Spinocerebellar ataxia type 2 has multiple ancestral origins.

INTRODUCTION: Spinocerebellar ataxia type 2 (SCA2) is a dominant neurodegenerative disorder due to expansions of a CAG repeat tract (CAGexp) at the ATXN2 gene. Previous studies found only one ancestral haplotype worldwide, with a C allele at rs695871. This homogeneity was unexpected, given the severe anticipations related to SCA2. We aimed to describe informative ancestral haplotypes found in South American SCA2 families. METHODS: Seventy-seven SCA2 index cases were recruited from Brazil, Peru, and Uruguay; 263 normal chromosomes were used as controls. The SNPs rs9300319, rs3809274, rs695871, rs1236900 and rs593226, and the STRs D12S1329, D12S1333, D12S1672 and D12S1332, were used to reconstruct haplotypes. RESULTS: Eleven ancestral haplotypes were found in SCA2 families. The most frequent ones were A-G-C-C-C (46.7 % of families), G-C-C-C-C (24.6 %) and A-C-C-C-C (10.3 %) and their mean (sd) CAGexp were 41.68 (3.55), 40.42 (4.11) and 45.67 (9.70) (p = 0.055), respectively. In contrast, the mean (sd) CAG lengths at normal alleles grouped per haplotypes G-C-G-A-T, A-G-C-C-C and G-C-C-C-C were 22.97 (3.93), 23.85 (3.59), and 30.81 (4.27) (p < 0.001), respectively. The other SCA2 haplotypes were rare: among them, a G-C-G-A-T lineage was found, evidencing a G allele in rs695871. CONCLUSION: We identified several distinct ancestral haplotypes in SCA2 families, including an unexpected lineage with a G allele at rs695871, a variation never found in hundreds of SCA2 patients studied worldwide. SCA2 has multiple origins in South America, and more studies should be done in other regions of the world.

An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean.

Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.

Use of non-invasive stimulation in movement disorders: a critical review.

BACKGROUND: Noninvasive stimulation has been widely used in the past 30 years to study and treat a large number of neurological diseases, including movement disorders. OBJECTIVE: In this critical review, we illustrate the rationale for use of these techniques in movement disorders and summarize the best medical evidence based on the main clinical trials performed to date. METHODS: A nationally representative group of experts performed a comprehensive review of the literature in order to analyze the key clinical decision-making factors driving transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in movement disorders. Classes of evidence and recommendations were described for each disease. RESULTS: Despite unavoidable heterogeneities and low effect size, TMS is likely to be effective for treating motor symptoms and depression in Parkinson's disease (PD). The efficacy in other movement disorders is unclear. TMS is possibly effective for focal hand dystonia, essential tremor and cerebellar ataxia. Additionally, it is likely to be ineffective in reducing tics in Tourette syndrome. Lastly, tDCS is likely to be effective in improving gait in PD. CONCLUSIONS: There is encouraging evidence for the use of noninvasive stimulation on a subset of symptoms in selected movement disorders, although the means to optimize protocols for improving positive outcomes in routine clinical practice remain undetermined. Similarly, the best stimulation paradigms and responder profile need to be investigated in large clinical trials with established therapeutic and assessment paradigms that could also allow genuine long-term benefits to be determined.

SPIKES-D: a proposal to adapt the SPIKES protocol to deliver the diagnosis of dementia.

Dementia is a life-threatening and stigmatizing condition, with devastating impacts on the patient's personal identity and caregivers. There are many barriers to an effective diagnosis disclosure of dementia, including fear of causing distress, uncertainty of diagnosis, caregivers' objection and lack of training in communication skills in undergraduate medical schools. Although some studies have been published on how to help physicians deliver an Alzheimer's disease diagnosis, no specific protocol has been published yet. The SPIKES protocol is a didactic approach designed to deliver bad news related to cancer, but it has been used globally and in a variety of clinical settings, including the teaching of communication skills to medical students and residents. It is known, however, that the cognitive impairment of Alzheimer's disease and other dementias may limit the understanding of the diagnosis' complexity; hence, a few adaptations of this model were made after reviewing the current literature on dementia diagnosis disclosure. The suggested SPIKES-D protocol seems to encompass current guidelines about the communication of the diagnosis of dementia, keeping its didactic approach on breaking bad news and helping fulfill the gaps in this topic.

