International Genetic Testing and Counseling Practices for Parkinson's Disease.

BACKGROUND: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. OBJECTIVES: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. METHODS: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. RESULTS: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. CONCLUSIONS: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.

Genetic Testing in Parkinson's Disease.

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Worldwide barriers to genetic testing for movement disorders.

BACKGROUND AND PURPOSE: Despite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization. METHODS: The Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members. RESULTS: Survey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe. CONCLUSIONS: This survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Global Survey on Telemedicine Utilization for Movement Disorders During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic restricted usual healthcare management for movement-disorders patients, with a consequent upsurge in telemedicine to bridge the gap. OBJECTIVE: To assess global telemedicine usage in the context of the pandemic. METHODS: The Movement Disorder Society (MDS) Telemedicine Study Group surveyed telemedicine experts from 40 countries across all continents in March-April 2020. Four domains of telemedicine were assessed: legal regulations, reimbursement, clinical use, and barriers; comparing emerging responses to the pandemic versus the baseline scenario. RESULTS: All forms of telemedicine for movement disorders increased globally, irrespective of country income categorization, as an immediate response to the pandemic. This was aided by widespread availability of technology and updated government regulations. However, privacy concerns, lack of reimbursement, limited access, and lack of telemedicine training were barriers highlighted worldwide. CONCLUSIONS: Questions remain about the longevity and extent of changes in regulations and reimbursement regarding telemedicine in the aftermath of the pandemic. © 2020 International Parkinson and Movement Disorder Society.

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions.

Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

Treatable inherited rare movement disorders.

There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.

Optical coherence tomography (OCT) study in Argentinean Huntington's disease patients.

BACKGROUND: Huntington's disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration. METHODS: A cross-sectional study with 14 HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained. RESULTS: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls. CONCLUSIONS: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.

Telemedicine Use for Movement Disorders: A Global Survey.

BACKGROUND: Telemedicine is increasingly used to care for patients with movement disorders, but data regarding its global use are limited. INTRODUCTION: To obtain baseline international data about telemedicine use among movement disorder clinicians. METHODS: An online survey was sent to all 6,056 Movement Disorder Society members in 2015. Scope, reimbursement, and perceived quality of telemedicine were assessed. RESULTS: There were 549 respondents (9.1% overall response rate) from 83 countries. Most (85.8%) were physicians, and most (70.9%) worked in an academic or university practice. Half of respondents (n = 287, from 57 countries) used telemedicine for clinical care; activities included e-mail (63.2%), video visits (follow-up [39.7%] and new [35.2%]), and video-based education (35.2%). One hundred five respondents personally conducted video visits, most frequently to outpatient clinics (53.5%), patient homes (30.8%), and hospital inpatients (30.3%). The most common challenges were a limited neurological examination (58.9%) and technological difficulties (53.3%), and the most common benefits were reduced travel time (92.9%) and patient costs (60.1%). The most frequent reimbursements were none (39.0%), public insurance (24.5%), and patient payment (9.3%). Half of respondents planned to use telemedicine in the future, and three-quarters were interested in telemedicine education. CONCLUSIONS: More than 250 respondents around the world engage in telemedicine for movement disorders; most perceived benefit for patients, despite challenges and reimbursement for clinicians. Formal instruction on telemedicine is highly desired. Although the survey response was low and possibly biased to over represent those with telemedicine experience, the study provides baseline data for future comparison and to improve telemedicine delivery.

Prodromal Clinical Markers of Parkinson disease in Gaucher Disease Individuals.

Heterozygous mutations in the glucocerebrosidase (GBA) gene have been reported as a common risk factor for the development of Parkinson's disease (PD) in Gaucher disease (GD) patients and in heterozygous GBA mutation positive carriers. In this study, we analyzed the occurrence of prodromal markers of PD in an Argentinean cohort with type 1 GD. After signed informed consent, we evaluated 26 patients with type 1 GD under enzymatic replacement therapy from a cohort of the Hospital Ricardo Gutierrez GD Study Group in Buenos Aires City, Argentina. We performed an extensive neurological examination, including cognitive assessment by Montreal Cognitive Assessment (MoCA) and a questionnaire performed ad hoc, to identify non-motor PD symptoms. Parasomnias were reported by 7 patients (26.92%), rapid eye movement behavior disorders in 2 (7.69%), constipation in 2 (7.69%), hyposmia in 1 (3.84%), tremor in 1 (3.84%), and depression in 3 cases (11.53%). MoCA assessment was abnormal in 44.44% of patients. No patient fulfilled PD diagnostic criteria (Queen Square Brain Bank criteria). The identification of prodromal markers of PD in type 1 GD suggests that this population represents a very interesting cohort for identifying potential biomarkers and neuroprotective therapies for PD.

