duration of botulinum toxin relief and adverse effects. RESULTS A total of 125 patients were included and 75.2% were female. The mean age of onset was 54.3 years; 89.6% of the individuals started with contractions in eye region, and 39.2% of them spread to lower face or neck. Isolated blepharospasm group was compared with blepharospasm-plus group for demographic and clinical features, and therapeutic outcomes, without significant differences. Botulinum toxin treatment improved the severity of contractions (p=0.01) with low rate of side effects (14%). CONCLUSIONS Both groups - isolated blepharospasm and blepharospasm-plus - shared similar results concerning epidemiology, clinical features and therapeutic response to botulinum toxin.

Presence or absence of cognitive complaints in Parkinson’s disease: mood disorder or anosognosia?

Avaliar se pacientes com doenca de Parkinson (DP) sem demencia, com ou sem queixa cognitiva subjetiva, demonstram diferencas entre eles e comparativamente aos controles relativos a desempenho cognitivo e humor. Avaliados 77 individuos entre 30 e 70 anos: PD sem queixas cognitivas (n = 31), PD com queixas cognitivas (n = 21) e controles (n = 25). Testes aplicados: SCOPA-cognicao, Trail Making Test-B, Fluencia Fonemica, Teste do Relogio, Teste Nominativo de Boston, Inventario Neuropsiquiatrico, Escala Hospitalar de Depressao e Ansiedade (HADS)e Inventario de Depressao de Beck. PD sem queixas apresentaram menor pontuacao total na SCOPA-cognicao, comparativamente aos controles (p = 0,048). Por outro lado, PD com queixas apresentaram maior pontuacao no HADS (p = 0,011) em comparacao aos controles. O grupo PD sem queixas mostrou pior desempenho cognitivo em comparacao aos controles, mas foi semelhante ao PD com queixas. Este grupo foi diferente dos grupos PD sem queixas e controle em relacao ao humor.

The prevalence of PRKRA mutations in idiopathic dystonia

INTRODUCTION DYT-PRKRA (DYT16) is considered a rare cause of dystonia-parkinsonism. The significance of this gene as a cause of dystonia and its phenotypical characterization must be determined in larger cohorts. We aimed to investigate the role of PRKRA in patients with dystonia. METHODS We sequenced PRKRA in 153 unrelated Brazilian patients with idiopathic dystonia. The frequency of novel missense variants was investigated in healthy Brazilian controls and in public databases. Homozygosity in the PRKRA region was assessed through polymorphic markers. RESULTS PRKRA variants were identified in seven probands with isolated dystonia, including a novel c.C795A variant in compound heterozygosity with the previously described c.C665T variant. Heterozygosity in the gene region was observed in two probands who were homozygous for c.C665T, indicating that this mutation originated from independent events, suggesting a hotspot. CONCLUSION PRKRA is not an unusual cause of idiopathic dystonia. In this cohort, it was responsible for 4.5% of the total of cases (4.9% of the isolated dystonia cases). The most common phenotype was early-onset isolated focal dystonia followed by generalization, parkinsonism was not observed. This is first report of PRKRA causing adulthood-onset dystonia. Screenings of large cohorts are recommended to investigate the role of this gene in isolated dystonia, as well as in dystonia-parkinsonism cases worldwide.

Patients with essential tremor can have manual dexterity and attention deficits with no impairments in other cognitive functions

Essential tremor (ET) was long believed to be a monosymptomatic disorder. However, studies have evidenced structural changes and attention is now being focused on non-motor symptoms. The objective of the study is to describe and compare ET patients with control groups according to their cognitive functions, and secondarily, to compare their sociodemographic characteristics and other clinical features. All participants were assessed using the Fahn-Tolosa-Marin Tremor Rating Scale for the severity of tremor; a neuropsychological assessment battery and a screening questionnaire for mood and anxiety symptoms. There were no significant age and gender differences between all groups. As for neuropsychological assessment results, a significant difference was found only in the Pegboard test. We also found a significant negative correlation between a poorer cognitive test results and disease severity and a significant differences regarding depression or anxiety symptoms in patients with ET. The study results suggest that patients with ET have impaired manual dexterity and attention.