A demência é uma condição incurável e estigmatizada, com impacto devastador na identidade pessoal do paciente e seus cuidadores. Existem muitas barreiras para uma adequada comunicação do diagnóstico às pessoas com demência, incluindo medo de causar estresse psicológico, incerteza do diagnóstico, objeção dos cuidadores e falta de treinamento em habilidades de comunicação nas escolas de medicina. Embora alguns artigos sobre como auxiliar a equipe médica a comunicar um diagnóstico de demência tenham sido publicados, nenhum protocolo específico foi publicado até o presente momento. O protocolo SPIKES é uma abordagem didática desenvolvida para auxiliar a comunicação de más notícias relacionadas ao câncer, mas tem sido utilizado em todo o mundo e nos mais diversos contextos clínicos, inclusive no ensino de habilidades de comunicação para estudantes e residentes de medicina. Entretanto, é sabido que o declínio cognitivo inerente à doença de Alzheimer e outras demências pode limitar a compreensão da complexidade do diagnóstico, tendo sido realizadas, portanto, algumas adaptações nesse protocolo após revisão da literatura acerca da comunicação do diagnóstico das demências. O protocolo SPIKES-D aqui sugerido parece englobar as diretrizes atuais sobre a comunicação do diagnóstico de demências, preservando seu caráter didático na comunicação de más notícias e auxiliando no preenchimento das lacunas neste tópico.

Selective Forces Related to Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.

Correction to: Selective Forces Related to Spinocerebellar Ataxia Type 2.

The original version of this article unfortunately contained a mistake. The spelling of the surname of one co-author from the publication entitled "Selective Forces Related to Spinocerebellar Ataxia Type 2" that was recently published in the journal "The Cerebelum" was incorrect.

Managing Gait, Balance, and Posture in Parkinson's Disease.

PURPOSE OF REVIEW: Postural instability and gait difficulties inexorably worsen with Parkinson's disease (PD) progression and become treatment resistant, with a severe impact on autonomy and quality of life. We review the main characteristics of balance instability, gait disabilities, and static postural alterations in advanced PD, and the available treatment strategies. RECENT FINDINGS: It remains very difficult to satisfactorily alleviate gait and postural disturbances in advanced PD. Medical and surgical interventions often fail to provide satisfactory or durable alleviation of these axial symptoms, that may actually call for differential treatments. Exercise and adapted physical activity programs can contribute to improving the patients' condition. Gait, balance, and postural disabilities are often lumped together under the Postural Instability and Gait Difficulties umbrella term. This may lead to sub-optimal patients' management as data suggest that postural, balance, and gait problems might depend on distinct underlying mechanisms. We advocate for a multidisciplinary approach from the day of diagnosis.

Medical and surgical management of advanced Parkinson's disease.

Advanced Parkinson's disease is characterized by the presence of motor fluctuations, various degree of dyskinesia, and disability with functional impact on activities of daily living and independence. Therapeutic management aims to extend levodopa benefit while minimizing motor complications and includes, in selected cases, the implementation of drug infusion and surgical techniques. In milder forms of motor complications, these can often be controlled with manipulation of levodopa dose and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase B inhibitors, and dopamine agonists including apomorphine. Clinical experience and evidence from published studies indicate that when these agents cannot satisfactorily control motor complications, patients should be assessed and considered for device-aided therapies. This review article summarizes some of the newer available therapeutic opportunities such as use of enzyme inhibitors like opicapone and safinamide, adenosine A2A receptor antagonists, apomorphine and levodopa/carbidopa intestinal gel infusion, deep brain stimulation including the role of closed-loop and adaptive stimulation, and MRI-guided focused ultrasound. © 2018 International Parkinson and Movement Disorder Society.

How to keep medical preceptors effectively motivated in a web-learning environment? An overview / ¿Cómo mantener a los preceptores médicos motivados de manera efectiva en un entorno de aprendizaje en la web? Una visión general

Distance learning has strengthened medical education, especially in geographically extensive regions. Despite the many characteristics of these web-based resources, the motivation of students to perform effectively in virtual educational programs remains a challenge

La educación a distancia ha permitido potenciar la educación médica, especialmente en regiones geográficas más extensas. A pesar de la gran cantidad de propiedades de los recursos Web, los aspectos motivacionales de los alumnos para un desempeño efectivo en los programas de educación virtual siguen siendo un desafío

Variants in SNCA Gene Are Associated with Parkinson's Disease Risk and Cognitive Symptoms in a Brazilian Sample.

Genetic susceptibility contributes to the etiology of sporadic Parkinson's Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin-American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs - rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample. In addition, we investigated their potential interactions with environmental factors and specific clinical outcomes (motor and cognitive impairments, depression, and anxiety). A total of 105 PD patients and 101 controls participated in the study. Single locus analysis showed that the risk allele of all SNPs were more frequent in PD patients (p < 0.05), and the associations of SNPs rs2583988, rs356219, and rs2736990 with increased PD risk were confirmed. Further, the G-rs356219 and C-rs2736990 alleles were associated with early onset PD. T-rs2583988, G-rs356219 and C-2736990 alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. In addition, in a logistic regression model, we found an association of cognitive impairment with PD, and the practice of cognitive activity and smoking habits had a protective effect. This study shows for the first time an association of SNCA polymorphism and PD in a South-American sample. In addition, we found an interaction between SNP rs356219 and a specific clinical outcome, i.e., the increased risk for cognitive impairment in PD patients.

Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes.

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.

PINK1 polymorphism IVS1-7 A-->G, exposure to environmental risk factors and anticipation of disease onset in Brazilian patients with early-onset Parkinson's Disease.

Parkinson's disease (PD) etiology has been attributed both to genetic and environmental factors, although the exact mechanisms of its pathogenesis remains elusive. We investigated Brazilian early-onset PD (EOPD) patients with PINK1 polymorphisms (SNPs) in order to find possible correlations between SNPs, environmental exposure, and disease age of onset. We enrolled 48 patients and 61 controls. PINK1 SNPs and environmental exposure (living in rural areas, well-water drinking, exposure to pesticides, herbicides and organic solvents and smoking) were investigated in both groups. We divided our group of patients into four subgroups, according to the presence/absence of PINK1 SNP IVS1-7 A-->G and the presence/absence of environmental factors exposure. We found a significant decrease (ANOVA test: p=0.02) of age at disease onset in those patients that had the IVS1-7 A-->G SNP and were exposed to environmental risk factors. Our data suggest that the interaction of PINK1 SNP IVS1-7 A-->G and environmental risk factors together have an important role in EOPD: each of them individually has a minor influence, whereas their interaction is associated with a significant effect in anticipating the disease clinical onset.

Conjugal amyotrophic lateral sclerosis in Brazil.

UNLABELLED: The origin of amyotrophic lateral sclerosis (ALS) remains unknown, although it seems to be multifactorial. The role of environmental factors has been frequently investigated and suspicion of its influence can be obtained when clusters of a rare disease are described. OBJECTIVE: To describe conjugal cases of ALS in Brazil. METHOD: We describe 2 couples in which both spouses were affected by ALS. Both couples had lived in southeast Brazil and were married for at least 20 years. RESULTS: There was a great variability in clinical presentation of ALS in our patients. In both couples the interval between disease onsets was short. No precise environmental factors could be identified at the origin of these conjugal cases. CONCLUSION: The occurrence of ALS in couples living in the same area may be epidemiologically important, but we cannot exclude that cases may be due to a chance association.

Genetic and environmental findings in early-onset Parkinson's disease Brazilian patients.

Parkinson's disease (PD) etiology has been attributed both to genetic and environmental factors. In this study, we investigated Brazilian early-onset PD (EOPD) patients for mutations in PARK2 and PARK8, exposure to environmental factors and possible correlations between PARK2 polymorphisms, environmental exposure, and disease age of onset. We enrolled 72 EOPD index patients and 81 healthy volunteers. Both groups were investigated for environmental exposure. EOPD patients were screened for PARK2 and PARK8 mutations. PARK2 coding polymorphisms Ser167Asn and Val380Leu were investigated in both groups. Mutations were present in 18% of the patients and in 32% of those with a positive family history. PARK2 mutations represented 12.5% and PARK8 mutations accounted for 5.5% of the mutations. A novel PARK2 mutation (D53X) was identified in 2 patients. A positive correlation was found between EOPD and well water drinking. In patients exposed to well water, a later age of onset was observed for those who carried at least one PARK2 380Leu allele. PARK2 mutations have an important role in EOPD Brazilian patients and PARK8 might be the second most important disease causing gene in this group. Well water drinking exposure represents a risk factor for EOPD and the PARK2 coding polymorphism Val380Leu might be interacting with environmental factors acting as a disease modifier.

Young onset Hemifacial Spasm in patients with Chiari type I malformation.

Hemifacial spasm (HFS) resulting from Chiari type I malformation (CIM) is rare. We retrospectively evaluated five patients with CIM and HFS among a series of 103 subjects. The frequency of HFS associated to CIM was of 4.85%. The clinical profile did not differ from the classical primary cases except for young-onset development of facial spasms in patients with CIM. Three patients were treated with BTX-A injections with favorable outcome. Although rare HFS may be associated with CIM especially in young subjects with peculiar phenotypic characteristics (short neck). Moreover, BTX may be an alternative to posterior fossa decompression in selected cases.

Chorea-ballism as a manifestation of decompensated type 2 diabetes mellitus.

Chorea and ballism are movement disorders that result from a variety of conditions. Hyperglycemia is an unusual recognized cause of these movement disorders. We report 3 cases of new-onset chorea-ballism induced by nonketotic hyperglycemia in elderly patients, highlighting that chorea may be the first manifestation of undiagnosed decompensated diabetes mellitus.