[Rational use of psychotropic medications and sedative load in older adults with and without dementia]. / Uso de psicofármacos y carga sedativa en pacientes adultos con y sin demencia.

Sedative drugs use has been associated with more cognitive impairment and increased mortality. Sedative load refers to cumulative exposure to multiple drugs with sedative properties. OBJECTIVE: Describe the use of psychotropic drugs and sedative load in older adults with and without dementia. MATERIAL AND METHODS: We conducted a cross-sectional study from 2014-2015 (Sanatorio Trinidad Mitre), in hospitalized patients older than 65 years old. Drugs were classified according to the WHO ATC system. The sedative load of drugs was calculated using the Linjakumpu model. RESULTS: 152 PsD and 35 PcD patients were registered, mean age 80.8±8.42. Polypharmacy was present in 44.39% being higher in patients with dementia than without dementia (62.80% vs 40.13%, p=0.0147). In 40.64% at least one psychotropic/sedative medication was used, greater in PcD (60% vs 36.18%, p=0.0097). The CS was: 1.32±1.59; 2.14 in PcD and 1.13 in PsD (p<0.001). Atypical antipsychotics and benzodiazepines were the most common (51.43 and 40% respectively) in patients without dementias. CONCLUSION: we evidenced a high level of prescription psychotropic or sedative drugs, mostly in patients with dementia. In those, the sedative load was greater. This finding highlights the importance of implementing strategies to optimize sedative drug use among older people.

Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures.

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed "ATCCT interruptions," experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confer a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling.

Suicide attempt in a dopamine agonist withdrawal syndrome in Parkinson's disease.

Dopamine agonist withdrawal syndrome (DAWS) results from the reduction or suspension of dopamine agonist medications; it encompasses mainly psychiatric symptoms, including suicidal behaviors. In patients with Parkinson's disease (PD), the impact of DAWS can be significant in terms of distress and disability; however, we must take this syndrome into account as a threatening condition because suicidal behaviors could be developing in the context of DAWS. Here we present a brief case of DAWS affecting a young man with PD, whom abruptly discontinued DA treatment and developed psychiatric symptoms within two weeks which led to a suicidal attempt.

The role of genetics in the treatment of dystonia with deep brain stimulation: Systematic review and Meta-analysis.

BACKGROUND: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that lead to involuntary postures or repetitive movements. Genetic mutations are being increasingly recognized as a cause of dystonia. Deep brain stimulation (DBS) is one of the limited treatment options available. However, there are varying reports on its efficacy in genetic dystonias. This systematic review of the characteristics of genetic dystonias treated with DBS and their outcomes aims to aid in the evaluation of eligibility for such treatment. METHODS: We performed a PUBMED search of all papers related to genetic dystonias and DBS up until April 2022. In addition to performing a systematic review, we also performed a meta-analysis to assess the role of the mutation on DBS response. We included cases that had a confirmed genetic mutation and DBS along with pre-and post-operative BFMDRS. RESULTS: Ninety-one reports met our inclusion criteria and from them, 235 cases were analyzed. Based on our analysis DYT-TOR1A dystonia had the best evidence for DBS response and Rapid-Onset Dystonia Parkinsonism was among the least responsive to DBS. CONCLUSION: While our report supports the role of genetics in DBS selection and response, it is limited by the rarity of the individual genetic conditions, the reliance on case reports and case series, and the limited ability to obtain genetic testing on a large scale in real-time as opposed to retrospectively as in many cases.

Treatment of Alzheimer's Disease in the New Era of Monoclonal Antibodies Against Cerebral Amyloid-ß: Pharmacological Prescription and Knowledge in Argentina.

Background: Alzheimer's disease (AD) presents a significant global health challenge. Understanding the current and upcoming treatment landscape is crucial for effectively managing patients. Objective: The aim of this study was to assess the pattern of prescription and knowledge about new therapies by physicians who treat AD patients in Argentina. Methods: A cross- sectional and analytic study was conducted. A survey was elaborated about pharmacological treatment in AD. Statistical analysis of answers of specialists in cognitive disorders (SCD), non-specialists in cognitive disorders (NSCD), recommended treatment, non-recommended treatment (NRT), and off-label treatment was performed. Results: 155 physicians answered the survey. A 19.35%prescribed at least one NRT for dementia. 78.06%prescribed at least an off-label treatment or an NRT for mild cognitive impairment (MCI). 31%would prescribe monoclonal antibodies (MABs) against cerebral amyloid-ß (Aß) to AD patients, and 42.6%responded that they were not aware of any adverse effect of these. Quetiapine was the most frequent treatment for psychotic symptoms (88.4%) and escitalopram (32.3%) for apathy. A 70%of potential prescribers of MABs (n = 100) would request biomarkers of cerebral Aß in the initial assessment. There were significant differences between the responses of SCD and NSCD regarding the prescription of MABs (52.17%versus 23.08, respectively) and knowledge about adverse events (76.09%versus 38.46%, respectively). Conclusions: A considerable percentage of physicians indicated NRT and off-label medication in MCI and dementia. In Argentina, there are many physicians who would indicate a MABs for AD, but many are not completely aware of its safety profile.

Management of rare movement diseases in different world regions.

To evaluate the management of rare movement disorders (RMD) at the international level and identify care needs to be addressed, the Rare Movement Disorders Study Group of the International Parkinson and Movement Disorders Society (MDS) has conducted an exploratory survey. We sent an online survey to experts in Africa, Asia, Oceania and American continents following the classification of the MDS Regional Sections: Africa, Asia and Oceania (A&O), and Pan-America. We did not include Europe as the European Reference Network for Rare Neurological Diseases recently performed a similar care needs survey across European countries. We obtained responses from experts from 20 African, 26 A&O and 19 Pan-American countries. According to the respondents, only 55% of African countries had movement disorders experts, while these were present in 96% of A&O and 91% of Pan-American. Access to care for patients with RMD was stated difficult in 70% of African, 54% of A&O, and 65% of Pan-American countries. Africa was the region with greatest difficulties in accessing diagnostic tests. However, in Pan-America and A&O, large inequalities were observed between countries with quite variable access to therapeutic options such as deep brain stimulation. The survey results reflect wide variability in the management of RMD and provide evidence that a worldwide care-focused network is highly warranted. Scientific and medical organisations should raise awareness of deficits in managing RMD and care disparities among regions. The goals should be to facilitate the training of professionals, establish improvement strategies, and increase support and budgeting for these diseases.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Triphasic waves and brain atrophy in patients with acute encephalopathy.

Introduction: Triphasic waves (TW) constitute an electroencephalographic pattern associated with certain kinds of encephalopathy. Brain atrophy may be a predisposing factor linked with TW. Objective: To compare the degree of brain atrophy and white matter disease between patients with acute encephalopathy with and without TW. Methods: A retrospective observational study including adult patients with encephalopathy, with and without TW, hospitalized between 2016 and 2017. The degree of brain atrophy and white matter lesion were defined using the Global Cortical Atrophy and Age Related White Matter Changes (ARWMC) scales, respectively. Scores were compared between groups. Mortality rates were registered. Results: Sixteen patients with TW were identified matched by age and sex with 30 patients without TW. The mean age was 80 years in the TW group. Women represented 87.5%. Multifactorial encephalopathy was the most frequent diagnosis followed by metabolic encephalopathy. Patients with TW had more brain atrophy (10.43 vs 6.9, p= 0.03). Mean ARWMC was 9.43±6.5 and 8.5 ±7.89 in patients with and without TW respectively (p= 0.5). Mortality rate was higher in the TW group (31.25 vs 6.66% p= 0.02). Conclusions: Patients with acute encephalopathy and TW had higher degree of cerebral atrophy. It is possible that this structural alteration predisposes to the appearance of TW. There was no significant difference in white matter lesion degree. The mortality of the TW group was high, so future studies are necessary to determine their prognostic value.

Introducción: Las ondas trifásicas (OT) constituyen un patrón electroencefalográfico asociado con diversas encefalopatías. La atrofia cerebral podría predisponer a su aparición. Objetivo: Comparar el grado de atrofia cerebral y de lesión de sustancia blanca en pacientes con encefalopatía aguda con y sin OT. Métodos: Estudio observacional retrospectivo, incluyó pacientes adultos con encefalopatía aguda con y sin OT internados entre 2016 y 2019. El grado de atrofia cerebral y de lesión de sustancia blanca se definieron según las escalas Global Cortical Atrophy y Age Related White Matter Changes (ARWMC), respectivamente. Se compararon los puntajes entre grupos. Se registró la mortalidad. Resultados: Se identificaron 16 pacientes con OT y 30 sin OT pareados según edad y sexo. La edad promedio del grupo con OT fue 80 años. El 87.5% fueron mujeres. La encefalopatía multifactorial fue el diagnóstico más frecuente seguido de la encefalopatía metabólica. El grado de atrofia fue mayor en pacientes con OT (10.43 vs 6.9, p= 0.03). El puntaje ARWMC fue 9.43 ±6.5 y 8.5 ±7.89 en pacientes con y sin OT respectivamente (p= 0.5). La mortalidad fue mayor en el grupo con OT (31.25 vs 6.66% p= 0.02). Conclusiones: Pacientes con encefalopatía aguda y OT tuvieron mayor grado de atrofia cerebral. Dicha alteración estructural podría relacionarse con la aparición de OT. No hubo diferencias significativas en el grado de lesión de sustancia blanca. La mortalidad del grupo con OT fue elevada. Son necesarios estudios para determinar su valor pronóstico.

Discharges With Triphasic Morphology as Marker of the Risk of Death in Acute Encephalopathy.

Introduction. In clinical practice, it is difficult to define the prognosis of patients with acute encephalopathy; a syndrome characterized by cognitive dysfunction and altered sensorium. Discharges with triphasic morphology (DTM) are an electroencephalographic pattern that might be useful to establish the risk of death. The aim of this study was to define the prognostic value of DTM regarding mortality in patients with acute encephalopathy. Methods. We conducted an observational retrospective cohort study including patients with acute encephalopathy with and without DTM paired by age and gender in a 1:2 ratio. We calculated the odds ratio (OR) to determine the association between DTM and mortality. In addition, we calculated sensibility, specificity, and predictive values. Results. We included 72 patients, 24 with DTM and 48 without DTM. Mortality was higher in patients with DTM (41.6% vs 14.5%, P = .01). Factors associated with a higher risk of death were DTM (OR = 4.1, 95% confidence interval [CI] 1.3-13, P = .01) and sequential organ failure assessment score (OR = 1.3, 95% CI 1.04-1.67, P = .02). A higher Glasgow coma scale score was associated with a lower risk of death (OR = 0.65, 95% CI 0.51-0.83, P = .001). The sensibility and specificity of DTM were 59% and 75%, respectively. Positive and negative likelihood ratios were 2.36 and 0.55. Discussion. Our results revealed high mortality in patients with acute encephalopathy and DTM. This electroencephalographic pattern was associated with 4 times higher risk of death. However, its usefulness for predicting death was limited.

Review of Hereditary and Acquired Rare Choreas.

Background: Movement disorders are often a prominent part of the phenotype of many neurologic rare diseases. In order to promote awareness and diagnosis of these rare diseases, the International Parkinson's and Movement Disorders Society Rare Movement Disorders Study Group provides updates on rare movement disorders. Methods: In this narrative review, we discuss the differential diagnosis of the rare disorders that can cause chorea. Results: Although the most common causes of chorea are hereditary, it is critical to identify acquired or symptomatic choreas since these are potentially treatable conditions. Disorders of metabolism and mitochondrial cytopathies can also be associated with chorea. Discussion: The present review discusses clues to the diagnosis of chorea of various etiologies. Authors propose algorithms to help the clinician in the diagnosis of these rare disorders.